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  • pharmacokinetics  (182)
  • Springer  (182)
  • PANGAEA
  • MDPI Publishing
  • 1975-1979  (182)
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  • Springer  (182)
  • PANGAEA
  • MDPI Publishing
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  • 1
    Electronic Resource
    Electronic Resource
    Haemodynamic effects and pharmacokinetics of a new selective beta1-adrenoceptor agonist, prenalterol, and its interaction with metoprolol in man (1979)
    Springer
    European journal of clinical pharmacology 15 (1979), S. 9-13 
    Details
    ISSN: 1432-1041
    Keywords: prenalterol ; metoprolol ; haemodynamics ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The haemodynamic effects of the selectiveβ 1-adrenoceptor agonist prenalterol were studied in healthy subjects before and after therapeutic doses of the selectiveβ 1-adrenoceptor blocker metoprolol. Plasma levels of the drugs were also determined in order to calculate certain pharmacokinetic variables. Intravenous infusion of prenalterol 0.13, 0.25 and 0.50 mg induced a dose-dependent decrease in total electromechanical systole (QA2) and pre-ejection period (PEP). The effect on left ventricular ejection time (LVET) was not significant. Increases in systolic blood pressure and heart rate were dose-dependent. Diastolic blood pressure did not change significantly. When metoprolol had been administered in a cumulative dose of 150 mg (mean maximal plasma level, 284 nmol/1) prenalterol had to be administered in doses that were twelve times higher than before theβ-blocker in order to induce the same haemodynamic effects. Prenalterol was rapidly distributed with an average half life of 8 min. This indicates that distribution equilibrium will be achieved within 30 min after intravenous administration. The overall elimination rate in the post-distributive phase corresponded to an average half life of 2.0 h.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00563552
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  • 2
    Electronic Resource
    Electronic Resource
    Absorption of digoxin in severe right heart failure (1979)
    Springer
    European journal of clinical pharmacology 15 (1979), S. 115-120 
    Details
    ISSN: 1432-1041
    Keywords: digoxin ; right heart failure ; absorption ; absolute bioavailability ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The absorption of digoxin has been investigated in 8 patients before and after successful treatment of severe right heart failure.3H-digoxin 0.1 mg as a solution, and un-labelled digoxin 0.25 mg as a tablet, were given to fasted patients. Blood samples were taken at various time intervals up to 120 hours and urine was collected over the same period. The concentrations of labelled digoxin in plasma and urine were measured in a liquid scintillation counter, unlabelled digoxin was estimated by radioimmunoassay, and various pharmacokinetic parameters were calculated. There was no significant difference in the plasma concentration curves in severe right heart failure and after its successful treatment, nor did any of the calculated pharmacokinetic parameters change significantly. Therefore, inhibition of the absorption of digoxin appears unlikely. In an additional study to estimate absolute bioavailability two different groups of patients in severe right heart failure were given3H-digoxin 0.1 mg or unlabelled digoxin 0.25 mg i. v. and the pharmacokinetic parameters were compared with those from the previous study. The bioavailability of the3H-digoxin solution and of the digoxin tablet were in the same range as values previously published for healthy volunteers, and patients both with and without cardiac failure.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00609874
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  • 3
    Electronic Resource
    Electronic Resource
    Disposition of guanethidine during chronic oral therapy (1979)
    Springer
    European journal of clinical pharmacology 15 (1979), S. 121-125 
    Details
    ISSN: 1432-1041
    Keywords: guanethidine ; chronic therapy ; urinary excretion ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The plasma level and urinary excretion rate of guanethidine have been measured in 30 patients during oral maintenance therapy, and in 5 patients following discontinuation of therapy. A significant correlation was found between the daily average urinary excretion and the maintenance dose, although wide interindividual variation was noted among patients maintained on the same dose. A statistically significant correlation was also observed between the area under the plasma level curve during the dose interval and the oral maintenance dose. After discontinuation of chronic therapy, the half-life of 1.5 days of the initial phase of elimination was essentially in agreement with the half-life of almost 2 days determined in acute studies. In addition, a second phase of elimination with a half-life of 4 to 8 days was observed.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00609875
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  • 4
    Electronic Resource
    Electronic Resource
    Pharmacokinetics of quinidine related to plasma protein binding in man (1979)
    Springer
    European journal of clinical pharmacology 15 (1979), S. 187-192 
    Details
    ISSN: 1432-1041
    Keywords: quinidine ; plasma protein binding ; pharmacokinetics ; man
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The disposition and plasma protein binding of quinidine after intravenous administration were studied in 13 healthy subjects. Plasma protein binding, expressed as the fraction of quinidine unbound ranged from 0.134–0.303 (mean 0.221). Elimination rate constant (β) varied from 0.071 to 0.146 h−1 (mean 0.113), and apparent volume of distribution (Vβ) varied from 1.39–3.20 l · kg−1β (mean 2.27). Total body clearance was 2.32–6.49 ml min−1 · kg−1. There was a positive linear correlation between the plasma fraction of unbound quinidine and both Vβ (r=0.885, p〈0.01) and total body clearance (r=0.668, p〈0.05). No significant correlation existed between the fraction of unbound quinidine in plasma and the elimination rate constant. The results show that both the apparent volume of distribution and total body clearance of quinidine are proportional to the unbound fraction in plasma. This implies that the total plasma concentration of quinidine at steady state will change with alterations in plasma binding, whilst the concentration of unbound compund and its elimination rate will remain unaffected.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00563104
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  • 5
    Electronic Resource
    Electronic Resource
    Influence of food on the absorption of phenytoin in man (1979)
    Springer
    European journal of clinical pharmacology 15 (1979), S. 269-274 
    Details
    ISSN: 1432-1041
    Keywords: phenytoin ; food-intake ; bioavailability ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The influence of food intake on the absorption of phenytoin was examined in eight healthy volunteers, by study of single-dose kinetics following ingestion of phenytoin 300 mg either with a standardized breakfast or on an empty stomach. Blood samples were collected at regular intervals from 0 to 48 h, and serum concentrations of unmetabolized phenytoin were determined by gas chromatography. Serum concentrations of the major metabolite of phenytoin, 4-hydroxyphenytoin, were measured by mass fragmentography. Concurrent intake of food and phenytoin appeared to accelerate absorption of the drug from the formulation used, and the peak concentrations were significantly higher (mean increase 40%) in the postprandial than in the preprandial state. As reflected by the AUC (area under the curve), the amount of drug absorbed was increased during postprandial conditions, although the difference only reached borderline significance. It is suggested that phenytoin should always be taken in a defined relation to meals.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00618516
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  • 6
    Electronic Resource
    Electronic Resource
    Indobufen (K 3920), a new inhibitor of platelet aggregation: Effect of food on bioavailability, pharmacokinetic and pharmacodynamic study during repeated oral administration to man (1979)
    Springer
    European journal of clinical pharmacology 15 (1979), S. 329-333 
    Details
    ISSN: 1432-1041
    Keywords: indobufen ; platelet aggregation ; food effect on bioavailability ; repeated administration ; pharmacodynamics ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The effect of food on bioavailability of indobufen tablets was investigated in 6 healthy volunteers. Subsequently, the same subjects took 100 mg b.i.d. for 7 days. Plasma levels and urinary excretion of indobufen were determined by GLC. Platelet aggregation induced by several concentrations of adrenaline was determined turbidimetrically at various times after the first and last doses. The absorption of indobufen tablets was not substantially impaired by the presence of food in the GI tract, although peak plasma levels and AUCs were slightly reduced after food. Pharmacokinetic analysis of plasma and urinary levels of indobufen did not indicate any change in drug disposition after repeated dosing. Adrenaline-induced platelet aggregation was markedly inhibited for up to 12 h after the first dose and the intensity and duration of this effect did not change after repeated administration. A twice-daily dosing appears suitable for clinical trials.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00558436
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  • 7
    Electronic Resource
    Electronic Resource
    Lorcainide infusion in the treatment of ventricular premature beats (VPB) (1979)
    Springer
    European journal of clinical pharmacology 16 (1979), S. 1-6 
    Details
    ISSN: 1432-1041
    Keywords: lorcainide ; ventricular premature beats ; plasma levels ; pharmacokinetics ; side effects
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The plasma level and antiarrhythmic effect of lorcainide (R 15889) have been investigated in 15 patients with ventricular premature beats (VPB). Therapy was initiated with an intravenous dose of 1.9 mg/kg given over 10 min, followed by a constant infusion of 0.18 mg/kg/h for 24 h. In 8 patients the corresponding doses were increased to 2 mg/kg and 0.27 mg/kg/h. After the intravenous doses patients were treated orally with 100 mg tid for 6–7 days. The two dosage regimens were selected so as to achieve theoretical steady-state plasma levels (css) of 200 and 300 ng/ml, respectively. The combined intravenous treatment approached (181 ± 6.8 ng/ml and 273±28.5 ng/ml, respectively) the desired css within 2 to 4 h. During the oral administration, the minimal plasma concentrations following the lower intravenous dose (184±18 ng/ml) were significantly (p=0.0001) lower than after the higher intravenous dose (264±20.5 ng/ml). The dealkylated metabolite of lorcainide was not detectable after the intravenous doses, but it accumulated during oral treatment, when its concentration exceeded that of the parent compound. In 5 of the 7 patients receiving the lower dose VPB were effectively reduced. However, in only 4 of the 8 patients on the higher dosage schedule could a significant antiarrhythmic effect be demonstrated. In addition, side effects were observed in 6 of the subjects.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00644958
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  • 8
    Electronic Resource
    Electronic Resource
    Pharmacokinetics of cefoxitin in patients with normal or impaired renal function (1979)
    Springer
    European journal of clinical pharmacology 16 (1979), S. 119-124 
    Details
    ISSN: 1432-1041
    Keywords: cefoxitin ; renal impairment ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The pharmacokinetics of cefoxitin have been determined after a single i.v. injection of 15 mg/kg body weight in 10 patients with normal renal function and 20 patients with varying degrees of renal impairment. The kinetics of the antibiotic followed an open two-compartment model. In patients with normal renal function the following pharmacokinetic parameters were found: $$\begin{gathered} \begin{array}{*{20}c} {\alpha = 8.66 h^{ - 1} } & {\beta = 1.21 h^{ - 1} } & {K_{12} = 3.47 h^{ - 1} } \\ \end{array} \hfill \\ \begin{array}{*{20}c} {K_{21} = 3.17 h^{ - 1} } & {K_{13} = 3.15 h^{ - 1} } & {V_c = 4.24 l.} \\ \end{array} \hfill \\ \begin{array}{*{20}c} {V_p = 4.87 l.} & { Vd_{ss} = 9.11 l.} \\ \end{array} \hfill \\ \end{gathered}$$ In the patients with renal impairment there was a significant decrease in $$\mathop \alpha \limits_, \mathop \beta \limits_, $$ K12, K21 and K13, and an increase in the apparent volume of distribution. The degree of plasma protein binding in patients with normal renal function was 73.6% and this was diminished in patients with renal impairment. A linear relationship between K13 of cefoxitin and creatinine clearance was demonstrated. The dosage regimen for patients with renal impairment should be adjusted by modifying the dosage interval whilst maintaining the amount administered.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00563118
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  • 9
    Electronic Resource
    Electronic Resource
    Kinetics of canrenone after single and multiple doses of spironolactone (1979)
    Springer
    European journal of clinical pharmacology 16 (1979), S. 255-262 
    Details
    ISSN: 1432-1041
    Keywords: spironolactone ; canrenone ; fluorimetry ; high performance liquid chromatography ; linear kinetics ; saturation kinetics ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary In Study I 20 normal volunteers received a single oral dose of spironolactone 100 mg. In Study II a further 20 normal volunteers were given first spironolactone 100 mg b.i.d. and subsequently spironolactone 100 mg once a day for a further 4 days. In Study III 5 normal subjects were given a single dose of spironolactone 500 mg. The concentration of canrenone in serum was determined both by fluorimetry and HPLC for 0–48 h in Study I, 120–168 h in Study II and 0–36 h in Study III. The total AUCs after the single 100 mg dose did not differ from the AUCs within the dosing interval during steady state. The half-lives of the terminal log-linear phases were almost identical (14.99±0.80 h and 15.69±0,80 h) when determined by fluorimetry, and were sligthly, but significantly (p〈0.01), longer when determined by HPLC — 20.14±1.62 and 18.71±1.04. The mean ratio of the specific AUC determined by HPLC and the fluorimetrically determined AUC was 0.3 after the single 100 mg dose. It did not differ from the corresponding value during steady state (0.34). In contrast, the ratio after the single 500 mg dose was approximately 50% higher. Fluorimetrically determined AUCs after 100 and 500 mg doses did not show dose-proportionality in contrast to the HPLC-determined AUCs. It was concluded that Canrenone contributes much less to the conventional fluorimetric determination than was previously assumed. It may not provide more than 1/10 and 1/4 of the antimineralocorticoid activity of spironolactone after single dose and multiple doses, respectively. Whereas linear kinetics apply after single and multiple 100 mg doses of spironolactone, after 500 mg saturation kinetics must be assumed with respect to metabolism. Thus, in bioavailability studies high doses of spironolactone should be avoided. For such studies the fluorimetric assay seems to be the appropriate bioanalytical method in spite of its lower specificity.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00608404
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  • 10
    Electronic Resource
    Electronic Resource
    Kinetics of salicylates in blood and joint fluid (1979)
    Springer
    European journal of clinical pharmacology 16 (1979), S. 279-285 
    Details
    ISSN: 1432-1041
    Keywords: salicylate ; synovitis ; osteoarthritis ; arthritis ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Samples of blood and joint fluid from 30 patients who had taken buffered acetylsalicylic acid were examined for concentrations of total salicylates (TSA), acetylsalicylate (ASA) and salicylate (SA). The data were arranged in groups according to diagnosis of the joint disease. Analysis of the data did not show significant difference in the kinetics of TSA into blood. In groups the time to first appearance of 0.3 mg/l averaged 6.3 min for TSA; these values averaged 7.7 min for ASA and 10.9 min for SA. Close to maximum concentrations in blood averaged 18.9 mg/l for TSA, 3.3 mg/l for ASA, and 23.3 mg/l for SA. The time for first appearance of 0.3 mg/l of total salicylates in joint fluid ranged from 10 to 34 min with an average of 18.1 min; the values of ASA averaged 19.4 min and those of SA 21.9 min. The maximum concentration in joint fluid averaged 15.7 mg/l for TSA, 2.5 mg/l for ASA, and 14.5 mg/l for SA. Transport of salicylates from blood to joint fluid showed a pattern consistent with the type of joint disease. Support was found for the hypothesis that diffusion was the major factor in the movement of salicylates from blood to joint fluid.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00608407
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  • 11
    Electronic Resource
    Electronic Resource
    Timolol pharmacokinetics and effects on heart rate and blood pressure after acute and chronic administration (1979)
    Springer
    European journal of clinical pharmacology 16 (1979), S. 243-249 
    Details
    ISSN: 1432-1041
    Keywords: timolol ; beta blockade ; pharmacokinetics ; pharmcodynamics ; acute administration ; chronic administration
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The pharmacokinetics and effects of various oral doses of timolol administered either acutely or after chronic medication for 7 days were studied in healthy volunteers. After acute administration of timolol maximum plasma concentrations were attained within 1–2 h and thereafter declined exponentially with time. The mean apparent half-life of elimination from plasma was 2.5 h and was independent of dose. Area under the plasma concentration-time curve (AUC) was proportional to the orally administered dose. Plasma concentrations, apparent elimination half-life and AUC were not altered after one week of chronic administration. The effect of timolol on heart rate and blood pressure response to three sequentially increasing ‘steady state’ work loads were studied. After acute administration of timolol maximum reduction of systolic blood pressure, resting heart rate, and the different parameters of the work-heart rate (or blood pressure) relationships were produced by 5 mg timolol. Increasing the dose prolonged the duration over which these variables were reduced. The relationship between timolol plasma concentration and inhibition of different parameters of the exercise response was hyperbolic with half maximum inhibition at concentrations of about 3–4 ng/ml of timolol and maximum inhibition above 30 ng/ml. Maximum drug effects and duration of action of timolol on the different variables were similar after acute and chronic administration.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00608402
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  • 12
    Electronic Resource
    Electronic Resource
    Analysis of the pharmacokinetics of lithium in man (1979)
    Springer
    European journal of clinical pharmacology 16 (1979), S. 271-277 
    Details
    ISSN: 1432-1041
    Keywords: lithium ; litarex ; single dose ; multiple dose ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary An analysis of the single and multiple dose pharmacokinetics of lithium in 7 healthy volunteers is presented. A solution of lithium chloride was administered in single dose experiments and the same solution and a sustained release preparation were employed in multiple dose experiments, which were carried out at steady state. A fixed dose of 24 mmol was used in the single dose experiments and in the subsequent multiple dose experiments in the same subjects the same dose was administered once daily for a week. Distinct two-compartment characteristics were found, with a mean disposition rate constant (β) of 0.035 h−1±0.010 SD, corresponding to a mean biological half-life of about 19.8 h. The mean half-time of the distributory α-phase was about 1.15 h. The absorption of lithium from an orally administered solution took place with a half-time of about 0.15 h in the single dose experiments. The apparent volume of distribution of the central compartment (Vc) was 0.307 1 kg−1±0.046 SD, less than half that of Vde at equilibrium. Vdβ (Vdarea) was 0.8291 kg−1±0.184 SD and mean total body clearance was 27.6 ml kg−1 h−1±4.7 SD.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00608406
