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  • Articles  (55)
  • protein binding  (55)
  • Springer  (55)
  • American Association for the Advancement of Science
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  • Springer  (55)
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  • 1
    Electronic Resource
    Electronic Resource
    Binding of aprindine and moxaprindine to human serum, α1-acid glycoprotein and serum of healthy and diseased humans (1982)
    Springer
    European journal of clinical pharmacology 21 (1982), S. 427-431 
    Details
    ISSN: 1432-1041
    Keywords: aprindine ; moxaprindine ; cirrhosis ; rheumatoid arthritis ; uraemia ; protein binding ; serum protein ; alpha1-acid glycoprotein
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary A comparison was made between the binding of the anti-arrhythmic agents aprindine and moxaprindine to human serum, to human serum albumin (HSA), to α1-acid glycoprotein (α1-AGP) and to a mixture of HSA and α1-AGP. In serum from healthy volunteers (n=4) the binding of aprindine-HCl 5 µg/ml (13.8 µM) was 93.8% (SD±1.0), and that of moxaprindine-HCl 5 µg/ml (12.8 µM) was 94.1% (SD±1.1). Their binding to the mixture of α1-AGP and albumin approximated their binding to serum. For α1-AGP, the binding was similar for both compounds, whereas for HSA the binding of aprindine was more pronounced than that of moxaprindine: for both products the affinity coefficient for binding to α1-AGP was about 100 times greater than that for binding to albumin. In serum from rheumatoid patients and from patients with renal failure a small but significant increase in binding of aprindine and moxaprindine was observed, approximately 1%. Increased and decreased binding was seen in serum from cirrhotic patients; for example, for aprindine the range in cirrhosis was 96.7%–79.8%, and the range in controls was 95.0%–92.4%. Free drug fraction and α1-AGP concentration were inversely correlated. The results show that α1-AGP plays an important role in the binding of aprindine and moxaprindine, and that alteration in the binding of the two compounds in disease states to a large extent can be explained by changes in serum α1-AGP concentration.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00542331
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  • 2
    Electronic Resource
    Electronic Resource
    The protein binding of vinblastine in the serum of normal subjects and patients with Hodgkin's disease (1983)
    Springer
    European journal of clinical pharmacology 24 (1983), S. 683-687 
    Details
    ISSN: 1432-1041
    Keywords: vinblastine ; protein binding ; Hodgkin's disease
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The protein binding of vinblastine was measured in the serum from 6 normal subjects and 9 patients with Hodgkin's disease. Cellulose acetate electrophoresis showed that the predominant binding protein fractions were the α1- and α2-globulins with little binding to albumin and β- and γ-globulins. At a serum concentration of 10 nM a significantly lower percentage bound was found in the patient group (p=0.001). Binding to both groups was very high at 99.7% bound in the normal subjects and 98.9% bound in the patient group. Binding in both groups was best described by a two class protein binding model with higher and lower affinity binding sites. No significant difference was found on inter-group comparisons of binding parameter values.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00542223
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  • 3
    Electronic Resource
    Electronic Resource
    Nonlinear plasma protein binding and haemodialysis clearance of prednisolone (1982)
    Springer
    European journal of clinical pharmacology 23 (1982), S. 65-74 
    Details
    ISSN: 1432-1041
    Keywords: haemodialysis ; protein binding ; prednisolone ; clearance ; renal transplant ; free clearance ; dialysate loss
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The impact of nonlinear plasma protein binding of a drug on its removal by haemodialysis has been quantified. Prednisolone 10–100 mg was given i.v. to 10 renal transplant patients on haemodialysis for acute tubular necrosis. Dialysate and afferent and efferent blood samples were collected simultaneously in 67 instances. Total and unbound prednisolone in plasma and its total concentration in blood and dialysate were assessed by high performance liquid chromatography and equilibrium dialysis. The amount of prednisolone lost, as measured directly in the dialysate (21.8±4.4 µg/min, $${{\bar x}}$$ ± SE), was predictable from the afferent-efferent blood concentration differences (20.1±4.8 µg/min), but not from measurements of total afferent-efferent prednisolone concentrations in plasma (13.1±3.0 µg/min). The amount of prednisolone lost in the dialysate increased linearly with unbound (r 2=0.96) and hyperbolically with the total prednisolone concentration in plasma. The latter hyperbolic relationship is adequately described by the equation for nonlinear plasma protein binding, using the affinity and capacity constants of albumin and transcortin for prednisolone (r 2=0.98). Thus, the haemodialysis clearance of total prednisolone is concentration-dependent, while the clearance of unbound prednisolone is constant (76 ml/min). Free clearance values or measurements of afferent-efferent blood concentrations are mandatory for a drug showing nonlinear plasma protein binding in order to predict the amount lost in the dialysate.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF01061379
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  • 4
    Electronic Resource