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  • 13
    Electronic Resource
    Electronic Resource
    Pharmacokinetic and pharmacodynamic interactions of diazepam with different alcoholic beverages (1979)
    Springer
    European journal of clinical pharmacology 16 (1979), S. 263-270 
    Details
    ISSN: 1432-1041
    Keywords: diazepam ; alcoholic beverages ; plasma level ; pharmacokinetics ; co-ordination skills ; red wine ; white wine ; whisky
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Twenty paid healthy students ingested diazepam 10 mg 30 min after the administration of ethanol 0.8 g/kg. The alcoholic beverage used was varied in randomized double-blind experiments, which were repeated at one-month intervals. Psychomotor performance, plasma diazepam, and alcohol concentration in breath were measured 30, 60, 90 min and 2, 3, 4, 6 and 24 h after the ingestion of diazepam. Beer and white wine elevated the plasma level of diazepam and the effect lasted for up to 2 h. Whisky elevated the diazepam level for 90 min. Red wine did not affect it significantly. The alcohol-diazepam combination impaired tracking skills and oculomotor co-ordination and enhanced nystagmus, more than diazepam alone. Red wine produced a breath alcohol concentration higher than after white wine. More nystagmus was recorded after red wine and diazepam, although white wine led to a higher plasma diazepam concentration. It appears that simultaneous ingestion of alcohol and diazepam accelerates the absorption of diazepam. This pharmacokinetic alteration may not contribute much to the combined psychomotor effects of diazepam and alcohol, which were mainly due to pharmacodynamic interaction at receptor level.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00608405
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  • 14
    Electronic Resource
    Electronic Resource
    Pharmacokinetic model based on circulatory transport (1979)
    Springer
    European journal of clinical pharmacology 16 (1979), S. 287-293 
    Details
    ISSN: 1432-1041
    Keywords: linear system theory ; perfusion model ; cardiac output ; pulmonary extraction ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Assessment of pharmacokinetics in terms of circulatory drug transport is proposed using the methods of linear system theory. In this model-independent approach drug distribution and disposition are characterized by the total extraction ratio, the mean residence time in the body and the volume of distribution at steady state. In analyzing concentration(c)-time(t) data, the procedure requires calculation only of the areas under the c(t)-and c(t)×t-curves to estimate kinetic parameters, and for prediction of the steady state concentration following continuous infusion or multiple doses. Pulmonary clearance of drugs is included in the theory.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00608408
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  • 15
    Electronic Resource
    Electronic Resource
    Multicompartment pharmacokinetics of netilmicin (1979)
    Springer
    European journal of clinical pharmacology 16 (1979), S. 331-334 
    Details
    ISSN: 1432-1041
    Keywords: netilmicin ; radioenzymatic assay ; drug accumulation ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The pharmacokinetics of a single dose of netilmicin (NM) was studied in 6 healthy volunteers. Elimination of the drug was followed in serum and urine for 24 h and 72 h, respectively. NM concentrations were measured with a modified radioenzymatic assay. A three compartment open model was employed to calculate the pharmacokinetic parameters. Following the rapid initial distribution, biphasic elimination with half lives of 1.99 h (t1/2β) and 36.89 h (t1/2γ) was demonstrated. Measurable amounts of NM were excreted in the urine for up to 72 h. The volume of distribution at steady-state (Vdss) of 0.68 l/kg was 3 to 4 times larger than previously reported for this antibiotic. NM plasma clearance was 91 ml/min and the renal clearance was 67 ml/min. The data indicate that on repetitive dosing the amount of drug in the body would be considerably underestimated if the prolonged terminal elimination phase were not taken into account. During prolonged treatment, accumulation of NM in renal and other tissues is likely to occur, as has been described for other aminoglycosides. The possible consequences of this pharmacokinetic behaviour are discussed.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00605631
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  • 16
    Electronic Resource
    Electronic Resource
    Plasma levels and negative chronotropic effect of metoprolol following single doses of a conventional and sustained-release formulation (1979)
    Springer
    European journal of clinical pharmacology 15 (1979), S. 97-103 
    Details
    ISSN: 1432-1041
    Keywords: metoprolol ; tachycardia ; healthy subjects ; conventional tablets ; slow release tablets ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Plasma levels and associated reduction in exercise-induced tachycardia have been examined following the administration of single doses of metoprolol in conventional and slow-release tablets at different times to six healthy male subjects. The study was carried out in two parts. Initially, the tablets were given at 9 a. m. and the subjects were studied up to 14 h and then at 24 h. Subsequently, the same doses were given at 9 p. m. and the subjects were studied 12–24 h after drug administration (i. e. 9 a. m.–9 p. m. the next day). After giving the slow-release tablets the peak plasma levels were significantly lower but the drug persisted in the plasma at higher levels than after the conventional tablet. However, the beta-blocking effect was comparable from the two dosages. The results obtained for the period 12–24 h after the evening dose differed from the corresponding values after morning administration in that the plasma levels were higher and the betablocking effects more marked. Furthermore, the half-life values calculated from these data were significantly longer.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00609871
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  • 17
    Electronic Resource
    Electronic Resource
    Oral absorption of cimetidine and its clearance in patients with renal failure (1979)
    Springer
    European journal of clinical pharmacology 15 (1979), S. 153-157 
    Details
    ISSN: 1432-1041
    Keywords: cimetidine ; renal failure ; elimination half life ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The plasma concentration curve after a single oral dose of cimetidine 200 mg was followed in 27 patients with varying degrees of chronic renal failure (creatinine clearance 1–52 ml/min) and in 46 patients with normal serum creatinine. Compared to the latter patients, the plasma concentration was higher and the elimination rate was slower in all uraemic subjects, including a group with moderate renal impairment. The preliminary recommendations of dosage for patients with a creatinine clearance below 5 ml/min, and for patients on regular haemodialysis, is cimetidine 200 mg every 12 h, 5–15 ml/min 200 mg every 12 to 8 h, 15–30 ml/min 200 mg every 8 h and 30–52 ml/min 200 mg every 6 h.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00563098
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  • 18
    Electronic Resource
    Electronic Resource
    Human pharmacokinetics of nitrazepam: Effect of age and diseases (1979)
    Springer
    European journal of clinical pharmacology 15 (1979), S. 163-170 
    Details
    ISSN: 1432-1041
    Keywords: nitrazepam ; epilepsy ; age ; disease ; plasma concentration ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Plasma concentrations of nitrazepam were measured by gas-liquid chromatography in: young healthy volunteers, in geriatric and psychiatric patients and in epileptic children. The disposition of nitrazepam was described in terms of a two-compartment open model. After a single oral dose of nitrazepam 5 mg the most prominent differences between the experimental groups were in the β-phase half-life-mean 29 h in the young volunteers and 40 h in geriatric patients, and in the apparent volume of distribution during the β-phase of 2.4 vs 4.8 l/kg. Total plasma clearance and the average steady state concentration in both groups were equal. The plasma level rose at a rate proportional to the β-phase half-life, and so, they were achieved more rapidly in the young than in the old subjects (3.5 vs 7.5 d). No change in steady-state level or in the half-life of nitrazepam were found during long term treatment, which indicates lack of enzyme induction or inhibition. In 95% of the epileptic children with a good to fair clinical response, the plasma concentration of nitrazepam was 40–180 ng/ml (mean 114 ng/ml). As all of the patients were on combined antiepileptic therapy, no attempt was made to correlate plasma level with therapeutic response.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00563100
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  • 19
    Electronic Resource
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    Pharmacokinetics of clorazepate in pregnant and non-pregnant women (1979)
    Springer
    European journal of clinical pharmacology 15 (1979), S. 175-180 
    Details
    ISSN: 1432-1041
    Keywords: clorazepate ; nordiazepam ; pregnancy ; pharmacokinetics ; intramuscular injection
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary A single dose of clorazepate 20 mg was injected i.m. in 7 pregnant and 7 non-pregnant women. Blood samples were collected for one week, and urine was collected for 24 h after the dose. The concentrations of clorazepate and its metabolite nordiazepam were determined by electron capture gas liquid chromatography. There was no difference between the two groups on physical examinations. Clorazepate was rapidly absorbed and the peak concentration was reached within 2h. Mean pharmacokinetic parameters for clorazepate were absorption half life 0.77h in pregnant women and 0.56h in non-pregnant women; elimination half life 1.3h in pregnant women and 2.0h in non-pregnant women; volume of distribution: 0.43 l · kg−1 in the pregnant women and 0.33 l · kg−1 in non-pregnant women. Nordiazepam reached its peak concentration within 12h after dosing; its mean half life of elimination was 180h in pregnant women and 60h in non-pregnant women. Within 24h, 1.3% of the clorazepate was recovered in urine from pregnant women and 7% in urine from the non-pregnant women.
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    URL: http://dx.doi.org/10.1007/BF00563102
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    Pharmacokinetics of the placental transfer and distribution of clorazepate and its metabolite nordiazepam in the feto-placental unit and in the neonate (1979)
    Springer
    European journal of clinical pharmacology 15 (1979), S. 181-185 
    Details
    ISSN: 1432-1041
    Keywords: clorazepate ; nordiazepam ; pregnancy ; placental transfer ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Clorazepate 20mg was given i. m. to 49 mothers during the first stage of labour. The elimination of the drug was studied in 27 newborns produced by these mothers. The same dose was given to 13 women who underwent amniocentesis and to 7 women who were breast-feeding. “Total nordiazepam”, i.e. the sum of clorazepate and its metabolite nordiazepam, was determined by gas-liquid chromatography in maternal blood, umbilical cord blood (both arterial and venous), amniotic fluid and in milk. Clorazepate was found to cross the placental barrier slowly, but nordiazepam was transferred more rapidly. Nordiazepam was found in the milk and in the blood of neonates after breast-feeding had started.
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    URL: http://dx.doi.org/10.1007/BF00563103
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  • 21
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    Blood level of cimetidine in relation to age (1979)
    Springer
    European journal of clinical pharmacology 15 (1979), S. 257-261 
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    ISSN: 1432-1041
    Keywords: cimetidine ; H2-receptor antagonist ; aging ; single dose ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The blood level versus time curve for unchanged cimetidine after a 200 mg oral dose has been determined in 20 apparently healthy subjects, ranging from 22 to 84 years of age. A significant relationship between the area under the curve (AUC) and age was found (r=0.81; P〈0.001). The peak concentrations of cimetidine were significantly inversely related to body weight (r=−0.71; P〈0.001). The age-related increase in bioavailability of oral cimetidine, as measured by AUC, was probably due to decreased total clearance of the drug, which resulted from the opposed changes (by themselves not significant) of distribution volume towards a decrease and of half-life towards an increase with age. Reduction in the standard oral dose of cimetidine by one third to one half should be feasible in the elderly without loss of efficacy, and it may be advisable in order to obviate extreme individual responses that may occur in this population.
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    URL: http://dx.doi.org/10.1007/BF00618514
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  • 22
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    Pharmacokinetics of bromocriptine during continuous oral treatment of Parkinson's disease (1979)
    Springer
    European journal of clinical pharmacology 15 (1979), S. 275-280 
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    ISSN: 1432-1041
    Keywords: Parkinson's disease ; bromocriptine ; pharmacokinetics ; plasma concentration
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The plasma kinetics of bromocriptine (BCT), a long-acting dopamine agonist, was studied in twelve patients with Parkinson's disease, using a newly developed gas chromatographic method of analysis. Each patient received BCT for at least three weeks in a constant but different dose regimen. Concomitant treatment with 1-DOPA was not allowed. During a 6-day hospitalization period, a blood sample was taken immediately before the afternoon dose at 14.00 h (Cmin) to determine the steady-state level. On the 6th day blood samples were collected every hour during two 8 h dose intervals. The results showed a significant correlation between the mean values of the AUC and the Cmin. First order elimination kinetics appeared to be followed by BCT, at least for the plasma concentrations commonly found. Considerable inter-individual variation was demonstrated both for the dose/plasma concentration ratio and for calculated plasma clearances. No serious side-effects were observed during the investigation.
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    URL: http://dx.doi.org/10.1007/BF00618517
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  • 23
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    Clofibrate disposition in renal failure and acute and chronic liver disease (1979)
    Springer
    European journal of clinical pharmacology 15 (1979), S. 341-347 
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    ISSN: 1432-1041
    Keywords: clofibrate ; chlorophenoxyisobutyric acid ; disposition ; hepatitis ; cirrhosis ; renal failure ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The disposition of clofibrate over 96 hours was observed following single oral dose in six patients with acute viral hepatitis, six patients with liver cirrhosis, seven patients with renal insufficiency, and six control subjects. No parameter of the disposition of CPIB (active form of clofibrate) was significantly altered in acute hepatitis. In liver cirrhosis, the mean plasma half-life was unchanged compared to controls (20.9 vs. 17.5 h), but plasma clearance of the non-protein bound drug was reduced (115 vs. 243 ml×min−1), plasma protein binding was reduced (92.8 vs. 97.2 percent), and the apparent volume of distribution was increased (0.20 vs. 0.141×kg−1). In renal insufficiency plasma half-life was prolonged 2 to 6-fold, depending on the degree of renal impairment. Total plasma clearance (3.4 vs. 7.1 ml×min−1) and plasma clearance of the unbound drug (81 vs. 243 ml×min−1 were reduced in patients with renal failure, the clearance of the unbound drug being inversely correlated with the serum creatinine concentration. Renal failure was also associated with decreased protein binding and an increased volume of distribution of CPIB, and with reduced urinary excretion of CPIB and its glucuronide metabolite. The dose of clofibrate should be halved in patients with cirrhosis. In renal insufficiency, the dose should be adjusted according to the individual serum creatinine level: only 10 to 15% of the usual weekly dose should be given in complete renal failure.
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    URL: http://dx.doi.org/10.1007/BF00558438
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    Pharmacokinetic, bioavailability and pharmacodynamic study of indobufen (K 3920), an inhibitor of platelet aggregation, after a single dose in man (1979)
    Springer
    European journal of clinical pharmacology 15 (1979), S. 323-327 
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    ISSN: 1432-1041
    Keywords: indobufen ; platelet aggregation ; single dose ; bioavailability ; pharmacodynamics ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Six healthy volunteers received single iv and oral doses of 2-[p-(1-oxo-2-isoindolinyl)phenyl] butyric acid 100 mg (indobufen; K 3920), an inhibitor of platelet aggregation. Plasma levels and urinary excretion of the drug were determined by GLC. Collagen-induced platelet aggregation was assessed turbidimetrically at various intervals after administration. The plasma half-life of the drug was 7–8 h and more than 70% of the administered dose was recovered within 48 h in urine, as unchanged drug and as the glucuronide of indobufen. After oral administration of tablets of two different formulations, the drug was completely absorbed, but one formulation showed faster absorption. The maximal inhibitory effect on platelet aggregation was observed 1 to 4 h after iv administration, and it had decreased by 8 h. After tablets, peak effect and the time of the peak were similar, but activity was significantly prolonged, in accordance with the higher plasma levels found at 8 h. The data suggest that the effect of indobufen on platelets is reversible, and that for this drug platelets behave as a compartment that slowly equilibrates with plasma.
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  • 25
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    The protein binding of methotrexate by the serum of normal subjects (1979)
    Springer
    European journal of clinical pharmacology 15 (1979), S. 363-366 
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    ISSN: 1432-1041
    Keywords: methotrexate ; protein binding ; ultrafiltration ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The protein binding of methotrexate by serum from eight normal volunteers was assessed by continuous ultrafiltration at pH 7.4 and 37°C. Methotrexate concentrations were measured by radioimmunoassay and the data analysed by the method of Scatchard. The major binding protein was albumin which bound 87.3% of the drug in serum. Analysis of the Scatchard plots indicated two distinct groups of binding sites. Class I was found to have 0.16±0.05 (S D) binding sites with an intrinsic association constant of 71.15±35.98 (S D)×104 M−1: Class II had 2.01±0.93 (S D) binding sites and an affinity of 0.18±0.15×104 M−1. No great change in the percentage of methotrexate bound occurred until the total concentration of the drug exceeded 50 µMol 1−1.