    Electronic Resource
    Pharmacokinetics of chlormethiazole in healthy volunteers and patients with cirrhosis of the liver (1980)
    Springer
    European journal of clinical pharmacology 17 (1980), S. 275-284 
    Details
    ISSN: 1432-1041
    Keywords: chlormethiazole ; cirrhosis of the liver ; antipyrine ; protein binding ; pharmacokinetics ; healthy volunteers
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The pharmacokinetics of chlormethiazole after oral and intravenous administration was studied in six healthy volunteers and eight patients with alcoholic cirrhosis of the liver. Plasma concentration-time curve after the intravenous infusion could adequately be described by two- or three-compartment open models both in healthy volunteers and in the patients. Based on the areas under the plasma concentration-time curves, the systemic bioavailability of oral chlormethiazole was about ten times greater in the patients than in healthy controls. The elimination of chlormethiazole was relatively less retarded in the patients, as indicated by a decrease of about 30% in its plasma clearance. In the patients the plasma protein binding of chlormethiazole was decreased, but the volume of distribution and half-life of elimination were unchanged. The increase in bioavailability of chlormethiazole was associated with significant alteration in the serum levels of bilirubin, albumin, alkaline phosphatase, prothrombin-proconvertin activity (P + P) and elimination rate of antipyrine or14C-aminopyrine. The increased bioavailability of oral chlormethiazole was due to impaired first-pass metabolism in the cirrhotic liver. A considerable reduction in dose seems to be indicated if oral chlormethiazole is used in patients with advanced cirrhosis of the liver. A substantial fraction of dose, averaging 15%, was lost during the intravenous infusion, presumably due to adsorption to the infusion tubing.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00625801
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  • 5
    Electronic Resource
    Electronic Resource
    Pharmacokinetics of naproxen in subjects with normal and impaired renal function (1980)
    Springer
    European journal of clinical pharmacology 18 (1980), S. 263-268 
    Details
    ISSN: 1432-1041
    Keywords: naproxen ; renal insufficiency ; metabolism ; protein binding ; single dose ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The pharmacokinetics of naproxen after a single oral dose of 250 mg has been studied in 8 subjects with normal renal function and 16 patients with varying degrees of chronic renal insufficiency. Unchanged naproxen and its main unconjugated metabolite, 6-0-desmethylnaproxen, were determined fluorometrically in serum. In healthy subjects the elimination half-life of naproxen was 17.7± 3.0 h (mean±SD) and it was not significantly prolonged in patients with renal failure (18.1±5.3) h. No accumulation of naproxen in serum occurred in uraemic patients. On the contrary, serum drug levels were slightly but significantly lower in patients with severe renal failure. The total body clearance and apparent volume of distribution of naproxen were significantly increased in this group of patients. Decreased binding of naproxen to serum proteins was observed in patients with renal failure. The apparent half-life of desmethylnaproxen was of the same order of magnitude as that of naproxen (18.6± 4.4 h), and was also independent of renal function. A good correlation was found between the area under the curve (AUC), the peak concentration of the metabolite and the serum creatinine concentration. These observations suggest increased metabolism and an increased apparent volume of distribution of naproxen in severe renal failure, probably caused by decreased serum protein binding of the drug. However, it is proposed that in naproxen therapy no adjustment of the dosage regimen is necessary in patients with impaired renal function.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00563009
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  • 6
    Electronic Resource
    Electronic Resource
    Comparison of the serum protein binding of maprotiline and phenytoin in uraemic patients on haemodialysis (1981)
    Springer
    European journal of clinical pharmacology 19 (1981), S. 73-77 
    Details
    ISSN: 1432-1041
    Keywords: maprotiline ; phenytoin ; uraemia ; protein binding ; alpha1-acid glycoprotein ; haemodialysis
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The serum protein binding of maprotiline and phenytoin has been compared in a group of 22 uraemic patients receiving haemodialysis. Determination of protein binding was carried out in vitro using equilibrium dialysis at 37°C and14C-labelled drug. The mean percentage unbound maprotiline found in patients (10.0%, SD 2.5) was not significantly different from that obtained in healthy volunteers (mean 10.5%, SD 1.0). However, there was a significantly increased variability in binding in patients compared with healthy subjects. The mean percentage unbound phenytoin in the same patients (22.2%, SD 3.3) was significantly greater than that obtained in healthy control subjects (12.5%, SD 0.6). Although there was no correlation between maprotiline and phenytoin binding and serum concentrations of α1-acid glycoprotein, there was a significant correlation between percentage unbound maprotiline and serum albumin concentrations. The findings indicate that the binding of this tricyclic antidepressant is essentially normal in uraemia, although there may be increased interindividual variability in the free fraction of drug.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00558388