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    URL: http://dx.doi.org/10.1007/BF00558441
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  • 26
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    A pharmacokinetic study of neostigmine in man using gas chromatography-mass spectrometry (1979)
    Springer
    European journal of clinical pharmacology 15 (1979), S. 367-371 
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    ISSN: 1432-1041
    Keywords: myasthenia gravis ; neostigmine ; gas chromatography-mass spectrometry ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary To permit rational evaluation of the empirical pharmacotherapy of myasthenia with cholinesterase inhibitors, a sensitive and selective method for the determination of neostigmine has been developed. Analysis is based on ion-pair extraction of neostigmine into methylene chloride and determination by gas chromatography-mass spectrometry (chemical ionization). As neostigmine was found to be metabolized in plasma in vitro, deuterated (d6) neostigmine was immediately added to the plasma sample as the internal standard. The limit of quantitation of the method was about 1 ng/ml (∼ 3nmol/l). The kinetics following i. v. administration were studied in four patients, who received neostigmine 2.5–3.0 mg iv to antagonize pancurone administered during anaesthesia. Elimination was rapid with a half-life t1/2 (β-slope) of 0.89±0.05 h (mean ± SE). The volume of distribution was 1.08±0.11 l/kg and plasma clearance was 0.84±0.04 l/kg/h. In three fasting myasthenic patients plasma concentrations of neostigmine were followed for 5 h after a single oral dose of 30 mg. Considerable interindividual differences in absorption were expressed in the peak concentrations, which occurred 1–2 h following drug ingestion. The bioavailability of neostigmine was estimated to be 1–2% of the ingested dose. Neostigmine concentration in plasma was found to differ considerably (up to forty-fold) between myasthenic patients on their ordinary dose-schedules of cholinesterase inhibitors.
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  • 27
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    Disposition pharmacokinetics of bezafibrate in man (1979)
    Springer
    European journal of clinical pharmacology 16 (1979), S. 31-38 
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    ISSN: 1432-1041
    Keywords: bezafibrate ; hyperlipoproteinemia ; bioavailability ; pharmacokinetics ; GC-MS
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The disposition kinetics of bezafibrate, a newly developed drug of great lipid-lowering potency, were investigated in normal male subjects. Five male volunteers received14C-labelled bezafibrate orally in solution, and a further 10 were given the same dose (300 mg) of un-labelled drug as tablets. The concentration of bezafibrate in serum and urine from the latter was determined by GC, and in the former total radioactivity in serum, urine and feces was followed for 48 h, and urinary excretion products were analysed by TLC and GC-MS. Rapid absorption from the gastrointestinal tract led to peak serum levels 30 min and 2 h after administration of solution and tablets, respectively. Since approximately 95% of the administered14C-bezafibrate was excreted in urine within 48 h, and almost all the remainder was detected in feces, absorption can be regarded as complete after administration in solution. The relative optimal bioavailability from the tablets was also complete, since in both cases approximately 50% of the administered dose was detected as unchanged bezafibrate in urine within 24 h by GC in the tablet study, and by TLC in the solution study. Of the decomposition products, more than 20% of the dose was present as glucuronides and the remainder consisted of several more polar compounds, one of which was identified as a hydroxyderivative of bezafibrate. Since the apparent halflife of bezafibrate in serum was 2.1 h, this new drug possesses favourable pharmacokinetic features: rapid and complete absorption, even from tablets, combined with a conveniently short half-life, and clearance which is half renal (56 ml/min) and half metabolic (43 ml/min), giving a total clearance of 99 ml/min.
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    Plasma and urinary levels of triamterene and certain metabolites after oral administration to man (1979)
    Springer
    European journal of clinical pharmacology 16 (1979), S. 39-44 
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    ISSN: 1432-1041
    Keywords: triamterene ; pharmacokinetics ; diuretic effects
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The plasma and urinary levels of triamterene and two metabolites were measured using a specific method of analysis. Urinary excretion was completed after 48 h, which permitted a rough estimate of its half-life as longer than two hours. The areas under the curve were 672.5±160.3 and 1.311.3±399.1 µg/ml × h after the triameterene 150 mg and 300 mg p.o., respectively and correspondingly 4.2±1.4% and 3.7±0.6% of the dose were excreted as unchanged drug. The principal metabolite of triamterene found was the sulfate conjugate. The area under the curve of this metabolite amounted to 6.672±2.120 and 11.941±5.005 µg/ml × h after the of 150 mg and 300 mg triamterene doses, respectively. The urinary excretion of the metabolite varied between 25.0±4.0% and 17.5±3.5% of the dose after either dose. In healthy subjects an effect on sodium excretion was observed after a dose of 150 mg, whereas the potassium-retaining effect was observed only after the dose of 300 mg.
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    Absolute bioavailability of quinidine in two sustained release preparations (1979)
    Springer
    European journal of clinical pharmacology 16 (1979), S. 45-48 
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    ISSN: 1432-1041
    Keywords: quinidine ; slow release formulation ; pharmacokinetics ; bioavailability
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The bioavailability of quinidine in two sustained release preparations A and B has been compared in three females and three males with i.v. administration of quinidine. The initial rate of oral absorption did not differ between the two drug preparations; the peak concentration was observed after 4 h both for A and B, but was significantly higher after B. A slower decrease in plasma concentration was observed after preparation A than B. Absolute bioavailability did not differ significantly between A (median value 78.4%) and B (median 87.1%). Drug absorption in vivo was in good agreement with the results of in vitro dissolution tests on both preparations. The slower decrease in plasma concentration found for the new sustained release form of quinidine should be of clinical advantage.
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    Single and chronic dose pharmacokinetic studies of sodium valproate in epileptic patients (1979)
    Springer
    European journal of clinical pharmacology 16 (1979), S. 23-29 
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    ISSN: 1432-1041
    Keywords: valproate ; epilepsy ; pharmacokinetics ; drug interaction
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary In four refractory epileptic patients, peak plasma levels of sodium valproate occurred within 1.5 to 3 h after a single oral dose of valproate and the decline in plasma levels followed a monoexponential course with a t1/2 of 11.4 ± 0.1 h. The mean value for apparent volume of distribution was 0.176 ± 0.013 l/kg and for total plasma clearance 0.0106 ± 0.0009 l/h/kg. Steady state plasma levels were predicted using the method of superposition utilizing pharmacokinetic parameters determined following a single dose of valproate and were 78–123% of the predicted values for two patients receiving valproate alone, and 37–64% of the predicted values for the two patients receiving carbamazepine in addition to valproate. In a further group of 20 patients the mean daily doses of valproate for 8 patients receiving valproate alone (25.4 ± 4.9 mg/kg) was significantly less than those for the 12 patients receiving concomitant anticonvulsant therapy (41.6 ± 12.3 mg/kg) (p〈0.005). In addition, the steady state predose plasma levels of valproate were significantly higher in the valproate alone patients (90.3 ± 8.7 µg/ml) compared to the patients receiving additional anticonvulsants (75.3 ± 13.8 µg/ml) (p〈0.01). The higher dose requirements of valproate and lower predose and steady state plasma levels for those patients on multiple anticonvulsants indicate an interaction between valproate and other anticonvulsants.
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    Pharmacokinetics of cephacetrile in patients undergoing haemodialysis (1979)
    Springer
    European journal of clinical pharmacology 16 (1979), S. 49-52 
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    ISSN: 1432-1041
    Keywords: cephacetrile ; haemodialysis ; pharmacokinetics ; renal failure
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The pharmacokinetics of cephacetrile were studied after its administration as a single i.v. bolus injection of 15 mg/kg body weight to 11 patients with terminal renal inpairment undergoing haemodialysis for 6 h. A two-compartment kinetic model was used to describe the biphasic decrease in plasma concentration. The quantities of antibiotic in the central and peripheral compartments, and the amounts eliminated, were calculated for different times. During haemodialysis sessions, the average pharmacokinetic parameters of cephacetrile determined at the dialyser input were: α=5.03 h−1,β=0.458 h−1, K12=2.337 h−1, K21=1.996 h−1 K13=1.154 h−1, Vc=5.508 l, Vp=6.448 l, Vdss=11.956 l. As a function of the pharmacokinetic parameters of cephacetrile, a regimen of multiple doses was established for patients with terminal renal impairment, which will guarantee safe and effective concentrations of the antibiotic.
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    Pharmacokinetics of methadone during maintenance therapy: Pulse labeling with deuterated methadone in the steady state (1979)
    Springer
    European journal of clinical pharmacology 16 (1979), S. 53-57 
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    ISSN: 1432-1041
    Keywords: methadone ; mass fragmentography ; pulse labeling ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary A technique is presented for study of steady state kinetics of methadone using pulse labeling with deuterated methadone (d3) and mass fragmentography to measure both unlabeled and labeled methadone in blood. Seven subjects maintained on methadone for at least 10 months were admitted to a closed metabolic ward. The daily dose of unlabeled methadone (d0) was substituted by one dose of methadone-d3 and plasma levels of methadone-d0 and methadone-d3 were followed for 48 h using a precise (SD±5%) and sensitive (30 pmol/ml) mass fragmentographic technique. Plasma half-lives (t1/2) for both methadone-d0 and metadone-d3 were calculated from samples obtained 8–24 h following the dose of methadone-d3. The t1/2 of oral methadone-d3 was shorter (22±2 h) than that of methadone-d0 (52±20 h). The same pattern was observed after intravenous administration. The results indicate multiple pools of methadone in the body.
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    Pharmacokinetics of dihydroquinidine in congestive heart failure patients after intravenous quinidine administration (1979)
    Springer
    European journal of clinical pharmacology 16 (1979), S. 101-105 
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    ISSN: 1432-1041
    Keywords: dihydroquinidine ; congestive heart failure ; intravenous administration ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The pharmacokinetics of dihydroquinidine were studied in 8 patients with congestive heart failure following a 22 min intravenous infusion of a quinidine preparation that contained 5.9% dihydroquinidine as an impurity. Using a thin layer chromatography-fluorometric assay procedure for dihydroquinidine, the post-infusion plasma dihydroquinidine concentrations declined biexponentially. The half-life of the fast and slow dispositional processes was 4.42±1.81 min and 6.52±2.40 h, respectively. The central compartment volume for dihydroquinidine in these patients was 0.44±0.11 l/kg with an overall apparent volume of distribution of 1.14±0.38 l/kg. The computed values of total body plasma clearance of dihydroquinidine ranged from 1.29 to 2.69 ml/min/kg with a mean value of 1.94±0.60 ml/min/kg. In these patients, approximately 16% of the administered dihydroquinidine dose was excreted intact into the urine in 48 h. The estimated value of renal clearance was 0.314±0.129 ml/min/kg. When compared to control cardiac patients, the data showed that the apparent volume of distribution for dihydroquinidine is smaller in patients with congestive heart failure and as a result of this diminished volume, the clearance rate of dihydroquinidine was slower. The net effect of these differences was the production of higher plasma concentrations of dihydroquinidine in the heart failure group.
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    Prazosin, pharmacokinetics and concentration effect (1979)
    Springer
    European journal of clinical pharmacology 16 (1979), S. 177-181 
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    ISSN: 1432-1041
    Keywords: prazosin ; alpha receptor blockade ; blood pressure ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The pharmacokinetics and effects of prazosin have been studied after intravenous and oral dosing (1 mg) to 6 normal male volunteers. The mean terminal (β) half-life was 2.9 h after intravenous and oral routes. Oral bioavailability was 56.9%. The effects of prazosin on blood pressure were more pronounced after intravenous than oral administration, and the hypotensive effect greater on erect blood pressure. There was a significant correlation (P〈0.02) between the fall in blood pressure and the plasma drug concentration after intravenous prazosin.
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    Influence of the defective metabolism of sparteine on its pharmacokinetics (1979)
    Springer
    European journal of clinical pharmacology 16 (1979), S. 189-194 
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    ISSN: 1432-1041
    Keywords: sparteine ; pharmacogenetic defect ; defective metabolism ; pharmacokinetics ; renal excretion
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Sparteine is metabolized by N1-oxidation, which in some subjects is defective. The defect has a pronounced effect on the kinetics of the drug. In non-metabolisers elimination of sparteine proceeds entirely via renal excretion by a capacity-limited process, 99,9% of the dose being excreted as unchanged drug. In metabolisers the drug is mainly eliminated by metabolic degradation. Pronounced differences in β-phase half-life and total plasma clearance were observed between metabolisers (156 min; 535 ml · min−1) and nonmetabolisers (409 min; 180 ml · min−1).
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    Pharmacokinetics of metformin after intravenous and oral administration to man (1979)
    Springer
    European journal of clinical pharmacology 16 (1979), S. 195-202 
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    ISSN: 1432-1041
    Keywords: metformin ; biguanides ; pharmacokinetics ; absorption
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The kinetics of14C-metformin have been studied in five healthy subjects after oral and intravenous administration. The intravenous dose was distributed to a small central compartment of 9.9±1.61 ( $$\bar X$$ ±SE), from which its elimination could be described using three-compartment open model. The elimination half-life from plasma was 1.7±0.1 h. Urinary excretion data revealed a quantitatively minor terminal elimination phase with a half-life of 8.9±0.7 h. After the intravenous dose, metformin was completely excreted unchanged in urine with a renal clearance of 454±47 ml/min. Metformin was not bound to plasma proteins. The concentration of metformin in saliva was considerably lower than in plasma and declined more slowly. The bioavailability of metformin tablets averaged 50–60%. The rate of absorption was slower than that of elimination, which resulted in a plasma concentration profile of “flip-flop” type for oral metformin.
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    Absolute bioavailability of chlorthalidone in man: A cross-over study after intravenous and oral administration (1979)
    Springer
    European journal of clinical pharmacology 15 (1979), S. 35-50 
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    ISSN: 1432-1041
    Keywords: chlorthalidone ; pharmacokinetics ; oral and i.v. doses ; bioavailability
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Seven normal human volunteers each received a constant-rate infusion of chlorthalidone for 2 h, and the same (commonly 50 mg) single oral dose on separate occasions. The concentration of unchanged chlorthalidone was analyzed over a 100 to 220 h period in plasma, red blood cells, urine and faeces after both dosage forms. A three compartment model was required to describe the intravenous plasma concentrations in five of the subjects. A two compartment model sufficed to account for the decay of the oral plasma concentrations in all seven subjects. The mean plasma t1/2 after i.v. dosing was 36.5 h (±10.5 SD), and the mean plasma t1/2 after oral doses was 44.1 h (±9.6 SD). The mean red blood cell concentration t1/2 after i.v. doses was 46.4 h (±9.9 SD), and the mean red blood cell t1/2 after the oral doses was 52.7 h (±9.0 SD). The shorter i.v. half-live was not equally manifest in all subjects, being mainly apparent in three of them. In all cases the urinary excretion rate plots were parallel to the plasma concentration curves. As the faster decay after i.v. administration was not accompanied by increased renal clearance, the difference must have been due to non-renal mechanism. The mean total of 65.4 (±8.6 SD) % of the intravenous dose was excreted in urine over infinite time, whereas the mean total excretion after the oral dose was 43.8 (±8.5 SD) %. Faecal excretion ranged from 1.3–8.5% of dose in the i.v. study to 17.5–31.2% of dose in the oral study. The sum of the amounts present in urine plus faeces pointed strongly to an important metabolic route of elimination of chlorthalidone. Bioavailability estimates (F) from three sets of data were — a mean F of 0.61 from plasma concentrations, 0.67 from urinary excretion measurements and 0.72 from the erythrocyte concentrations. Simulations with a non-linear model indicated lesser validity of the estimate from erythrocyte concentrations. It was concluded that the average of plasma and urine data, F=0.64, yielded the best estimate of the oral availability of chlorthalidone 50 mg in man.
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    Pharmacokinetics of a single oral dose of muzolimine in cardiac failure (1979)
    Springer
    European journal of clinical pharmacology 15 (1979), S. 105-108 
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    ISSN: 1432-1041
    Keywords: muzolimine ; cardiac failure ; pharmacokinetics ; high ceiling diuretics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The pharmacokinetics of a new “high ceiling” diuretic, muzolimine (Bay g 2821), were investigated after a single oral dose of 40 mg in 7 patients with cardiac failure (Stages I–IV, New York Heart Association classification), and in 2 healthy subjects. Plasma concentrations peaked 1–3 h after administration and declined according to a two-compartment model. The α-phase (distribution phase) lasted until 12–16 h after administration and the mean t1/2α was 3.6 h (range 2.3–4.7) in patients, and 2.6 h (range 2.3–2.9) in healthy subjects. The mean t1/2β was 13.5 h (range 7.4–22.4) in the patients and 14.0 h (range 12.4–14.6) in healthy subjects. T1/2β was not correlated with the degree of heart failure or with the area beneath the plasma concentration curve, which varied three-fold. The renal clearance of muzolimine was in the range 2.7–15.3 ml · min−1 in 5 subjects in whom it was investigated. The pharmacokinetics of muzolimine appear not to be significantly altered by cardiac failure. The prolonged half-lives of the drug are probably responsible for the longer duration of diuretic action reported for muzolimine than for furosemide and bumetamide.