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  • 7
    Electronic Resource
    Electronic Resource
    Pharmacokinetics of intravenous and oral tolmesoxide (1981)
    Springer
    European journal of clinical pharmacology 19 (1981), S. 119-125 
    Details
    ISSN: 1432-1041
    Keywords: tolmesoxide ; metabolite ; volunteers ; pharmacokinetics ; intravenous ; oral ; protein binding
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary A high pressure liquid chromatographic assay was developed for simultaneous measurement of the plasma levels of tolmesoxide and its principal metabolite, RX71112. The assay was used to study the disposition of intravenous and oral tolmesoxide in ten normotensive subjects. Two exponential terms were required to describe the disposition of the drug following intravenous administration, whilst a single exponential term sufficied to account for the decay in the plasma concentration after oral administration. The bioavailability of oral tolmesoxide from capsules averaged 84.5% and was independent of dose. The mean half-life after i. v. dosing was 2.6 h (±0.3 SEM) compared to values of 1.9 h (±0.1 SEM) and 2.7 h (±0.5 SEM) following 200 and 400 mg oral doses respectively. In all subjects RX71112 appeared in plasma shortly after tolmesoxide following both routes of administration. The terminal half-life of the metabolite was significantly longer than tolmesoxide with a mean value of 4.9 h (±0.9 SEM) following the 200 mg oral dose of tolmesoxide. The binding of tolmesoxide and RX71112 at therapeutic plasma concentration was 36.8% (±0.5 SEM) and 58.5% (±0.3 SEM) and this remained unchanged at higher concentrations.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00568398
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  • 8
    Electronic Resource
    Electronic Resource
    Intravenous quinidine in congestive cardiomyopathy (1981)
    Springer
    European journal of clinical pharmacology 19 (1981), S. 173-176 
    Details
    ISSN: 1432-1041
    Keywords: cardiomyopathy ; quinidine ; left ventricular performance ; protein binding
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Eight male patients with compensated congestive cardiomyopathy received single 300-mg doses of intravenous quinidine by 15-min infusion. Left ventricular (LV) performance was evaluated by echocardiography at multiple points in time during the next 24 h. Quinidine kinetics and protein binding were determined from multiple serum samples drawn for up to 36 h after dosage. LV function was not impaired. Instead, quinidine transiently increased ejection fraction (mean: +39%) and rate of circumferential shortening (mean: +46%). Endsystolic and end-diastolic LV internal diameter likewise were decreased (means: −13% and −7%). Blood pressure and ventricular rate were not significantly altered. Compared to 8 healthy controls matched for age, sex, and weight, quinidine volume of distribution among patients was smaller (means: 2.27 vs 1.90 l/kg), as was total quinidine clearance (3.49 vs 2.84 ml/min/kg); however, differences were not statistically significant. Well-controlled, slow intravenous infusion of quinidine does not impair LV performance and is safe for patients with compensated congestive cardiomyopathy. However, such patients may have reduced quinidine clearance and hence require lower doses than expected based on age and weight.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00561944
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  • 9
    Electronic Resource
    Electronic Resource
    Effect of probenecid on excretion and natriuretic action of furosemide (1980)
    Springer
    European journal of clinical pharmacology 18 (1980), S. 489-495 
    Details
    ISSN: 1432-1041
    Keywords: furosemide ; probenecid ; protein binding ; natriuretic ; interaction ; diuretic effect
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Furosemide and inulin were given simultaneously by intravenous infusion to nine subjects over 2 h. The concentrations of sodium and of the two drugs in serum (free and protein bound) and in urine were followed during the infusion. In 6 male subjects the investigation was repeated after 3 days of oral treatment with probenecid 500 mg twice daily. Probenecid reduced the average ratio furosemide clearance/inulin clearance from 0.92 to 0.44. In experiments in which no probenecid had been given an average of 2% of the furosemide in urine was excreted by glomerular filtration. In vitro studies showed that the protein binding of furosemide was decreased in the presence of probenecid. The displacing effect of probenecid was confirmed in vivo, and during probenecid treatment glomerular filtration produced an average of 8% of the furosemide excreted by the kidney. The fraction of furosemide excreted by tubular secretion decreased during probenecid treatment from 98.0±0.6% to 91.7±5.6% (p〈0.05). Prior to administration of probenecid, the fraction of the filtered sodium recovered from the urine during furosemide administration was 24.7%. Probenecid reduced that fraction to 21.0% (p〈0.05). The excretion rate of furosemide appeared to be a better predictor of the natriuretic effect than its plasma concentration. Probenecid caused a significant change (p〈0.05) in the regression line relating the log plasma concentration to the natriuretic effect, but it had no effect on the regression line relating the log urinary excretion rate of furosemide to its natriuretic effect. Although the decrease in the furosemide excretion rate during probenecid treatment averaged 25%, the sodium excretion rate was reduced by less than 15%. It is suggested that the natriuretic effect of furosemide is more pronounced if the furosemide molecules enter the tubular lumen at a more proximal level, and it is strongest if they do so by filtration through the glomerulus.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00874661