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    Cyclobarbital as a test substance for oxidative drug metabolism in man. Findings in neuropsychiatric patients (1979)
    Springer
    European journal of clinical pharmacology 15 (1979), S. 433-441 
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    ISSN: 1432-1041
    Keywords: cyclobarbital ; barbiturates ; pharmacokinetics ; drug interaction ; volunteers ; patients
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The disappearance of cyclobarbital from plasma has been followed in healthy volunteers and in neurological and psychiatric patients after oral administration of one tablet of Phanodorm®, containing cyclobarbital calcium 200 mg. Plasma levels were measured by a thin-layer chromatographic method with in situ densitometry. The average t1/2 in healthy female and male volunteers was 13.3 h, and with the assumption of complete availability a mean distribution coefficient of 0.69 l/kg−1 and a clearance of 40.4 ml/min−1 were calculated. Repeated experiments in seven volunteers revealed good reproducibility of all values. When the healthy volunteers were combined with a group of untreated epileptics, a dependence of t1/2 and of the apparent volume of distribution on age was found, while clearance did not change with increasing age (range 17–54 years). Long half-lives caused by low clearance values were observed in several individuals with moderate obesity. No consistent change in cyclobarbital kinetics followed acute exposure of volunteers to alcohol or on treatment of neurological patients with carbamazepine. Patients under treatment with perazine exhibited more or less normal kinetic values. In terms of drug interaction, cyclobarbital differs from phenazone in several respects, and so it may prove a useful additional substance for measurement of the rate of drug oxidation in humans.
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    Pharmacokinetics of theophylline in young children with asthma: Comparison of rectal enema and suppositories (1979)
    Springer
    European journal of clinical pharmacology 16 (1979), S. 133-139 
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    ISSN: 1432-1041
    Keywords: theophylline ; asthma ; pharmacokinetics ; children
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Six children, aged 2 months – 4 years, received theophylline 5–6 mg/kg intravenously. Its disposition could be described by a two-compartment open model, the mean serum half life (t1/2 β) was 3.75 h, i. e., shorter than in adults, but there was a considerable interindividual variation (1.8–7.0 h, in one patient 13.3 h). Thirteen children (2 months – 4 years) received theophylline suppositories in a dose of 3.8–5.0 mg/kg, and ten (6 months – 4 years) in a dose of 8.4–14.5 mg/kg. Absorption was slow (mean half-time 43 min), incomplete and variable (biological availability 8–100%, mean 80%). Only four of the patients given the higher dose and none given the lower dose reached a therapeutic serum concentration (10–20 µg/ml). Nine children (6 months – 4 years) received rectal enemas of theophylline 4.1–9.2 mg/kg. Absorbtion was rapid (mean half-time 5.5 min) and biological availability averaged 100%. Six patients reached a serum concentration within the therapeutic range. Using the mean values of the calculated pharmacokinetic parameters, rectal enemas providing a dose of theophylline of 6–8 mg/kg t. i. d. were computed to give serum concentrations between 8–20 µg/ml, without producing too high a level during the absorption phase.
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    Relationship between plasma concentration and effect of dantrolene sodium in man (1979)
    Springer
    European journal of clinical pharmacology 16 (1979), S. 203-209 
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    ISSN: 1432-1041
    Keywords: dantrolene sodium ; spasticity ; twitch tension ; dose response ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Dantrolen sodium is a muscle relaxant, which is used in the treatment of spasticity. Although it is given chronically, little is known about its pharmacokinetic behaviour. The relationship between the effect of a single oral dose of dantrolene sodium and its plasma concentration in healthy volunteers was studied by measuring the effect on the twitch tension, and in spastic patients on the decrease in muscle hypertonia. On the twitch tension dantrolene gave a depression of 49.1±9.4% (±SD) within 1.15 and 3.45 h after ingestion of 100 mg. The mean maximal plasma concentration was 1.24±0.32 µg/ml (±SD). The effect and the plasma concentration were correlated. No relationship between the plasma concentration of dantrolene sodium and its effect could be established in patients, although definite activity in 6 out of 7 patients was observed after a single oral dose of 100 mg, and plasma concentration of dantrolene sodium greater than 0.3 µg/ml were consistently associated with better results than placebo treatment in 6 out of 7 patients.
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    Food-induced reduction in bioavailability of atenolol (1979)
    Springer
    European journal of clinical pharmacology 16 (1979), S. 327-330 
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    ISSN: 1432-1041
    Keywords: atenolol ; food intake ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The influence of food intake on the bioavailability of the beta-adrenoceptor blocker atenolol was assessed by measurement of its single-dose kinetics in ten healthy volunteers, who took 100 mg both in the fasting state and together with a standardized breakfast. Food intake significantly shortened the time to reach peak concentration (2.7 h vs 1.5 h), but caused a significant reduction in AUC values, the mean decrease being 20%. The elimination half-life was unaffected. Atenolol, which is relatively hydrophilic, is incompletely absorbed in the fasting state, and escapes first-pass metabolism. The present findings indicate that food intake causes further impairment of its absorption, even though the absorption rate may initially be enhanced. This contrasts with previous observations on the more lipophilic beta-adrenoceptor blockers propranolol and metoprolol.
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    Bioavailability and pharmacokinetics of cimetidine (1979)
    Springer
    European journal of clinical pharmacology 16 (1979), S. 335-340 
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    ISSN: 1432-1041
    Keywords: cimetidine ; enterohepatic circulation ; irregular absorption ; bioavailability ; pharmacokinetics ; volunteers
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The bioavailability and pharmacokinetics of cimetidine have been studied in healthy volunteers after administration of single intravenous (100 mg) and oral doses (100, 400 and 800 mg). After i.v. administration, the kinetics of cimetidine could be described by a linear, two compartment open model. Substantial variation in half-life was observed between subjects, with a mean value of 2.1 h (range 0.9–4.7). Cimetidine had a low hepatic extraction ratio and a high total plasma clearance, due to extensive urinary excretion of unchanged drug. After oral administration, the plasma concentration vs time curves in most subjects exhibited two marked peaks, an observation that seemed to be constant within individuals and was independent of dose. Bioavailability, estimated as the area under the plasma concentration vs time curves (AUC), after oral doses as compared to the intravenous dose, in most cases exceeded 100%. There was no correlation between bioavailability estimated as AUC and as urinary excretion of unchanged drug. These observations may indicate an enterohepatic circulatory mechanism, predominantly after oral administration. Both unchanged drug and its sulphoxide metabolite appear to be excreted in bile. The latter was shown in vitro to be reduced to cimetidine by fecal bacteria.
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    The disposition of intravenous doxapram in man (1979)
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    European journal of clinical pharmacology 16 (1979), S. 411-416 
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    ISSN: 1432-1041
    Keywords: doxapram ; intravenous infusion regimen ; pharmacokinetics ; data-point weighting ; healthy subjects
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The pharmacokinetics of intravenous doxapram in healthy individuals is consistent with a three-compartment open model. Doxapram was administered by bolus injection (1.5 mg · kg−1) and by intravenous infusion (6.5 mg · kg−1 for 2 h) to 5 subjects on separate occasions. There was no significant difference in mean terminal plasma half-lives (355 and 448 min) or in mean total body clearances (5.9 and 5.6 ml · min−1 · kg−1) following i. v. bolus injection or infusion respectively. In 3 subjects plasma doxapram concentrations during and after i. v. infusion agreed with those predicted from pharmacokinetic values obtained from the bolus injection study. Since mean steady-state concentrations (9.9 µg · ml−1) would be reached only after an extended interval (mean 15.2 h), a variable-rate infusion regimen was calculated to produce and maintain a concentration of 2 µg · ml−1 from 15–25 min onwards. A regimen in which the infusion rate is reduced step-wise is recommended to achieve early near-constant plasma doxapram concentrations.
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    Clinical pharmacokinetics of procainamide infusions in relation to acetylator phenotype (1979)
    Springer
    Journal of pharmacokinetics and pharmacodynamics 7 (1979), S. 69-85 
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    ISSN: 1573-8744
    Keywords: procainamide ; pharmacokinetics ; constant-rate infusion ; acetylator phenotype ; pharmacogenetics ; renal impairment
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract The pharmacokinetics of procainamide was determined in 21 lidocaine-resistant patients who received the drug according to a pharmacokinetically designed double-infusion technique. Thirteen patients were phenotyped as slow acetylators, seven as fast, and one as intermediate. The total body clearances (ClT) of PA in slow and fast acetylators were 22.6 and 34.8 liters/hr, respectively. The fraction of PA cleared by the formation of NAPA in the corresponding acetylator group was 0.2 and 0.4. Renal impairment affected the pharmacokinetics of PA more profoundly as the ClTs of PA in patients with and without renal impairment were 17.9 and 31.2 liters/hr, respectively. None of the calculated volumes of distribution was affected by acetylator phenotype or renal impairment. These data identify the contribution of at least two of the major factors accounting for variability in PA disposition in patients undergoing therapy.
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    Kinetics of biotransformation of clonazepam to its 7-amino metabolite in the monkey (1979)
    Springer
    Journal of pharmacokinetics and pharmacodynamics 7 (1979), S. 87-95 
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    ISSN: 1573-8744
    Keywords: clonazepam ; in vivo biotransformation ; 7-amino metabolite ; pharmacokinetics ; monkeys ; anticonvulsants
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract The pharmacokinetic behavior of the 7-amino metabolite of clonazepam administered exogenously and formed endogenously from the parent drug was studied in a group of rhesus monkeys using constant rate intravenous infusions. Plasma levels of the 7-amino metabolite and/or clonazepam were determined with a GC-CI-MS method. The biological half-life of the 7-amino metabolite (2.2 ± 1.0 hr) was shorter than that of clonazepam (4.9 ± 0.2 hr). Total body clearance of the metabolite (0.83 ± 0.16 liters/hr/kg) was larger than that of the parent drug (0.55 ± 0.09 liters/hr/kg). The kinetics of in vivo biotransformation were described by a two- compartment model in which formation and disposition of the metabolite follow first-order processes. The fraction of a dose of clonazepam appearing in the systemic circulation as 7-amino metabolite was 0.70 ± 0.30. This value may underestimate the actual fraction formed, if the metabolite is susceptible to first- pass metabolism following in situ formation.
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    Attenuation of furosemide's diuretic effect by indomethacin: Pharmacokinetic evaluation (1979)
    Springer
    Journal of pharmacokinetics and pharmacodynamics 7 (1979), S. 265-274 
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    ISSN: 1573-8744
    Keywords: furosemide ; indomethacin ; prostaglandin ; pharmacokinetics ; pharma-codynamics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract The pharmacokinetics and pharmacodynamics of intravenous furosemide, 40 mg, were studied in four normal males in a crossover fashion with and without indomethacin pretreatment. In each study 16 plasma and 10 urine samples were collected over 24 hr. Fluid and electrolyte urinary losses were replaced orally throughout the study. Unchanged furosemide and indomethacin were measured using HPLC; urinary sodium was measured by flame photometry. Pretreatment with indomethacin resulted in increased and prolonged furosemide plasma levels, increased area under the curve, decreased plasma clearance, decreased renal clearance, increased half-life, no change in volume of distribution, and decreased sodium excretion and urine volume. Analysis of sodium excretion rate with time shows that the inhibiting effect of indomethacin was greater during the first 2 hr than at later times.
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    Pharmacokinetics of digoxin: Relationship between response intensity and predicted compartmental drug levels in man (1979)
    Springer
    Journal of pharmacokinetics and pharmacodynamics 7 (1979), S. 47-61 
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    ISSN: 1573-8744
    Keywords: digoxin ; pharmacokinetics ; response kinetics ; three-compartment model ; serum digoxin kinetics ; systolic time intervals ; radioimmunoassay
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract A study designed to investigate the relationship between the pharmacokinetics of digoxin and a measure of its pharmacological effect has been conducted. Serum digoxin concentrations and systolic time intervals were measured concurrently in 12 normal male volunteers following a 1.0 mg i.v. bolus injection. The averaged serum digoxin concentration- time and response-time data were analyzed pharmacokinetically using a three-compartment open model and nonlinear least- squares fitting. When only the serum level-time data were analyzed, a close relationship was found between calculated digoxin levels in the slowly distributing (deep) peripheral compartment and response of the heart to digoxin, as measured by changes in the QS2 index δQS2I. Although it was not possible to distinguish clearly a linear from a nonlinear relationship between digoxin levels in the deep compartment and δQS2I, the nonlinear relationship gave the best overall fit when both serum digoxin and δQS2I data were fitted simultaneously. The simultaneous fityielded a total body clearance of digoxin of 3.6 ml/min/kg and a terminal t1/2 of 42 hr.
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    Single- and multiple-dose kinetics of oral lorazepam in humans: The predictability of accumulation (1979)
    Springer
    Journal of pharmacokinetics and pharmacodynamics 7 (1979), S. 159-179 
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    ISSN: 1573-8744
    Keywords: lorazepam ; benzodiazepines ; pharmacokinetics ; drug accumulation ; antipyrine
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract Six healthy volunteers participated in single- and multiple-dose pharmacokinetic studies of oral lorazepam. Following single 4-mg oral doses, peak plasma lorazepam concentrations ranging from 40 to 70 ng/ml were reached within 3 hr of the dose. Values of absorption half-life averaged 25min (range 10.3–42.7min), and elimination half-life (t 1/2β ) averaged 14.2 hr (range 8.4–23.9 hr). During 15 consecutive days of 3 mg per day administered in divided doses, accumulation to the steady-state condition was complete within several days of the initiation of therapy. Values of accumulation half-life (mean 21.1 hr) were slightly longer than t 1/2β , and the two were not well correlated. Observed accumulation ratios (mean 1.88) were very close to those predicted from the single-dose study (mean 1.77), but the correlation between the two (r=0.51) was not significant in the small sample size. “Washout” half-life values (mean 14.9 hr) were highly correlated with t 1/2β (r=0.92). Clearance of a single intravenous dose of antipyrine determined prior to the multiple- dose lorazepam study (mean 0.86 ml/min/kg) was essentially identical to that determined after the study (mean 0.87 ml/min/kg). Overall, the rate and extent of lorazepam accumulation during multiple dosage were reasonably well predicted by the single-dose kinetic study. However, accurate prediction for any specific individual was not always achieved. Stimulation or inhibition by lorazepam of its own clearance probably does not explain imprecise prediction, since single-dose t 1/2β .
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    Disposition of synthetic glucocorticoids I. Pharmacokinetics of dexamethasone in healthy adults (1979)
    Springer
    Journal of pharmacokinetics and pharmacodynamics 7 (1979), S. 249-264 
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    ISSN: 1573-8744
    Keywords: dexamethasone ; pharmacokinetics ; renal excretion ; high-performance liquid chromatography
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract The pharmacokinetics of dexamethasone alcohol is described in six male and six female healthy adult volunteers who each received 8 mg of dexamethasone phosphate by bolus intravenous injection. Quantitation of the alcohol was done using a high-performance liquid Chromatographic method with improved specificity. Statistical evaluation of the results generated by nonlinear least-squares regression analysis of the plasma concentration-time data shows that the phosphate ester is very rapidly hydrolyzed to the alcohol and a biexponential equation is the simplest poly exponential equation that is consistent with the data. The terminal phase half-lifet 1/2β was significantly greater (p〈0.05) in males (mean 201.5 min) than in females (mean 142.3 min). The prolongedt 1/2β in males did not appear to be caused by an impaired capacity to eliminate dexamethasone since the total plasma clearance did not differ between males (mean 247.5ml/min) and females (mean 242.9 ml/min). There was, however, a high positive correlation betweent 1/2β and $$V_{d_{ss} } $$ among the 12 adults (r=0.92, p〈0.001). There were also significant correlations between $$V_{d_{ss} } $$ and body weight (r=0.67, p〈0.05) andt 1/2β (r=0.80, p〈0.01).The difference in body weight between the sexes seems to be the main factor contributing to the difference observed in t 1/2β. An average of only 2.6% of the dose was found unchanged in a 24-hr urine sample, and hence it appears that dexamethasone is primarily eliminated by extrarenal, probably hepatic, mechanisms.