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  • 10
    Electronic Resource
    Electronic Resource
    The influence of blood collection technique on serum and plasma protein binding of disopyramide (1982)
    Springer
    European journal of clinical pharmacology 22 (1982), S. 185-189 
    Details
    ISSN: 1432-1041
    Keywords: disopyramide ; protein binding ; vacutainer® ; alpha-1-acid-glycoprotein
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Serum and plasma disopyramide (D) protein binding was compared after blood was collected from four normal subjects in various Vacutainer® tubes. The fraction of disopyramide bound to proteins in control serum and plasma was drug concentration dependent and correlated well with the capacity factor (N) associated with a high affinity protein binding site. D free fraction increased 60% at a post-equilibrium concentration of 2 µg/ml in plasma following exposure of blood to green-top Vacutainer® stoppers due to a 60% reduction in the affinity constant associated with the high affinity protein binding site. Heparin and EDTA had no effect on the plasma protein binding of D. These results suggest a competitive inhibition of disopyramide binding to α1-acid-glycoprotein following contact of blood with rubber Vacutainer® stoppers.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00542466
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  • 11
    Electronic Resource
    Electronic Resource
    Plasma protein binding of etidocaine during pregnancy and labour (1982)
    Springer
    European journal of clinical pharmacology 22 (1982), S. 451-457 
    Details
    ISSN: 1432-1041
    Keywords: etidocaine ; protein binding ; pregnancy ; alpha1-acid glycoprotein ; labour ; free fatty acids
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Preliminary studies of the ultrafiltration method for measuring the extent of plasma protein binding of etidocaine showed that etidocaine binding was both pH and concentration dependent. Etidocaine (1 µg/ml) was found to bind avidly to a physiological concentration (74 mg/dl) of α1-acid glycoprotein (α1-AGP) (7.23±0.64%, mean ± SD, unbound). In vitro investigation of etidocaine binding in plasma obtained from blood bank donors and from 19 pregnant women prior to induction of labour, during early labour, mid-labour and delivery showed no difference in etidocaine binding (10.3±3.3%, 7.06±2.66%, 8.15±2.57%, 7.84±3.74% and 9.28±6.06% unbound respectively). There was a significant increase in the mean plasma total free fatty acid (FFA) concentration from pre-labour (0.535±0.240 mM) to delivery (0.948±0.28 mM), while plasma albumin and β-lipoprotein concentrations remained constant. α1-Acid glycoprotein concentration tended to increase slightly from pre-labour to early labour (p〈0.1) but was still within the normal physiological range. There was no correlation between etidocaine binding ratio and the concentrations of FFA or plasma proteins except for a poor correlation with the α1-AGP concentration (r=0.361, p〈0.05). Storage of plasma and inadequate control of plasma pH during ultrafiltration appeared to give spurious binding values. These studies with the extensively bound basic drug etidocaine suggest that unlike many acidic drugs which are bound predominantly to serum albumin, the binding of α1-AGP — bound basic drugs may be unaffected by pregnancy and labour.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00542552
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  • 12
    Electronic Resource
    Electronic Resource
    The effect of sulphinpyrazone on oxidative drug metabolism in man: Inhibition of tolbutamide elimination (1982)
    Springer
    European journal of clinical pharmacology 22 (1982), S. 321-326 
    Details
    ISSN: 1432-1041
    Keywords: sulphinpyrazone ; tolbutamide ; drug metabolism ; drug interaction ; protein binding ; elimination of tolbutamide
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The effect of sulphinpyrazone on tolbutamide elimination was investigated in 6 healthy male volunteers. Co-administration of sulphinpyrazone (200 mg, 6 hourly) reduced mean plasma tolbutamide clearance by 40% and prolonged mean tolbutamide half-life by 80%. Twenty four hours after the cessation of a one week period of chronic sulphinpyrazone therapy tolbutamide plasma clearance (30% reduction) and half-life (19% prolongation) were still significantly different to control values, even though sulphinpyrazone could not be detected in the plasma of any of the subjects at this time. In vitro studies of the plasma protein binding of tolbutamide demonstrated concentration dependent binding but displacement of tolbutamide by sulphinpyrazone in vitro only became apparent at high concentrations of added sulphinpyrazone. Although the concentration dependence of tolbutamide protein binding demonstrated in vitro was also observed in the subject plasma samples, the magnitude of this effect was small. It is concluded that sulphinpyrazone and its metabolite(s) decrease the plasma clearance of tolbutamide by inhibition of oxidative metabolism.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00548400
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  • 13
    Electronic Resource
    Electronic Resource
    Doxorubicin and 5-fluorouracil plasma concentrations and detectability in parotid saliva (1983)
    Springer
    European journal of clinical pharmacology 24 (1983), S. 261-266 