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    Chlorpheniramine. II. Effect of the first-pass metabolism on the oral bioavailability in dogs (1979)
    Springer
    Journal of pharmacokinetics and pharmacodynamics 7 (1979), S. 383-396 
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    ISSN: 1573-8744
    Keywords: chlorpheniramine ; pharmacokinetics ; oral absorption ; first-pass effect ; saturation kinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract The pharmacokinetics of chlorpheniramine has been studied in six dogs by following the time course of plasma concentration of the drug after intravenous and oral administration of its maleate salt in solution form. After intravenous dosing the decline in chlorpheniramine plasma concentration was typically biexponential. The drug distributed rapidly and extensively to the extravascular tissues. The mean distribution phase halflife was 12.5 min, and the mean apparent volume of distribution, Vdβ, was 525% ofthe body weight in four dogs with normal hematocrits. The mean half-life of elimination was 1.7hr. The percent absolute availability following oral administration of the drug in the aqueous solution form was found to be dose dependent. At 100-mg dose, in six dogs, an average of 36% of the orally administered dose was found to be systemically available. At 50-mg dose, in one of the four dogs studied, no measurable plasma levels of chlorpheniramine were obtained, and the average bioavailability was only 9.4%. The average availability in four dogs at 200-mg dose was 39.4%. Even at 200-mg oral dose, the dogs did not show any signs of sedation and remained alert all through the experiment. Saturable first-pass gut and/or hepatic elimination has been postulated. The possible implications of these findings on the therapeutic effectiveness of the usual dosing regimen of chlorpheniramine in dogs are discussed.
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    Pharmacokinetics of phenylethylacetylurea (pheneturide), an old antiepileptic drug (1979)
    Springer
    Journal of pharmacokinetics and pharmacodynamics 7 (1979), S. 453-462 
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    ISSN: 1573-8744
    Keywords: pheneturide ; antiepileptics ; pharmacokinetics ; TLC-UV densitometry
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract The pharmacokinetics of pheneturide (a decarboxylation product of phenobarbital), used to prevent psychomotor seizures for many years, was studied in normal human volunteers. To measure the drug in plasma and urine, a highly sensitive and reproducible thin-layer chromatography-reflectance spectrophotometric assay was developed. The results show that pheneturide follows first-order kinetics in the dose range studied. Its half-life after single doses is 54 hr (range 31–90), and its total body clearance (100% nonrenal) is 2.6 liters/hr (range 1.73–3.59). After repetitive administration, half-life is 40 hr (but clearance remains unchanged because of a lower volume of distribution). Because of the long half-life, repetitive administration results in a continuous steady-state level and makes this drug (kinetically) ideal for long-term use.
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    Pharmacokinetics of clonidine in the rat and cat (1979)
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    Journal of pharmacokinetics and pharmacodynamics 7 (1979), S. 481-494 
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    ISSN: 1573-8744
    Keywords: clonidine ; pharmacokinetics ; blood and brain levels ; liver clearance
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract To investigate the pharmacokinetic behavior of clonidine, rats were given clonidine intravenously at 125, 250, and 500μg/kg and blood clonidine concentrations were followed for 6 hr. The disposition of clonidine in two brain regions was studied in rats after an i. v. dose of 500 μg/kg. The liver clearance in rats was investigated by liver perfusion techniques. The results obtained indicate that the disposition characteristics of clonidine can be described by a two-compartment open model in both rats and cats. The penetration of clonidine into tissues is rapid, and brain levels in rats were about 1.7 times higher than blood levels. Brain tissues were found to be an indistinguisible part of the central (blood) compartment. Dose-dependent pharmacokinetic behavior was found for clonidine in rats at the doses used. This was demonstrated by a decrease of both the rate constant of distribution to the peripheral compartment and the overall elimination rate constant from the body, with increase in dose. As a consequence, the volume of distribution and the clearance both decreased with increasing dose. Possible explanations for the dose-dependent behavior of clonidine are discussed.
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    Potential pitfalls in the conventional pharmacokinetic studies: Effects of the initial mixing of drug in blood and the pulmonary first-pass elimination (1979)
    Springer
    Journal of pharmacokinetics and pharmacodynamics 7 (1979), S. 527-536 
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    ISSN: 1573-8744
    Keywords: instantaneous distribution ; pharmacokinetics ; pulmonary first-pass effect
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract The classical concept of assuming that an i.v. dose instantaneously distributes into the central or plasma compartment is reviewed, as is the potential for pulmonary first-pass effect. Based on available literature, the concept is shown to lead to serious errors in estimating pharmacokinetic parameters, particularly for drugs with high clearance.
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    Multiple receptor responses: A new concept to describe the relationship between pharmacological effects and pharmacokinetics of a drug: Studies on clonidine in the rat and cat (1979)
    Springer
    Journal of pharmacokinetics and pharmacodynamics 7 (1979), S. 495-510 
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    ISSN: 1573-8744
    Keywords: clonidine ; pharmacokinetics ; analgesia ; blood pressure effects ; smooth muscle
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract The time course of an observed pharmacological effect is affected not only by the kinetics of the drug levels at the site of action but also by parameters such as the slope and maximum effect of the functional relationship between drug level and response. Using clonidine as a test drug, it was found that the kinetics of its effects on blood pressure and pain responses cannot be described by the time course of clonidine levels in the blood, brain, or the hypothetical tissue compartment of the two-compartment characteristics of this drug. However, the results can be explained assuming that the observed pharmacological effects of a drug are composed of the sum of responses from at least two receptor sites with different slopes and maximal effects. The effect of intravenously administered clonidine on blood pressure in the rat was found to be related to the blood concentrations at least at two receptor sites with opposite effects, one leading to a hypertensive and the other to a hypotensive response. Predictions indicate that a maximum decrease of arterial blood pressure is obtained when the steady-state blood concentration of clonidine is about 1 ng/ml and that no effect is seen at 10 ng/ml. Higher levels will produce an increase of the pressure. The kinetics of the analgesic effect of clonidine in the rat could best be related to the brain levels if the observed effect was considered to be derived from the sum of activity at two receptor sites each producing analgesia. The kinetics of the effects of clonidine on the nictitating membrane of the cat was found to be determined by the kinetics of the drug in the peripheral compartment of the two-compartment open model. Consideration of multiple receptor responses is suggested for future studies on the relationship between the kinetics of drug levels and pharmacological responses.
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    Plasma levels and β-blocking effect of α-hydroxymetoprolol—Metabolite of metoprolol—in the dog (1979)
    Springer
    Journal of pharmacokinetics and pharmacodynamics 7 (1979), S. 471-479 
    Details
    ISSN: 1573-8744
    Keywords: metoprolol ; α-OH-metoprolol ; active metabolites ; pharmacokinetics ; β- blocking effect
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract The plasma levels and the β- blocking effect of metoprolol and its active metabolite α- hydroxymetoprolol have been studied after i.v. bolus injections of the substances to dogs. For both substances the β- blockade increased with the dose, and there was a linear relationship between percent reduction in exercise heart rate and the logarithm of plasma concentration. The dose of the metabolite, however, had to be 5 times higher than that of metoprolol to induce the same degree of β- blockade. Because of differences in the volume of distribution, 2.0 liters/kg for α- OH-metoprolol and 3.5 liters/kg for metoprolol, the 5 times higher dose of α- OH-metoprolol resulted in 10 times higher plasma levels of the metabolite than of metoprolol. α- OH-Metoprolol was more slowly eliminated (t1/2∼7.0 hr, total body clearance ∼3.5 ml-kg−1-min−1) than metoprolol (t1/2∼2.0 hr, total body clearance ∼20.0 ml-kg−1-min−1). Approximately 5% of an i.v. dose of metoprolol was metabolized to α- OH-metoprolol. The half-life of the endogenously formed metabolite was the same as after an i.v. dose of the compound.
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    Pharmacokinetics of high-dose methotrexate treatment in children (1978)
    Springer
    European journal of clinical pharmacology 14 (1978), S. 143-147 
    Details
    ISSN: 1432-1041
    Keywords: Children ; leukemia ; high-dose methotrexate ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The pharmacokinetics of intravenous high-dose methotrexate were studied in two groups of children being treated for malignant diseases, mostly acute lymphatic leukemia. The peak serum level of methotrexate of 2.32·10−5 mol/l was found in children given 500 mg methotrexate/m2 by a 24 h infusion, and another group given 2790 mg/m2 during a 6 h infusion had serum levels as high as 2.16·10−4 mol/l. The decay of serum concentration of methotrexate after completion of the infusion followed a diphasic curve, with an initial serum half-life of 4.8 h, followed by a second half-life of 34.4 h at distribution equilibrium. The apparent volume of distribution was 56.8 litres/m2. Significant levels of methotrexate were found in cerebrospinal fluid, but penetration into cerebrospinal fluid was slow. Urinary excretion of methotrexate was considerable. Four to five days after commencement of the infusion, urinary concentrations of methotrexate still exceeded the serum levels.
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    The pharmacokinetics and metabolism of the anilide local anaesthetics in neonates (1978)
    Springer
    European journal of clinical pharmacology 14 (1978), S. 203-212 
    Details
    ISSN: 1432-1041
    Keywords: Mepivacaine ; pharmacokinetics ; neonates ; healthy adults ; metabolism ; renal excretion ; lignocaine
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The pharmacokinetics and metabolism of mepivacaine has been studied in premature neonates dosed subcutaneously and in healthy adults dosed intravenously. The pharmacokinetics of mepivacaine in four neonates (N) was compared with that in six adults (A). Newborns had a significantly longer terminal phase half-life than adults (N mean 8.69 h; A mean 3.17 h). Total plasma clearance normalized on body weight was significantly smaller in neonates (mean 2.34 ml/min/kg) than in adults (mean 5.47 ml/min/kg), as was the hepatic blood clearance (N mean 1.37 ml/min/kg; A mean 5.10 ml/min/kg). The renal plasma clearance, however, was significantly greater in neonates (mean 0.76 ml/min/kg) than adults (mean 0.20 ml/min/kg). There was an average six-fold increase in the fraction of the dose excreted unchanged in newborns (mean 43.3%) compared to adults (mean 7.1%) with acidified urine (pH 5.5–6.0). There was significantly more of the mono-N-demethylated metabolite of mepivacaine excreted by newborns (mean 11.4%) than by adults (mean 2.2%), but their capacity to carry out aromatic hydroxylation of mepivacaine was negligible. These results for mepivacaine were compared with those previously reported for lignocaine in premature infants. The immaturity of hepatic function appears to have diminished more profoundly the ability of premature infants to metabolize mepivacaine than lignocaine. These findings are discussed in terms of perfusion theory of hepatic drug elimination.
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    Rate of drug metabolism in man measured by14CO2-breath analysis (1978)
    Springer
    European journal of clinical pharmacology 14 (1978), S. 293-299 
    Details
    ISSN: 1432-1041
    Keywords: Breath analysis ; 14CO2 exhalation ; drug metabolism ; glycodiazine ; liquid chromatography ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Exhalation of14CO2 in breath has been used to assess the rate of hepatic demethylation of (14C-dimethyl)aminopyrine, but due to the complexity of aminopyrine metabolism the pharmacokinetics of the procedure are insufficiently understood. Therefore, studies were performed in five individuals after oral administration of (14C-methoxy)glycodiazine, a model substance with relatively simple kinetic properties. Plasma concentrations of the drug and urinary output of its metabolites measured by high pressure liquid chromatography were analysed by a two-compartment open model. The terminal disappearance of14CO2 from breath was practically identical with the terminal disappearance of glycodiazine from plasma, which could be correlated with the plasma clearance of free glycodiazine. The mean transit time of14C-atoms from plasma to breath was 3 h. These results contribute to the pharmacokinetic basis for use of14C-demethylation breath tests. In particular, they are consistent with the hypothesis that14CO2-breath analysis may be used to assess certain pharmacokinetic parameters of appropriately labelled test compounds. These parameters may not necessarily be a direct reflection of the rate of demethylation.
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    Binding of drugs to human muscle (1978)
    Springer
    European journal of clinical pharmacology 14 (1978), S. 335-340 
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    ISSN: 1432-1041
    Keywords: Drug binding to muscle ; interindividual differences ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Binding of 22 drugs to human muscle tissue has been determined by ultrafiltration. All drugs tested were bound, the bound fraction ranging from 13% (aminophenazone) to 〉98% (desipramine). Both linear and nonlinear binding was observed. For chemically related substances, binding to muscle tissue correlated with plasma binding and lipid solubility. There were significant differences in binding to muscle from different individuals. With respect to pharmacokinetics of drugs, it is suggested that binding to muscle tissue may be at least as important as plasma binding.
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    Elimination of hexamethylene diisocyanate cross-linked polypeptides in patients with normal or impaired renal function (1978)
    Springer
    European journal of clinical pharmacology 14 (1978), S. 405-412 
    Details
    ISSN: 1432-1041
    Keywords: Colloidal plasma substitutes ; cross-linked polypeptides ; Haemaccel® ; pharmacokinetics ; renal failure
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Infusions of 3.5% isocyanate cross-linked polypeptide solution 500 ml were given to 52 patients with normal or impaired renal function: glomerular filtration rate (GFR)=0–133 ml/min. The serum concentration and urinary excretion of hydroxyproline were measured and the equivalent polypeptide concentrations were calculated from the results. In patients with normal renal function (GFR〉90 ml/min) the proportion of polypeptide excreted in the urine up to 12 h was 45.4±2.6% ( $$\bar X$$ ±SEM), up to 24 h 47.7±2.9% and up to 48 h 49.3±3.4%. In patients with moderate renal insufficiency (GFR=30–90 ml/min) there was no decrease in polypeptide excretion and even in patients with more serious impairment of GFR (11–30 ml/min) 48-h urinary polypeptide excretion was still 40.6±5.9%. In patients with GFR of 2–10 ml/min polypeptide excretion fell to 10.7±3.2% during the first 12 h, although there was an increase in later collection periods as compared to patients with normal renal function −19.9±3.9% in 24 h and 27.0±3.5% in 48 h. The elimination half-life (t1/2) calculated from serum concentrations was 505±30 min ( $$\bar X$$ ±SEM) in patients with normal renal function (GFR〉90 ml/min). Only when the GFR fell below 30 ml/min did it slowly begin to increase. In patients with minimal residual renal function (GFR=0–0.5 ml/min), who were on haemodialysis, the elimination half-life was 985±49 min, i.e. approximately twice the normal. Twice weekly infusion of 3.5% polypeptide solution 500 ml over a period of 6 weeks did not produce any significant cumulation in haemodialysis patients (GFR=0–0.5 ml/min). A weekly dose of polypeptide 35 g appeared to be quite safe when given for several weeks, even to anuric patients. As no significant amount of polypeptide was lost during haemodialysis, the dose can be chosen without taking into account any effect of intermittent haemodialysis.
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    Pharmacokinetics of a microcrystalline theophylline preparation in patients with chronic obstructive airways disease (1978)
    Springer
    European journal of clinical pharmacology 13 (1978), S. 29-33 
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    ISSN: 1432-1041
    Keywords: Microcrystalline theophylline ; chronic obstructive airways disease ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Plasma theophylline concentrations have been measured in 9 patients with chronic obstructive airways disease following the oral administration of a microcrystalline theophylline preparation. Some measurements of FEV1 were also made. Four patients were given 375 mg as a single dose and then subsequently 375 mg stat and 125 mg 4 times daily for 3 days, (Group I). A further 5 patients took 250 mg as a single dose and then 250 mg 4 times daily for 3 days, (Group II). In both groups, following the single dose and again after the last dose of chronic administration, blood samples were obtained at frequent intervals up to 24 h for plasma drug estimation. During the 3-day course, blood samples were drawn before and 2 h after each morning dose. In Group I patients, substantial plasma theophylline concentrations were seen only after the loading dose. Thereafter, the mean concentrations before or 2 h after the morning doese were always less than 4.0 µg/ml. Trough concentrations were usually below 2.0 µg/ml. In contrast patients in Group II achieved substantially higher plasma theophylline concentrations, with mean peak concentrations always 10 µg/ml or greater, and trough concentrations greater than 5 µg/ml on at least one occasion in every subject. The elimination half-lives after chronic administration in both groups were not significantly different from those obtained after single doses. Mean drug accumulation, measured as AUCss/AUC1, was 0.87±0.07 in Group I and 0.72±0.14 in Group II, indicating that accumulation had not occurred with either regimen. The mean increase in FEV1 2 h after the administration of a single dose was 19.2% after 375 mg and 16.7% after 250 mg. These results indicate that the recommended dosage regimen for microcrystalline theophylline preparation (375 mg stat and 125 mg 4 times daily) produces inadequate plasma theophylline concentrations: 250 mg 4 times daily would appear to be likely to result in satisfactory theophylline levels in more patients.