    Details
    ISSN: 1432-1041
    Keywords: doxorubicin ; 5-fluorouracil ; pharmacokinetics ; parotid saliva ; plasma concentration ; protein binding
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Doxorubicin and 5-fluorouracil pharmacokinetics were studied in 19 volunteers with various advanced neoplastic diseases who received 50–90 mg doxorubicin or 600–1000 mg 5-fluorouracil intravenously, followed by plasma and parotid saliva collection over a 75 min period. The extent to which these chemotherapeutic agents are bound to plasma proteins, at concentrations chosen to approximate plasma concentrations, was measured by equilibrium dialysis. Both agents were quantitated by high-performance liquid chromatography. As reported previously, a wide range of plasma levels were found among patients receiving similar doses of either doxorubicin or 5-fluorouracil. It appears that in addition to being quickly cleared from the plasma both chemotherapeutic agents are excreted in detectable amounts in parotid saliva, a route of elimination heretofore given little or no attention. Excretion in the saliva exposes the mucosa of the upper gastrointestinal tract to 5-fluorouracil after intravenous administration and may play a part in causing stomatitis in patients receiving it by this route. Since there are huge interindividual and pronounced intraindividual differences in S/P ratios mostly not systematically related to the drugs' concentration in plasma, the concentration in parotid saliva was not useful in predicting the level of free doxorubicin or 5-fluorouracil in plasma.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00613829
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  • 14
    Electronic Resource
    Electronic Resource
    Bromocriptine concentration in saliva and plasma after long-term treatment of patients with Parkinson's disease (1980)
    Springer
    European journal of clinical pharmacology 18 (1980), S. 171-174 
    Details
    ISSN: 1432-1041
    Keywords: bromocriptine ; Parkinson's disease ; plasma level ; salivary level ; protein binding ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Salivary and plasma concentrations of bromocriptine (BCT), a dopamine agonist, were measured by gas chromatography in four patients with Parkinson's disease. All the patients had been on mono-therapy with BCT for years, and during the 3 weeks prior to the investigation they received constant but individually different dosage regimens. Paired samples of pure, parotid, serous saliva and of blood were collected hourly during one eight hour dose interval. The concentrations of BCT in saliva were very low and there was a ten-fold range in the areas under the salivary and plasma concentration/time curves. It is concluded that in clinical practice measurement of BCT in saliva is not suitable for exact estimation of the plasma concentration of BCT. Using the measured salivary pH and the plasma BCT concentration, calculations based on the Henderson-Hasselbalch equation showed that the assumption of about 99% plasma protein binding of BCT best fited the observed concentrations of BCT in saliva.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00561586
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  • 15
    Electronic Resource
    Electronic Resource
    Protein binding of piretanide in normal and uraemic serum (1982)
    Springer
    European journal of clinical pharmacology 21 (1982), S. 311-313 
    Details
    ISSN: 1432-1041
    Keywords: piretanide ; uraemia ; protein binding
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The protein binding of piretanide was assessed by continuous ultrafiltration of sera from six normal subjects and seven uraemic subjects (samples taken immediately pre-dialysis). Throughout the range of piretanide concentrations studied (0.5–4.5 mM), the mean protein binding for uraemic serum was less than that for normal serum. This difference was significant (p〈0.05) at piretanide concentrations of 1.5 mM and above, but not at 1 mM where mean protein binding for uraemic serum was 88.1% compared to 94.2% for normal serum. Analysis of piretanide protein binding characteristics using the Rosenthal plot showed no significant differences between uraemic and normal serum with respect to primary or secondary binding sites. Parallel assessment by the Scatchard method suggests, as expected, that albumin is the principal protein moiety responsible for binding piretanide.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00637619
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  • 16
    Electronic Resource
    Electronic Resource
    Pharmacokinetics of ceftriaxone following intravenous administration of a 3 g dose (1982)
    Springer
    European journal of clinical pharmacology 22 (1982), S. 71-75 
    Details
    ISSN: 1432-1041
    Keywords: cephalosporin ; ceftriaxone ; protein binding ; non-linear pharmacokinetics ; intravenous injection ; plasma levels
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The pharmacokinetic parameters of total (bound and unbound) and free (unbound) ceftriaxone in six healthy volunteers after intravenous injection of 39 were compared with low-dose data from a previous study. The dose-dependent behaviour of total drug was considerably more pronounced after the 3 gram dose. In contrast, total body clearance (Cl S F =258 ml/min), renal clearance (Cl R F =170 ml/min) and volume of distribution (V D(β) F =168 l) of free (unbound) drug did not differ from the data reported earlier. There was no significant change in biological half-life (t1/2(β)=7.8 h) or in the fraction excreted unchanged in urine (fu=0.67).
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00606428
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  • 17
    Electronic Resource
    Electronic Resource
    Human pharmacokinetics of long term 5-hydroxytryptophan combined with decarboxylase inhibitors (1982)
    Springer
    European journal of clinical pharmacology 23 (1982), S. 81-86 
    Details
    ISSN: 1432-1041
    Keywords: benserazide ; carbidopa ; serotonin ; 5HTP-treatment ; metabolism ; decarboxylase inhibitors ; cerebrospinal fluid metabolites ; protein binding
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary L-5-Hydroxytryptophan (5HTP) and its major metabolites 5-hydroxytryptamine (5HT) and 5-hydroxyindoleaceticacid (5HIAA) were measured in blood and cerebrospinal fluid from neurological patients receiving steady state treatment with 5HTP. There was accumulation of 5HT in blood platelets and 5HIAA in plasma in all patients, despite concomitant administration of the L-aromatic amino acid decarboxylase inhibitors, carbidopa and benserazide. There was no correlation between the 5HTP dose and the circulating concentrations of the amino acid or its metabolites. Preliminary comparison of the biochemical and therapeutic effects of carbidopa versus benserazide suggest that 5HTP: carbidopa is superior to 5HTP: benserazide. A direct proportionality between plasma 5HTP concentrations and the levels of 5HTP in the lumbar cerebrospinal fluid was found. The binding to serum proteins of 5HTP in the clinically relevant concentration range of 10 to 100 µM was investigated; 19% of circulating 5HTP was bound to serum proteins. 5HTP did not displace protein-bound tryptophan in serum.
    Type of Medium: Electronic Resource
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  • 18
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    Antihypertensive effect of diazoxide given intravenously in small repeated doses (1983)
    Springer
    European journal of clinical pharmacology 24 (1983), S. 151-156 
    Details
    ISSN: 1432-1041
    Keywords: hypertensive crisis ; diazoxide ; protein binding ; dose response ; diazoxide assay ; plasma half-life ; individual variation
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Seven patients with acutely elevated diastolic blood pressure (DBP≧135 mmHg) were treated with repeated injections of diazoxide 1 mg/kg body weight i. v. at 10-min intervals. If the DBP was not reduced to 110 mmHg or less after 5 injections, a dose of 5 mg/kg was given. Serum diazoxide (total and unbound) was determined by high pressure liquid chromatography. In all the patients it was possible to reduce the blood pressure to a satisfactory level (i.e. DBP〈110 mmHg). The individual plasma diazoxide concentrations necessary to achieve the desired response ranged from 20 to 85 µg/ml. A significant correlation was found between the initial venous concentration and the initial reduction in blood pressure (p〈0.02). A high initial concentration in venous blood was associated with high protein binding (“transport function”,p〈0.05), and so were the elimination half-lives, which ranged from 14.7 to 61.3 h (“depot function”,p〈0.05). It is concluded that the previously recommended therapy of injection of 5 mg/kg as a bolus should be given only to patients who do not respond to small repeated doses.
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    URL: http://dx.doi.org/10.1007/BF00613809
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  • 19
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    Family study of genetic and environmental factors determining the protein binding of propranolol (1983)
    Springer
    European journal of clinical pharmacology 25 (1983), S. 437-441 
    Details
    ISSN: 1432-1041
    Keywords: propranolol ; protein binding ; genetic factors ; environmental factors ; plasma orosomucoid ; plasma albumin
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The unbound fraction of propranolol was found to vary from 1.9 to 13.2% in 434 plasma samples from members of 132 families. As expected, there was a linear correlation between the ratio of bound/unbound propranolol and the orosomucoid concentration (r=0.67, P〈0.001). Albumin concentration did not influence propranolol binding. The unbound fraction was negatively correlated with obesity and alcohol intake, but was not significantly influenced by age and sex. By applying path analysis, 21% of the variability in propranolol binding could be ascribed to genetic factors and 5% to common environmental factors.
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    URL: http://dx.doi.org/10.1007/BF00542107
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  • 20
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    Pharmacokinetics of oral mexiletine in patients with acute myocardial infarction (1983)
    Springer
    European journal of clinical pharmacology 25 (1983), S. 773-777 
    Details
    ISSN: 1432-1041
    Keywords: mexiletine ; myocardial infarction ; pharmacokinetics ; gastro-intestinal absorption ; protein binding
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary To study the effects of acute myocardial infarction on its pharmacokinetics a single oral dose of 400 mg mexiletine HCl was administered to seven patients. The study was performed within 24 h of the onset of pain (Study I) and was repeated 10–14 days later, during the recovery phase (Study II). Mexiletine in plasma and urine was quantified by a GLC method. The peak plasma concentrations of mexiletine were 0.65±0.05 (SEM) µg/ml and 1.08±0.11 µg/ml (p〈0.05) in Studies I and II, respectively. The corresponding peak times were 4.68±2.04 h and 1.46±0.17 h (N.S.). The lag time averaged 0.48±0.08 h in Study I and 0.39±0.05 h in Study II (N.S.). The area under the plasma concentration-time curve remained unchanged. The elimination half-life was 15.03±0.61 h and 11.75±0.80 h (p〈0.01) in Studies I and II, respectively. The recovery of unchanged mexiletine in urine and its renal clearance was also the same in both studies. The plasma protein binding of mexiletine was similar in Studies I and II (61±2% and 63±3%; N.S.). Thus, the rate of gastrointestinal absorption of mexiletine was definitely slowed in the acute phase of myocardial infarction, whereas the extent of absorption was not altered. The prolongation of the elimination half-life of mexiletine in the acute phase of myocardial infarction is probably related to an increase in its volume of distribution.