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    Bioavailability of p-chlorophenoxyisobutyric acid (clofibrinic acid) after repeated doses of its calcium salt to humans (1978)
    Springer
    European journal of clinical pharmacology 13 (1978), S. 49-53 
    Details
    ISSN: 1432-1041
    Keywords: p-Chlorophenoxyisobutyric acid ; clofibrate ; steady-state plasma concentrations ; bioavailability ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Plasma concentrations and bioavailability of clofibrinic acid have been estimated under conditions approaching the steady-state during a ten-day period of administration as clofibrate or as a calcium clofibrinate-carbonate combination (1:1 w/w) at a dosage interval of 12 h. Formulation — related differences in bioavailability were not significant, and the 95% confidence limits of these differences were within −2% to +8% of the mean for the reference formulation of clofibrate. The mean steadystate plasma concentrations of clofibrinic acid measured on the tenth day of dosing were 116 µg/ml±22 S.D. and 119 µg/ml±23 S.D. after administration of 885 mg as clofibrate and the calcium clofibrinate-carbonate combination respectively. The peaks of mean plasma concentrations were 70 µg/ml±15 S.D., 119 µg/ml±32 S.D. and 131 µg/ml±26 S.D. on the first, fifth and tenth day of dosing with clofibrate, and 62 µg/ml±13 S.D., 127 µg/ml±S.D. and 143 µg/ml±25 S.D. on the corresponding days of dosing with the calcium clofibrinate-carbonate combination. After the last dose on the tenth day of dosing, the mean apparent half-lives of elimination of clofibrinic acid from plasma were 24.2 h±4.4 S.D. and 25.5 h±3.2 S.D. after administration of clofibrate and the calcium clofibrinate-carbonate combination respectively.
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    Metabolism of phenazone in man after hydrocortisone administration (1978)
    Springer
    European journal of clinical pharmacology 13 (1978), S. 69-72 
    Details
    ISSN: 1432-1041
    Keywords: Phenazone ; pharmacokinetics ; hydrocortisone ; elimination rate ; distribution volume
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The influence of a high plasma concentration of hydrocortisone on the metabolism of phenazone in humans has been studied. Two series of experiments were carried out, Group A to demonstrate any enzyme-inducing effect of hydrocortisone, and Group B to study the immediate effect of hydrocortisone on the metabolism of phenazone. 9 subjects (Group A) received a total 250–400 mg hydrocortisone i.m. twice daily for three days and the 24-hour elimination of phenazone was studied before and afterwards. In a further 5 subjects (Group B) the elimination of phenazone was examined during administration of hydrocortisone or placebo. The elimination rate and the apparent volume of distribution of phenazone remained unchanged under both experimental conditions.
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    The pharmacokinetics and metabolism of the anilide local anaesthetics in neonates (1978)
    Springer
    European journal of clinical pharmacology 13 (1978), S. 143-152 
    Details
    ISSN: 1432-1041
    Keywords: Lignocaine ; pharmacokinetics ; neonates ; metabolism ; renal excretion ; plasma concentrations
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The pharmacokinetics and metabolism of lignocaine in premature neonates was studied after subcutaneous administration. The collection of serial urine together with a limited number of blood samples from neonates enabled simultaneous computer fitting of data to a pharmacokinetic model. The disposition kinetics of lignocaine in four neonates were compared with similar data reported for adults. Neonates had prolonged t1/2 (neonate mean: 3.16 h; adult mean: 1.80 h), and an increased total volume of distribution (neonate mean: 2.75 l/kg; adult mean: 1.11 l/kg) compared with adults. Total plasma clearance (Cltp) normalised on body weight showed no significant difference between neonates (mean: 0.610 l/h/kg) and adults (mean: 0.550 l/h/kg). The urinary excretion of lignocaine and several of its metabolites was studied in 8 neonates and 11 adults. Neonates were shown to excrete much more unchanged lignocaine (mean: 19.67%) compared with adults (mean: 4.27%) and the proportion of the dose excreted as 4-hydroxyxylidine is considerably reduced in neonates (neonate mean: 8.89%; adult mean: 63.78%). The use of the two pharmacokinetic parameters, t1/2 and Cltp, as indices of drug elimination ability are discussed.
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    Absorption of oral and intramuscular chlordiazepoxide (1978)
    Springer
    European journal of clinical pharmacology 13 (1978), S. 267-274 
    Details
    ISSN: 1432-1041
    Keywords: Chlordiazepoxide ; benzodiazepines ; pharmacokinetics ; bioavailability ; intramuscular injection ; alcohol withdrawal
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The absorption of oral and intramuscular (i. m.) chlordiazepoxide hydrochloride (CDX · HCl) was compared in two pharmacokinetic studies. In Study One, single 50-mg doses of CDX · HCl were administered orally and by i. m. injection to 14 healthy volunteers using a crossover design. Whole-blood concentrations of chlordiazepoxide (CDX) and its first active metabolite, desmethylchlordiazepoxide (DMCDX), were determined in multiple samples drawn after the dose. Mean pharmacokinetic variables for CDX following oral and i. m. administration, respectively, were: highest measured blood concentration, 1.65 vs 0.87 µg/ml (p〈0.001); time of highest concentration, 2.3 vs 7.6 h after dosing (p〈0.001); apparent absorption half-life, 0.71 vs 3.39 h (p〈0.001). Biphasic absorption after i. m. injection, consistent with precipitation at the injection site, was observed in 9 of 14 subjects. Based upon comparison with previous intravenous data, the completeness of absorption was 100% for oral vs 86% for i. m. CDX · HCl (p〈0.1). In Study Two, 28 male chronic alcoholics with clinical manifestations of the acute alcohol withdrawal syndrome were randomly assigned to one of four treatment conditions: 50 or 100 mg doses of CDX · HCl, by mouth or by i. m. injection. Concentrations of CDX and DMCDX, determined in plasma samples drawn every 20 min for 5 h following the dose, were significantly higher after oral administration of a given dose than at corresponding points in time after i.m. injection after the same dose. Thus absorption of oral CDX is reasonably rapid and complete, whereas the absorption rate of i. m. CDX is slow.
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    Bioavailability of norethindrone in human subjects (1978)
    Springer
    European journal of clinical pharmacology 13 (1978), S. 35-39 
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    ISSN: 1432-1041
    Keywords: Norethindrone ; bioavailability ; man ; competitive protein binding ; sex differences ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary A competitive protein binding assay for norethindrone was developed to measure plasma levels in human subjects. The plasma levels were considerably higher in women than in men, especially at low dose levels. The plasma levels were directly related to the dose in men; but greater variations in the plasma levels were observed in women. The plasma half-life was about 5 h in both sexes with single oral doses of 5 to 20 mg. A comparative bioavailability study with norethindrone from 2 different manufacturers, formulated in the same manner, showed no significant differences in absorption characteristics and provided sufficient data for pharmacokinetic analysis.
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    Pharmacokinetics of bendroflumethiazide in hypertensive patients (1978)
    Springer
    European journal of clinical pharmacology 13 (1978), S. 119-124 
    Details
    ISSN: 1432-1041
    Keywords: Bendroflumethiazide ; pharmacokinetics ; hypertension ; renal clearance
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary After four weeks on placebo treatment, 8 hypertensive patients (WHO stage I) were treated for 2 weeks with bendroflumethiazide (bft) 2.5 mg and KCl 1.5 g daily. Subsequently they received bft 5 mg and KCl 1.5 g daily for a further fortnight. At the end of each period of treatment blood pressure was recorded and blood samples and urine were collected for analysis of bft by GLC. Before taking the daily dose of bft, no trace of the drug was found in plasma. Peak levels of bft were seen after 2.3 h and averaged 23 and 50 ng · ml−1 after 2.5 and 5 mg, respectively. After bft 2.5 mg the plasma level was too low for kinetic analysis. The plasma half-life after 5 mg averaged 4.1 h. The mean apparent volume of distribution was 1.18 l · kg−1. Non-renal clearance averaged 200 ml · min−1. The renal clearance of bft was significantly lower (p〈0.05) after 5 mg (48 ml · min−1) than after 2.5 mg bft (93 ml · min−1), although the creatinine clearance remained unchanged. No correlation was found between the plasma level of bft and its effect on blood pressure.
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    Pharmacokinetics and metabolism of the anilide local anaesthetics in neonates. 11 etidocaine (1978)
    Springer
    European journal of clinical pharmacology 13 (1978), S. 365-371 
    Details
    ISSN: 1432-1041
    Keywords: Etidocaine ; pharmacokinetics ; metabolism ; neonate
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The urinary elimination of etidocaine and several of its metabolites was investigated in neonates whose mothers had received one or more doses of etidocaine during labour. The urine collection period ranged among the neonates from 21.4 to 47.0 h post-partum. The total amounts of etidocaine and its metabolites recovered in neonatal urine represented a mean of 0.12 per cent of the maternal dose. Some differences in the pattern of urinary metabolites were observed between neonates and adults. Mean half-life of elimination of etidocaine calculated from sigma-minus plots of the neonatal urinary data was 6.42 h. This is greater than that previously reported following intravenous administration of etidocaine to adults (2.6 h). The slower rate of elimination in neonates is probably due to an increased neonatal volume of distribution since there is evidence to show that etidocaine is extensively metabolised by the neonate.
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    Influence of bed rest on the pharmacokinetics of phenazone (1978)
    Springer
    European journal of clinical pharmacology 13 (1978), S. 379-383 
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    ISSN: 1432-1041
    Keywords: Antipyrine ; pharmacokinetics ; phenzone ; posture ; immobilization
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The pharmacokinetics of a single dose of phenazone was studied in six subjects while ambulant and during bed rest for 3 days. Elimination of the drug was followed for 12 h after oral and intravenous administration. The elimination rate constant and total body clearance were significantly increased during bed rest as compared to the ambulant period, but the differences were small. The apparent volume of distribution decreased significantly. No consistent change due to bed rest was found in the rate of absorption or bioavailability of the oral dose.
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    Pharmacokinetics of a single oral dose of hydroflumethiazide in health and in cardiac failure (1978)
    Springer
    European journal of clinical pharmacology 14 (1978), S. 29-37 
    Details
    ISSN: 1432-1041
    Keywords: Hydroflumethiazide ; pharmacokinetics ; cardiac failure ; renal drug excretion ; metabolism ; 2,4-disulfamyl-5-trifluoro-methylaniline
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The pharmacokinetics of hydroflumethiazide (HFT) were investigated after single oral doses of 6 µmoles/ per kg body weight in five healthy subjects and in nine patients with moderate cardiac failure. HFT was excreted in urine together with 2,4-disulfamyl-5-trifluoromethylaniline (DTA), which was also present in the blood after administration of HFT. HFT and DTA were determined by TLC and spectrofluorodensitometry. Mean cumulative urinary excretion of HFT was 46.5 and 47.5 per cent of the dose both in healthy subjects and in patients. Distribution half-life (t1/2α) was about 2 h in both groups of subjects, while biological half-life (t1/2β) ranged from 12.4 to 26.9 h (mean 16.6) in healthy subjects, and from 6.3 to 13.7 h (mean 9.6) in patients. Mean renal clearance was 0.33 and 0.211 · h−1 · kg−1 in normal subjects and patients, respectively, and was almost equal to the total body clearance. HFT had a large apparent volume of distribution (Vβ), with mean values of 6.4 and 3.11 · kg−1 in normal subjects and patients. Mean cumulative urinary excretion of DTA was 1.8 and 1.9 per cent in healthy subjects and patients with cardiac failure. The apparent half-life of DTA, determined from urinary excretion rate in eleven subjects, ranged from 16 to 56 h but half-lives in three others were more than 100 h. The results indicate that HFT is partly metabolized in the body to DTA, and DTA and HFT are excreted in urine. The half-life of DTA was longer than that of the parent drug. The apparent volume of distribution, clearance and biological half-life of HFT were lower in patients with cardiac failure than in healthy subjects.
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    Preliminary studies of the kinetics of citalopram in man (1978)
    Springer
    European journal of clinical pharmacology 14 (1978), S. 69-73 
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    ISSN: 1432-1041
    Keywords: Citalopram ; pharmacokinetics ; man ; steady state levels ; metabolism
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The plasma concentrations of citalopram, a potent serotonin reuptake inhibitor, and its demethylated metabolite have been determined by a specific fluorescence coupling technique during single dose experiments in volunteers and in clinical tests. Citalopram was found to have linear kinetics within the dose range investigated, which were characterized by fairly rapid absorption and slow elimination (biological half-life 1–21/2 days). Steady state levels in the range 120–340 nM (i.e. slightly above those associated with pharmacodynamic activity in animals) were attained within a week. A drug/metabolite ratio of 2–3 was recorded.
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    Pharmacokinetics of sulfadiazine and trimethoprim in man (1978)
    Springer
    European journal of clinical pharmacology 14 (1978), S. 57-67 
    Details
    ISSN: 1432-1041
    Keywords: Chemotherapy ; sulfadiazine ; trimethoprim ; pharmacokinetics ; acetylation
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Sulfadiazine (SDZ) 800 mg and trimethoprim (TMP) 160 mg were given orally to 10 normal subjects and the concentration of SDZ and TMP in serum and urine was followed for 24 h. Both drugs showed a significant negative correlation between individual “peak” concentrations in serum and the body weight of the subject. Twelve hours after dosing the serum concentration was 12 to 25 µg/ml for SDZ and 0.3 to 1.1 µg/ml for TMP. Individual concentration ratios between SDZ and TMP in serum were 4.8 (1 h) – 145 (24 h), and in the urine the ratio was close to 6 throughout the 24 h collection period. The range of urinary concentrations was from 65 to 400 µg/ml for SDZ and from 13.8 to 93.4 µg/ml for TMP. The fraction acetylated SDZ/acetylated SDZ + SDZ was 21% during the 0–8 h period, 33% during the 8–15 h period and 41% during the 15–24 period. The average values for the notional volume of distribution, Vd, were 0.36±0.13 1/kg for SDZ and 1.39±0.25 1/kg for TMP. The average “t1/2” was 15.2±7.4 h for SDZ and 7.4±1.9 h for TMP. Individual subjects showed a significant correlation between the serum clearance of TMP and SDZ (p〈0.01) and also between the renal clearance of the two drugs (p〈0.05). The serum clearance was significantly correlated with the renal clearance for TMP but not for SDZ. For SDZ Vd was significantly negatively correlated with the elimination constant; for TMP no such correlation was found. The serum clearance of SDZ was significantly correlated with the percentage of SDZ which was excreted as the (presumably) acetylated compound. The renal clearance of SDZ was independent of the serum concentration of SDZ. There was a highly significant negative correlation between the renal clearance and serum concentration of TMP, as well as for “acetylated SDZ”. The renal clearance of “acetylated SDZ” averaged more than six times that of unconjugated SDZ. With increased urine flow the renal clearances of TMP and SDZ were significantly increased.
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  • 74
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    Distribution, elimination and natriuretic effect of furosemide in patients with severe arterial hypertension (1978)
    Springer
    European journal of clinical pharmacology 14 (1978), S. 237-244 
    Details
    ISSN: 1432-1041
    Keywords: Furosemide ; arterial hypertension ; protein binding ; sodium excretion ; renal function ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Furosemide 40 mg was injected intravenously in 7 patients with severe hypertension and vascular complications. A two compartment, open model was used to describe the disappearance of the drug from serum. The mean serum clearance (Cls=1.83 ml/min · kg) was significantly reduced compared to the mean Cls-value of a group of normals (2.96 ml/min · kg). A significant correlation was found between Cls and mean blood pressure, as well as between Cls and renal clearance (mean Clr=0.83 ml/min · kg); extrapolation of the regression line yielded a Cls-value of 50 ml/min for Clr=0. The Clr was also significantly negatively correlated with mean blood pressure. Protein binding of furosemide was normal, except in one patient, who had considerable impairment of renal function. Apparently more than 90% of unchanged furosemide passed in urine was excreted by tubular transport. A highly significant negative correlation was found between Cls and the fraction of furosemide excreted as a glucuronide. During the first two hours, significantly less sodium was excreted by the patients than by a comparable group of normal subjects. The correlation between serum concentration of furosemide and the amount excreted of sodium was not significant, but highly significant correlations were found between the amounts of furosemide and sodium excreted by the kidney in 0–30 and 0–60 min. In all the individual patients an approximately linear relationship with wide variation in the slope was found between the cumulative excretion of furosemide and sodium from 0–30 min to 0–60 and to 0–120 min. After 120 min deviations were observed in the curves from 4 of the patients, which indicated that smaller and smaller additional amounts of sodium were excreted with constant additional amounts of furosemide.
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    Plasma timolol levels after oral and intravenous administration (1978)
    Springer
    European journal of clinical pharmacology 14 (1978), S. 431-434 
    Details
    ISSN: 1432-1041
    Keywords: Timolol ; pharmacokinetics ; oral and intravenous dosing
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The plasma kinetics of timolol administered orally and intravenously to 5 male subjects were examined. Bioavailability was reduced by 25% when the drug was taken orally. Mean plasma half-life after oral dosing was 4.86 h, and after intravenous administration it was 4.56 h; the difference was not significant. The volume of distribution was 3.5 l/k. It is suggested that timolol is little affected by the ‘first pass effect’, even though there is marked interindividual variation in availability and peak plasma level.