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    URL: http://dx.doi.org/10.1007/BF00542518
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  • 21
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    Binding of piroxicam to synovial fluid and plasma proteins in patients with rheumatoid arthritis (1984)
    Springer
    European journal of clinical pharmacology 26 (1984), S. 457-461 
    Details
    ISSN: 1432-1041
    Keywords: piroxicam ; rheumatoid arthritis ; protein binding ; synovial fluid ; plasma
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The protein binding of piroxicam in synovial fluid and plasma from patients with rheumatoid arthritis was studied in vitro by equilibrium dialysis. The binding parameters were calculated from the experimental data with the Scatchard model, assuming binding to two classes of sites. Each plasma sample was diluted to an albumin concentration equal to that of synovial fluid from the same patient. The association constants for primary and secondary binding sites in the concentration range of piroxicam 4.5–90·10−5 mol/l were similar in synovial fluid and in plasma. For synovial fluid K1=2.38·105 l/mol and K2=2.29·103 l/mol; for plasma K1=1.93·105 l/mol and K2=2.08·103 l/mol. The number of binding sites was also the same in the two fluids. Although the concentration of piroxicam in synovial fluid was about half that in plasma, the binding of piroxicam to protein in synovial fluid was the same as in plasma.
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    URL: http://dx.doi.org/10.1007/BF00542141
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  • 22
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    Lack of effect of haemodialysis on mebendazole kinetics: Studies in a patient with echinococcosis and renal failure (1984)
    Springer
    European journal of clinical pharmacology 27 (1984), S. 243-245 
    Details
    ISSN: 1432-1041
    Keywords: mebendazole ; haemodialysis ; echinococcosis ; pharmacokinetics ; protein binding
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The effect of haemodialysis on mebendazole kinetics has been studied in a patient receiving both mebendazole therapy and haemodialysis. The procedure of haemodialysis did not influence the plasma concentration — time profiles or the mean daily plasma levels. The arterio-venous difference in the dialyser was negligible and no mebendazole could be detected in the dialysate. Protein binding of mebendazole was 90% before dialysis and 88% during dialysis and not significantly different from the binding in patients without renal disease (91.4±1.9%, n=22).
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    URL: http://dx.doi.org/10.1007/BF00544053
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  • 23
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    Naproxen disposition in patients with alcoholic cirrhosis (1984)
    Springer
    European journal of clinical pharmacology 27 (1984), S. 291-296 
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    ISSN: 1432-1041
    Keywords: naproxen ; cirrhosis ; pharmacokinetics ; protein binding ; nonsteroidal antiinflammatory drugs
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Chronic liver disease is known to alter the absorption and disposition of many drugs. To assess the influence of chronic alcoholic liver disease on the disposition of naproxen, we administered the drug both as a single dose and to steady state to 10 individuals with alcoholic cirrhosis and to 10 healthy controls. Plasma and serum samples collected after naproxen dosing were assayed for both total and (following equilibrium dialysis) unbound drug concentration. Clearance calculated based on both total and unbound naproxen concentration revealed no change in total plasma clearance of the drug at steady state but a marked reduction of approximately 60% in clearance based on unbound drug. Naproxen volume of distribution changed only minimally. Because clearance based on unbound drug concentration at a given dosing rate determines the plasma or blood free drug concentration, this concentration may increase significantly in patients with alcoholic liver disease given usual doses of naproxen. Unbound drug concentration is thought to determine the pharmacologic effect of a drug. We therefore recommend that naproxen dosing be reduced by at least half in patients with chronic alcoholic liver disease. In the absence of data to the contrary, this recommendation can be extended to individuals with other forms of hepatic disease.