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    URL: http://dx.doi.org/10.1007/BF00716385
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  • 76
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    The disposition kinetics of diazepam in pregnant women at parturition (1978)
    Springer
    European journal of clinical pharmacology 13 (1978), S. 275-284 
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    ISSN: 1432-1041
    Keywords: Diazepam ; pharmacokinetics ; pregnant women ; plasma clearance ; blood/plasma concentration ratio ; placental transfer
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The disposition of diazepam has been studied in pregnant women at parturition. The plasma concentration of diazepam was monitored for at least 3 days in 18 women who received a single intravenous injection of 10 mg during the 10 h-period prior to delivery. Fourteen mothers had uneventful puerperia (Group I) and in 13 of these cases there was a pronounced postnatal increase in the plasma concentration of diazepam. The terminal phase half-life (t1/2) was significantly greater for Group I (mean = 65 h; range = 24–114 h) than for age-matched non-pregnant patients (mean = 29 h; range = 18–44 h from literature). The prolonged t1/2 appeared to be related to changes in the distribution of diazepam and not to a reduction in hepatic elimination since the total plasma clearance (Cltp) in these 14 pregnant patients (mean = 28 ml/min; range = 18–43 ml/min) was not reduced compared to that reported for non-pregnant controls (mean = 30 ml/min; range = 22–45 ml/min). Four mothers underwent postnatal surgery for tubal ligation (Group II) and the plasma concentration-time profiles for this group did not show the same postnatal phenomenon as did the profiles obtained for Group I. The t1/2 for Group II was shorter (mean = 31 h; range = 24–37 h) than for Group I and similar to that for the non-pregnant controls. The Cltp for Group II was greater (mean = 56 ml/min; range = 48–63 ml/min) than for both Group I and non-pregnant controls. These results suggest that delivery alters the disposition of diazepam and is generally associated with a postnatal re-distribution of diazepam into the systemic circulation. The blood/plasma concentration ratio was determined in 9 patients (mean = 0.62; range = 0.54–0.77). There was no difference in the total blood clearance between the pregnant patients of Group I and the non-pregnant controls. In most cases the umbilical venous plasma concentration (Cpuv) of diazepam was greater than the peripheral maternal venous plasma concentration (Cpmv) at delivery. The foetus appears to constitute a slowly equilibrating tissue-group in which diazepam does not reach equilibrium with the maternal systemic circulation for at least 5–10 h at which time the diazepam concentration in maternal and foetal plasma is similar.
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  • 77
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    Pharmacokinetics of ordinary and sustained-release lithium carbonate in manic patients after acute dosage (1978)
    Springer
    European journal of clinical pharmacology 14 (1978), S. 267-271 
    Details
    ISSN: 1432-1041
    Keywords: Lithium ; sustained-release ; pharmacokinetics ; manic patients
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary An ordinary and a sustained-release lithium carbonate preparation were administered acutely at equivalent dosage (1.80 g=24.3 mmol) in a crossover fashion to manic patients. Serum lithium levels were determined by atomic absorption spectroscopy and pharmacokinetic parameters were calculated. Maximum mean serum levels of 1.13 mmol/l and 0.78 mmol/l were achieved at 6 h and 12 h respectively with the ordinary and sustained-release forms. The mean half-lives of absorption, redistribution and elimination were 0.78 h±0.05 (SE), 5.06 h±0.23, 26.8 h±4.5 and 3.73 h±0.37 (SE), 4.42 h±0.28 and 25.6 h±5.5 for the ordinary and sustained-release forms respectively. In healthy volunteers the ordinary preparation was completely absorbed but only 85% of the sustained-release form was absorbed in the manic subjects. Lithium ion distributed into two kinetic compartments and the final compartment appeared to correspond to total body water.
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  • 78
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    Clinical pharmacology in normal volunteers of praziquantel, a new drug against schistosomes and cestodes (1978)
    Springer
    European journal of clinical pharmacology 14 (1978), S. 281-291 
    Details
    ISSN: 1432-1041
    Keywords: Phase I clinical trial ; complex protocol ; tolerance ; pharmacokinetics ; praziquantel ; anthelmintic
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The tolerance of Praziquantel (2-cyclohexylcarbonyl-1, 3, 4, 6, 7, 11b-hexahydro-2H-pyrazino-[2, 1-a]isoquinoline-4-one) in oral doses of 1×20 mg/kg, 1×50 mg/kg, 3×10 mg/kg and 3×25 mg/kg body weight (τ=4 h) was tested in a complex study involving 36 healthy volunteers. In addition to the usual assessment of clinical chemistry, haematology, coagulation physiology, urinalysis, clinico-physiological examination including EEG, and medical examination, clinico-psychological parameters were also recorded and special neurological investigations were performed. No clinically relevant changes were found in any of the laboratory parameters, nor in the medical-neurological or clinico-physiological examinations. Based on a few clinicopsychological parameters and subjective comments, the largest daily dose tested (3×25 mg/kg=75 mg/kg) produced a slight, transient disturbance in general well-being, which was barely detectable on objective clinical examination. The pharmacokinetic behaviour was dominated by rapid metabolism and pronounced first-pass metabolism of praziquantel, which greatly limits the value of results obtained by GC analysis of unchanged drug in serum. The peak concentration in serum was reached after 1– h, and the elimination half-life for the period 2–8 h was 1–1.5 h.
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    Pharmacokinetics of furosemide in gestosis of pregnancy (1978)
    Springer
    European journal of clinical pharmacology 14 (1978), S. 361-366 
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    ISSN: 1432-1041
    Keywords: Furosemide ; gestosis of pregnancy ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Furosemide 50 mg was administered orally and intravenously to twelve gestotic women for brief periods as a part of a randomized, multicentre clinical trial comparing the efficacy of bed rest and pharmacological treatment. The pharmacokinetic profile was investigated using a gas-liquid chromatographic technique. The plasma half-life after oral and intravenous administration was 115±37.1 and 71.8±26.3 min and plasma clearance was 153±48 and 152±23 ml/min, respectively (mean±SD). Comparative data from healthy pregnant women cannot be obtained for ethical reasons. The results show that gestosis has only a marginal if any effect on the kinetics of furosemide in comparison with published kinetic parameters in healthy volunteers and patients with renal failure. The new-born babies where checked for side effects according to a protocol in use in a larger regional surveillance programme. No clinical side-effects were attributable to furosemide, but the small size of the group does not permit any definitive conclusions about this aspect.
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    URL: http://dx.doi.org/10.1007/BF00611907
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  • 80
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    Modification of the pharmacokinetics of doxycycline in man by ferrous sulphate or charcoal (1978)
    Springer
    European journal of clinical pharmacology 14 (1978), S. 277-280 
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    ISSN: 1432-1041
    Keywords: Doxycycline ; iron ; charcoal ; enteral cycling ; man ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary In order to study the intestinal interactions of doxycycline (DC) with Fe++ and charcoal, two groups of healthy volunteers were given either 200 mg or 100 mg DC in capsules at 2 p. m. and 9 p. m., and blood samples for fluorimetric assay of DC were collected for 24 h starting at 8.30 a. m. on the following morning. A 24-h-urine was also collected. The test was subsequently repeated at one-week intervals, when the volunteers also ingested either ferrous sulphate (80 mg Fe++) or charcoal (4.0 g) immediately after the zero-time sample of DC and at 3, 8 and 12 h. Charcoal completely adsorbed DC in vitro in an artificial small intestinal fluid. Ferrous sulphate or charcoal did not modify the serum level or urinary excretion of DC after the 200 mg+200 mg dose, but ferrous sulphate did reduce the 24-h urinary excretion of DC after the 100 mg+100 mg dose. The serum half-life and AUC of DC were reduced by ferrous sulphate given after the 100 mg+100 mg dose of DC. Charcoal did not modify any parameter, even after the 100 mg+100 mg dose of DC. The results do not support existence of important enteral cycling of DC. Although oral ferrous sulphate can lower the serum level and shorten the serum half-life of DC, the acute experiment suggested that a therapeutic serum level of DC can be maintained despite treatment with iron in the doses used in iron-deficiency, and charcoal in the doses used in diarrhoeic states, if the drugs are administered several hours apart.
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    Paracetamol (acetaminophen) kinetics in patients with Gilbert's syndrome (1978)
    Springer
    European journal of clinical pharmacology 13 (1978), S. 209-212 
    Details
    ISSN: 1432-1041
    Keywords: Paracetamol ; acetaminophen ; Gilbert's syndrome ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The pharmacokinetics of paracetamol after intravenous and oral administration has been studied in 6 patients with Gilbert's syndrome, and 6 healthy controls. Paracetamol clearance was significantly less in the patients (255 ml/min SE±23 ml/min) than in the normal subjects (352 ml/min SE±40 ml/min). Moreover, whilst paracetamol concentrations declined monoexponentially in the patients, the decline was biexponential in the controls. No difference in the bioavailability of 500 mg paracetamol given orally was observed between the two groups. The results suggest that not only is paracetamol elimination impaired in Gilbert's syndrome, but that its distribution kinetics are also abnormal. Both these findings could be attributed to a decrease in hepatic glucuronyl transferase activity.
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    Preliminary data on the pharmacokinetics of Glaziovine in man (1978)
    Springer
    European journal of clinical pharmacology 13 (1978), S. 219-222 
    Details
    ISSN: 1432-1041
    Keywords: Glaziovine ; pharmacokinetics ; plasma levels ; urinary excretion ; biliary excretion ; enteral absorption
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The pharmacokinetic parameters of Glaziovine, a pro-aporphine alkaloid with neuropharmacological properties, were investigated in healthy human volunteers. Glaziovine-14C 20 mg was administered in capsules (oral route) and in vials (i.v. route). Total radioactivity was measured in plasma, urine and faeces. When administered orally, peak plasma levels were encountered at 2 h. The cumulative urinary excretion of total radioactivity over a 24 h period was 38% after oral and 50% after i.v. administration. Investigation of metabolites in urine revealed Glaziovine glucuronide as the sole metabolite of the drug. By comparing the percentage of urinary excretion or the area under the plasma level-time curve (AUC) obtained in the first 24 hours after i.v. and oral administration, enteral absorption was found to range from 78 to 84%. Thus, glaziovine appears to show very high enteral absorption.
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  • 83
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    Output of14CO2 in breath after oral administration of (14C-methyl) aminopyrine in hepatitis, cirrhosis and hepatic bilharziasis: Its relationship to aminopyrine pharmacokinetics (1978)
    Springer
    European journal of clinical pharmacology 13 (1978), S. 223-229 
    Details
    ISSN: 1432-1041
    Keywords: Aminopyrine ; pharmacokinetics ; 14CO2 breath test ; hepatic disease
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The time-course of aminopyrine in plasma and of14CO2 in breath was determined for 6 hours after oral administration of (14C-methyl) aminopyrine to healthy controls and to patients with hepatitis and hepatic fibrosis, cirrhosis and hepatic bilharziasis.14CO2 in breath declined about 1.8 times more slowly than aminopyrine plasma levels, which suggests the occurrence of metabolite demethylation. This was confirmed by the slow elimination of14C from plasma, the formation of14CO2 after aminopyrine had disappeared and the presence of a considerable amount of monomethyl-aminopyrine in plasma. The mean14CO2 concentration in breath was correlated with but was not proportional to aminopyrine clearance, which was attributed to individual differences in aminopyrine half-life. Both a correlation and proportionality were found when14CO2 extrapolated to zero time was used as a parameter of14CO2 production. Hepatic disease affected aminopyrine clearance to a variable extent. In the hepatitis and fibrosis group, aminopyrine clearance was affected in 2 out of five subjects. In all except one cirrhotic subject aminopyrine clearance was markedly decreased. Moreover, in three out of seven cases aminopyrine absorption was impaired, presumably due to decreased gastrointestinal blood-flow. This may produce an erroneously low14CO2 concentration in breath during the first two hours after aminopyrine administration. Hepatic bilharziasis was accompanied by very low aminopyrine clearance in all four cases. In two patients high apparent Vd values were observed, probably due to “first-pass” metabolism. Patients with ascites had Vd values within normal limits.
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    Pharmacokinetics of furosemide in anephric patients and in normal subjects (1978)
    Springer
    European journal of clinical pharmacology 13 (1978), S. 41-48 
    Details
    ISSN: 1432-1041
    Keywords: Furosemide ; pharmacokinetics ; anephric patients ; metabolism ; protein binding
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The pharmacokinetics of furosemide 40 mg i.v. were compared in 7 anephric patients and in 7 normal subjects. The average serum clearance was 66 ml/min in the patients and 219 ml/min in the normal subjects, and the corresponding weight corrected clearances were 1.33 ml/min · kg and 2.96 ml/min · kg. Binding to serum proteins was significantly decreased in the anephric subjects, in whom a significant negative correlation was found between the percentage binding and the volume of distribution VDss. In the patients, but not in the normal subjects, there was a significant positive correlation between $$V_{D_{ss} } $$ and serum clearance. Both in normal and anephric individuals 4-chlor-5-sulphamoylanthranilic-acid (CSA) was found, but there was no evidence of special accumulation either of CSA or anthranilic acid in the anephric patients. In the patients the initial increase in serum concentration of sodium and protein followed by a more conspicuous decrease were more pronounced, but none of the changes were statistically significant.
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    Disposition of valproic acid in patients with liver disease (1978)
    Springer
    European journal of clinical pharmacology 13 (1978), S. 55-60 
    Details
    ISSN: 1432-1041
    Keywords: Valproic acid ; pharmacokinetics ; liver disease
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The disposition of valproic acid (di-n-propylacetate; VA) has been studied after a single oral dose of a solution of 450 mg in 7 patients with alcoholic cirrhosis and in 4 patients recovering from acute hepatitis. The diagnosis was based on biochemical function tests and histological findings. The pharmacokinetic parameters were compared with those reported for healthy volunteers. VA in therapeutic concentration (80 µg/ml) in plasma was less bound to plasma proteins in patients with alcoholic cirrhosis (70.7±11.3%) and in patients recovering from acute hepatitis (78.1±14.1%) than in controls (88.7±5.2%). The reduced binding affected the blood/plasma concentration ratio and the apparent distribution volume Vd(β); the latter was increased from the normal value of 0.14±0.05 l/kg to 0.22±0.09 (p〈0.05) in alcoholic cirrhotics, and to 0.20±0.07 (p=0.056) in patients recovering from acute hepatitis. The half-life of elimination T1/2 (β) (controls=12.2±3.7 h) was significantly (p〈0.05) prolonged in cirrhotics (18.9±5.1 h) and in patients recovering from acute hepatitis (17.0±3.7 h). The plasma $$\overline {Cl} $$ of total drug was not impaired, which can best be explained by the lower plasma protein binding, which might have increased the $$\overline {Cl} $$ of this drug which shows restricted clearance. In addition, the plasma $$\overline {Cl} $$ of free drug was significantly (p〈0.02) reduced in alcoholic cirrhotics. During a two day urine collection no measurable amount of unchanged VA was recovered. There was considerable excretion of VA-conjugates, which could be hydrolyzed either by HCl or by β-glucuronidase/arylsulphatase (4–23% of the dose). These percentages were in the same range as in normals (26.7±16.1%). The study indicates that elimination of VA is slightly impaired in patients with dysfunction of the liver.
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    Pharmacokinetics and side-effects of clonidine (1978)
    Springer
    European journal of clinical pharmacology 13 (1978), S. 97-101 
    Details
    ISSN: 1432-1041
    Keywords: Clonidine ; plasma level ; pharmacokinetics ; steady state ; urinary excretion ; side-effects
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary A single oral dose of clonidine 300 µg was administered to 8 healthy, normotensive subjects and the time course of its plasma concentrations was followed for 24 h. The plasma concentration of clonidine rose to a peak of 1.17±0.12 ng/ml at about 2 h: the absorption half-life was 0.6±0.2 h. Elimination followed first order kinetics with a half-life of 7.7±2.0 h. The correlation between the two most common side-effects of clonidine, sedation and dryness of the mouth, with the time course of its plasma concentrations was highly significant, p〈0.01. All the subjects complained of severe sedation. During continuous administration of clonidine (75 µg t.i.d.) for one week a steady state serum level of 0.30–0.35 ng/ml was achieved. One 75 µg tablet of clonidine raised the serum level to about 0.69±0.13 ng/ml in two hours. After cessation of dosing, the serum level declined with a half-life of 7.5±1.5 h. The urinary excretion of unchanged clonidine was found to be about onethird of the administered dose in 24 h during continuous administration and in the first 24 h after the single oral dose.
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  • 87
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    Model for retrospective estimation of serum levels of phenylbutazone: Application to two cases of digestive tract hemorrhage (1978)
    Springer
    European journal of clinical pharmacology 13 (1978), S. 439-443 
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    ISSN: 1432-1041
    Keywords: Phenylbutazone ; pharmacokinetics ; model ; retrospective analysis ; digestive-tract hemorrhage
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Phenylbutazone treatment can cause digestive-tract hemorrhages, but its concentration in the blood at the time of hemorrhage is generally not known. In two patients who had had digestive tract hemorrhages, the variation in the serum phenylbutazone concentration throughout treatment and just before hemorrhage was simulated by a two-compartment model based on assays (gas-liquid chromatography) made after the hemorrhage. Identification of the parameters of the model and simulation of changes in concentration during therapy suggested that the phenylbutazone level in serum at the time of hemorrhage was 101 and 125 µg/ml respectively.
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  • 88
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    Pharmacokinetics of cephacetrile in patients with normal or impaired renal function (1978)
    Springer
    European journal of clinical pharmacology 13 (1978), S. 445-448 
    Details
    ISSN: 1432-1041
    Keywords: Cephacetrile ; pharmacokinetics ; renal Impairment
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The pharmacokinetics of cephacetrile, administered as a single i. v. injection of 15 mg/kg, have been determined in 8 patients with normal renal function and in 12 patients with a varying degree of renal impairment. A two-compartment model was used to describe the biphasic decline in serum concentrations and to calculate the amount of antibiotic in the central and peripheral compartments. In patients with normal renal function the following values were obtained for various pharmacokinetic parameters: α=3.971 h−1; β=0.343 h−1; K12=1.745 h−1; K21=0.763 h−1; Kel=1.793 h−1; Vc=8.181; Vp=18.401 and Vdss=26.581. Cephacetrile had some of the highest apparent distribution volumes of all the cephalosporins. Impaired renal function significantly affected α, β, K12, and Kel. A linear relationship between Kel of cephacetrile and creatinine clearance was demonstrated. The elimination of cephacetrile in anuric patients was about ten times slower than in patients with normal renal function.
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  • 89
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    Pharmacokinetic interpretation of the enterohepatic recirculation and first-pass elimination of morphine in the rat (1978)
    Springer
    Journal of pharmacokinetics and pharmacodynamics 6 (1978), S. 505-519 
    Details
    ISSN: 1573-8744
    Keywords: morphine ; first-pass elimination ; pharmacokinetics ; enterohepatic recirculation ; availability ; routes of administration
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract Morphine was administered to rats by oral, intraportal, and intravenous routes in a dose of 7.6 mg · kg −1.From the serum concentration data after intraportal administration it was calculated that the first-pass elimination of morphine in the liver amounts to 72±2% (sd). The first-pass fraction eliminated after oral administration was 85±7% (sd), thus yielding a contribution by the gut mucosa of 46% to the overall first-pass elimination after an oral dose. The results were obtained with a general compartmental model which included the kinetics of enterohepatic recirculation. The oral availability was also estimated with the aid of pharmacological effect data. This availability was in good agreement with the corresponding value determined from the serum concentration data. The results suggest that morphine is subjected to enterohepatic recirculation and that the slowest phase of decline of morphine concentrations in serum might be due to this physiological process.
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    URL: http://dx.doi.org/10.1007/BF01062106
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    Critical evaluation of the potential error in pharmacokinetic studies of using the linear trapezoidal rule method for the calculation of the area under the plasma level-time curve (1978)
    Springer
    Journal of pharmacokinetics and pharmacodynamics 6 (1978), S. 539-546 
    Details
    ISSN: 1573-8744
    Keywords: trapezoidal rule ; area under the curve ; pharmacokinetics ; clearance ; bioavailability ; integration method ; sulfisoxazole
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract The linear trapezoidal rule method is commonly used for the estimation of the area under the plasma level-time curve. Error analyses are performed when the method is used in first-order absorption and first-order elimination kinetics in the one-compartment system. It is found that significant underestimations and overestimations in area during the absorption phase and postabsorption phase, respectively, can occur when the method is improperly used. During the exponential postabsorption phase the relative error is only a function of the ratio (n)of the time interval over the half-life of the two plasma data points in the interval. The error from the linear trapezoidal rule method at n=0.5 is about 1%. The error increases to 15.5% and 57.1 % when nis increased to 2 and 4, respectively. It is recommended that for most absorption studies the linear trapezoidal method be used for prepeak and plateau plasma data and the logarithmic trapezoidal method for postpeak plasma data.
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    URL: http://dx.doi.org/10.1007/BF01062108
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  • 91
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    Statistical moments in pharmacokinetics (1978)
    Springer
    Journal of pharmacokinetics and pharmacodynamics 6 (1978), S. 547-558 
    Details
    ISSN: 1573-8744
    Keywords: statistical moments ; network theory ; pharmacokinetics ; bioavailability ; deconvolution ; plasma concentration-time curve ; urinary excretion rate-time curve ; compartment models
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract Statistical moments are parameters that describe the characteristics of the time courses of plasma concentration (area, mean residence time, and variance of residence time) and of the urinary excretion rate that follow administration of a single dose of a drug. The relationship between the moments of a time-course curve and pharmacokinetic profiles of drug disposition, i.e., absorption, distribution, metabolism, and excretion, is described. The moments are related to the extent and rate of bioavailability, and it is shown that they can be effectively applied to the deconvolution operation.
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    URL: http://dx.doi.org/10.1007/BF01062109
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  • 92
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    Mathematical prediction of drug distributionin vivo: Studies with doxantrazole in rats (1978)
    Springer
    Journal of pharmacokinetics and pharmacodynamics 6 (1978), S. 521-537 
    Details
    ISSN: 1573-8744
    Keywords: compartmental analysis ; doxantrazole ; drug distribution ; mathematical prediction ; pharmacokinetics ; rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract A pharmacokinetic model incorporating 14 compartments and 29 transfer coefficients has been developed from experimental data obtained after intravenous administration of a single dose to describe the distribution of doxantrazole in the rat. The distribution calculated from the model agreed closely with that determined experimentally. In addition, the model was able to predict with considerable accuracy the distribution of doxantrazole after repeated dosing.
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    URL: http://dx.doi.org/10.1007/BF01062107
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  • 93
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    Linear systems analysis in pharmacokinetics (1978)
    Springer
    Journal of pharmacokinetics and pharmacodynamics 6 (1978), S. 265-282 
    Details
    ISSN: 1573-8744
    Keywords: pharmacokinetics ; linear systems analysis ; in vivo dissolution rates ; absorption rates ; metabolic rates ; bioavailability ; numerical desconvolution
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract The application of certain aspects of linear systems analysis to pharmacokinetic-problems is described. Topics covered include the evaluation of in vivodissolution rates, absorption rates, and metabolic rates, and the use of pharmacological data. Relevant numerical procedures are also discussed.
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    URL: http://dx.doi.org/10.1007/BF01312266
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  • 94
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    Chlorpromazine metabolism. IX. Pharmacokinetics of chlorpromazine following oral administration in man (1978)
    Springer
    Journal of pharmacokinetics and pharmacodynamics 6 (1978), S. 187-196 
    Details
    ISSN: 1573-8744
    Keywords: Chlorpromazine ; pharmacokinetics ; oral absorption ; single dose
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract A single oral dose (120 mg/m2) of Chlorpromazine hydrochloride was administered to four healthy subjects and the blood levels of Chlorpromazine were determined with time. Appropriate equations describing the two-compartment open model with zero-order absorption and the two-compartment model with first-order absorption, both with a lag time, were fitted to the observed data using weighted nonlinear least-squares regression analysis. Fitting the two-compartment model with zero-order absorption and a lag time to the observed data resulted in a significant reduction of the weighted sum of squared deviations, i.e., better correlation between the observed and calculated data, and a closer random scatter of the observed concentration data around the calculated curve with no apparent systematic deviations from the curve. These results suggest that Chlorpromazine absorption is zero order. Chlorpromazine began to appear in the systemic circulation after a mean lag time of 0.4 hr and continued to be absorbed for approximately 2.9 hr. The mean half-lives of the distribution and elimination phases were 1.63 and 17.7 hr, respectively.
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    URL: http://dx.doi.org/10.1007/BF01312261
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  • 95
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    Absorption of oral tetracycline in patients with Billroth-II gastrectomy (1978)
    Springer
    Journal of pharmacokinetics and pharmacodynamics 6 (1978), S. 295-303 
    Details
    ISSN: 1573-8744
    Keywords: tetracycline ; antibiotics ; Billroth-II gastrectomy ; gastrectomy ; pharmacokinetics ; bioavailability
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract The bioavailability of a single 250-mg oral dose of tetracycline hydroghloride was studied in seven patients following Billroth-II gastrectomy in comparison with seven control subjects matched for age and body weight. There were no significant differences between control subjects and gastrectomized patients in the apparent lag time prior to the start of absorption (23.6 vs. 22.8 min), peak serum tetracycline concentration (1.72 vs. 1.75 μg/ml), the time of attainment of peak concentrations (3.35 vs. 3.42 hr), the apparent first-order absorption half-life (1.8 vs. 1.4hr), or the apparent first-order elimination half-life (8.0 vs. 8.7hr). Completeness of tetracycline absorption, as judged by area under the 24-hr serum concentration curve, did not differ significantly between the two groups, nor did 24-hr urinary excretion of tetracycline. Thus the abnormalities of gastrointestinal structure and function produced by Billroth -II gastrectomy do not result in impairment of the rate and completeness of tetracycline absorption.
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    URL: http://dx.doi.org/10.1007/BF01060093
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  • 96
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    Pharmacokinetic analysis of percutaneous absorption; evidence of parallel penetration pathways for methotrexate (1978)
    Springer
    Journal of pharmacokinetics and pharmacodynamics 6 (1978), S. 315-325 
    Details
    ISSN: 1573-8744
    Keywords: percutaneous penetration ; methotrexate ; compartmental models ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract Compartmental models were developed to describe the penetration of a drug from a topically applied vehicle through the skin. Data for in vitro penetration of methotrexate through hairless mouse skin from vehicles varying in PH from 3.5 to 6.5 were computer- fitted to estimate model parameters. Comparison of lag time and the exponential coefficient suggested that parallel penetration pathways exist. The fraction of drug penetrating through the shunt pathway increased as vehicle pH and ionization increased. Penetration curves were quantitatively partitioned into bulk tissue and shunt contributions. At pH 6.5, flux through the shunt pathway predominated.
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    URL: http://dx.doi.org/10.1007/BF01060095
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  • 97
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    Disposition kinetics in dogs of diethyldithiocarbamate, a metabolite of disulfiram (1978)
    Springer
    Journal of pharmacokinetics and pharmacodynamics 6 (1978), S. 369-387 
    Details
    ISSN: 1573-8744
    Keywords: pharmacokinetics ; dog ; diethyldithiocarbamate metabolite of disulfiram ; presence of methyl ester ; kinetic evaluation of prior studies
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract Following the intravenous infusion of sodium diethyldithiocarbamate to dogs, the disposition kinetics of diethyldithiocarbamate (DDC), a metabolite of disulfiram, were assessed. Approximately 27% of the administered dose was S-methylated, this process exhibiting a mean first-order rate constant of 0. 0569 min−1 (t1/2=12.2 min), while the remainder was eliminated by other routes having a rate constant of 0.148 min−1 (t1/2=4.68 min). The methyl diethyldithiocarbamate (MeDDC) formed from DDC showed an elimination rate constant of 0.0141 min−1 (t1/2=49.2 min). These observations are discussed in the light of previous investigations where the presence of MeDDC has rarely been sought or reported. A few comparisons with prior studies, in which DDC or disulfiram was administered, are made by retrospective kinetic evaluation of published data. The results are discussed in relation to the duration of action of disulfiram in man.
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    URL: http://dx.doi.org/10.1007/BF01062720
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  • 98
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    Distribution and elimination of digoxin in infants (1977)
    Springer
    European journal of clinical pharmacology 11 (1977), S. 329-335 
    Details
    ISSN: 1432-1041
    Keywords: Digoxin ; pharmacokinetics ; two-compartment model ; radioimmunoassay ; neonates ; infants
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The distribution and elimination of intravenous digoxin were investigated in seven neonates and infants with heart failure. Serum digoxin concentrations during a 24 h period were determined by radioimmunoassay, using125I as tracer. The serum values declined biexponentially after the injection and could be fitted to a two-compartment open model by non-linear least-squares regression. The calculated mean half-lives of the distribution (alpha) phase in neonates and infants were 37 and 28 min, respectively. The mean half-life of the elimination (beta) phase in neonates was 44 h, as compared to 19 h in infants. The mean volume of the central compartment and the mean volume of distribution at steady-state were calculated to be 1.3 and 9.9 l/kg, respectively; no significant differences between neonates and infants were found. The relation between these volumes indicates that digoxin is extensively distributed in tissues. The steady-state distribution volumes of digoxin in neonates and infants exceed those reported in adults. The larger volume of distribution might explain in part why infants with cardiac insufficiency require larger doses of digoxin than adults (on a mg/kg body weight basis) to obtain the same serum concentrations. Elimination of digoxin from the body was slower in neonates than in infants.
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    URL: http://dx.doi.org/10.1007/BF00566529
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  • 99
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    Individual variation in the response to phenprocoumon (1977)
    Springer
    European journal of clinical pharmacology 11 (1977), S. 351-358 
    Details
    ISSN: 1432-1041
    Keywords: Phenprocoumon ; protein binding ; pharmacokinetics ; pharmacodynamics ; drug therapy ; myocardial infarction ; chronic disease
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary In nine patients, the synthesis rate Rsyn of the vitamin K-dependent clotting factors was calculated from changes in prothrombin-complex activity after intravenous administration of a synthesis-blocking dose of phenprocoumon (PPC). The biological half-life of PPC was between 2.70 and 7.01 days. No correlation was found between the level of the free fraction of this strongly protein-bound drug and its biological half-life. There was a positive correlation (p〈0.01) between the size of the free fraction of PPC and the apparent volume of distribution of the drug. Four of the patients had had an acute myocardial infarction and they showed increased sensitivity to PPC. In them the plasma level of PPC sufficient to reduce Rsyn to 50% of R°syn was significantly lower, and the depression of individual vitamin K-dependent coagulation factors was more pronounced and prolonged, than in five other patients with chronic disease. The degradation rate of coagulation factors was also found to be higher in the patients with acute myocardial infarction. In four patients with chronic disease, anticoagulant therapy with PPC was continued in the out-patient clinic. The calculated oral maintenance dose of PPC, assuming complete absorption, first-order elimination kinetics and a linear relationship between the pharmacological effect and the logarithm of the PPC-plasma concentration, showed good agreement with the dose actually found to produce the desired PP% level.
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    URL: http://dx.doi.org/10.1007/BF00566532
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  • 100
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    Biotransformation and pharmacokinetics of acenocoumarol (Sintrom®) in man (1977)
    Springer
    European journal of clinical pharmacology 11 (1977), S. 367-375 
    Details
    ISSN: 1432-1041
    Keywords: Acenocoumarol ; excretory balance man ; pharmacokinetics ; biotransformation ; plasma protein binding
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The absorption, biotransformation and elimination of the anticoagulant acenocoumarol, 3-[α- (4′-nitrophenyl)-β-acetylethyl]-4-hydroxycoumarin, have been studied by oral administration of 12 mg of a14C-labelled preparation to two male volunteers. Absorption from the gastro-intestinal tract was rapid and the plasma concentration of unchanged drug reached a maximum of 169 and 412 ng/ml, respectively, after 3 hours. The elimination half-life in the two subjects, calculated from the decline between 6 and 24 h, was 8.7 and 8.2 hours. A constant proportion of 98.7% of the drug was bound in vitro to serum proteins over a concentration range of 0.021–8.34 µg/ml, with little interindividual variation. The major portion of the binding was to human serum albumin (97.5%) at two classes of binding sites: association constant K1=1.04×105 l/mole (n1=1) and K2=5.55×103 l/mole (n2=4). In addition to unchanged acenocoumarol, four metabolites were determined in plasma by isotope dilution techniques: the amino-, acetamido-, alcohol1- and alcohol2-metabolites. Of them, the amino-metabolite showed the highest concentration, namely 278 ng/ml, after 6 h in Subject A, and 163 ng/ml after 10 hours in Subject B. Judged from the integrated concentrations, the compounds analyzed accounted for 76 and 89%, respectively, of the total radioactivity in plasma. All the metabolites detected in plasma showed anticoagulant activity when tested in mice. The quantities of the metabolites excreted in urine from 0–120 hours were (Subject A/Subject B): acenocoumarol 0.3/0.2%, amino-metabolite 12.3/7.7%, acetamido-metabolite 19.0/11.1%, alcohol1-metabolite 4.6/9.0%, alcohol2-metabolite 1.7/4.4%, 6-hydroxy-metabolite 6.9/18.3% and 7-hydroxy-metabolite 14.0/22.2%.
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    URL: http://dx.doi.org/10.1007/BF00566534
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