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  • 24
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    Pharmacokinetics of ketanserin in man (1983)
    Springer
    European journal of clinical pharmacology 25 (1983), S. 73-76 
    Details
    ISSN: 1432-1041
    Keywords: ketanserin ; pharmacokinetics ; protein binding ; excretion ; oral dosing ; i.v. injection ; first-pass effect ; antihypertensive drug ; serotonin antagonist
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Kinetic data for the new antihypertensive agent ketanserin were determined in six healthy subjects after single oral (40 mg) or intravenous (0.15 mg/kg) doses. Plasma protein binding was 94.0±1.8% (mean±SD). Cumulative urinary excretion of unchanged drug was less than 4% within 48 h following the single dose. The maximal plasma level (cmax) of 193±98.2 µg/l occured within 0.5 to 4.0 h after oral intake. The ketanserin plasma level declined biexponentially after oral administration, and triexponentially over the 36 h following intravenous injection. The terminal elimination half-life (term. t1/2) averaged 12.4±2.9 h and 12.8±4.8 h following oral and intravenous application, respectively. Total plasma clearance was 410±62.0 (i.v.) and 829±228 ml/min (p.o.) and the intravenous blood clearance averaged 602±91 ml/min, which indicates partly flowdependent hepatic elimination. A substantial first-pass effect led to a bioavailability of about 50% (range: 27–69%). Hepatic clearance of ketanserin followed the non-restrictive pattern. No change in blood pressure or heart rate was observed following ketanserin administration to normal volunteers.
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  • 25
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    Displacement of lidocaine from serumα 1-acid glycoprotein binding sites by basic drugs (1983)
    Springer
    European journal of clinical pharmacology 25 (1983), S. 413-417 
    Details
    ISSN: 1432-1041
    Keywords: lidocaine ; alpha1-acid glycoprotein ; protein binding ; free fraction ; displacement ; basic drug interaction
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Since little is known of the number and types of binding sites on α1-acid glycoprotein (AAG) and because drug-drug protein binding interactions often fail to fit a simple model, a study of the effect of 9 known AAG binding drugs on lidocaine free fraction (LFF) was performed. Serum was obtained from 10 healthy males, pooled and various concentrations (from 0.15 to 1 000 µg/ml) of amitriptyline, bupivacaine, chlorpromazine, disopyramide, imipramine, meperidine, nortriptyline, propranolol and quinidine were added. LFF was determined by equilibrium dialysis at an initial lidocaine concentration of 2.0 µg/ml. LFF increased from 0.30±0.019 (mean ± SD) in the absence of displacing agents to maximum values ranging from 0.59 (nortriptyline) to 0.73 (bupivacaine). Plots of LFF vs. the logarithm of displacing drug concentration yielded simple sigmoidal curves in all cases. LFF was increased 50% by an initial bupivacaine concentration of 6.0 µg/ml with all other drugs requiring more than 10 µg/ml to increase LFF to that extent. Lidocaine binding in a 4.5 g/dl albumin solution was unaffected by concentrations of quinidine, meperidine, nortriptyline and bupivacaine up to 200 µg/ml. Addition of AAG to serum reduced LFF as expected. A plot of the reciprocal of bound drug concentration vs. the reciprocal of free drug concentration in the presence and absence of quinidine suggested a competitive binding interaction. These data indicate that the binding interactions between lidocaine and the various displacing compounds are not significantly complicated by cooperative effects and that, with the possible exception of bupivacaine, displacement of lidocaine by any of these drugs is unlikely to be of clinical significance.
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  • 26
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    Protein binding of enprofylline (1983)
    Springer
    European journal of clinical pharmacology 25 (1983), S. 703-708 
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    ISSN: 1432-1041
    Keywords: enprofylline ; 3-propylxanthine ; protein binding ; equilibrium dialysis ; theophylline ; ultrafiltration ; pH effect ; species differences
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The protein binding of enprofylline, 3-propylxanthine, in plasma was studied by equilibrium dialysis and ultrafiltration under various experimental conditions. A limited comparison with theophylline was also undertaken. The mean fraction of enprofylline bound in human plasma at 20°C was 47.3±1.1% (SD), which was only 2% less than theophylline. The binding of the two drugs increased dramatically in the pH range 7.2 to 7.8, as reported previously for theophylline. Reasonable agreement was found between equilibrium dialysis and ultrafiltration, but the latter technique proved impractical, because pH control was difficult to achieve. A pronounced species difference in the binding of enprofylline was found. At pH 7.4 an almost constant level of binding of 57% in dog and 81% in rat was found up to 2 · 10−5 M (approx. 4 mg/l). Corresponding values in human and monkey plasma were 47 and 48%, respectively, up to 10−4 M (approx. 20 mg/l).
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  • 27
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    Pharmacokinetics of S-adenosyl-L-methionine in healthy volunteers (1984)
    Springer
    European journal of clinical pharmacology 27 (1984), S. 119-121 
    Details
    ISSN: 1432-1041
    Keywords: S-adenosyl-L-methionine ; pharmacokinetics ; protein binding ; dose-dependent kinetics ; healthy volunteers ; urinary excretion
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary S-Adenosyl-L-methionine (AdoMet) kinetics was studied in 6 male subjects given 100 and 500 mg i. v. Drug concentrations in plasma and urine were assayed using a radioenzymatic method. Pharmacokinetic parameters were estimated according to an open two-compartment model. The apparent volumes of distribution after the 100 and 500 mg doses were 407±27 and 443±36 ml/kg (mean±SEM), terminal half-lives 81±8 and 101±7 min and body clearances 3.7±0.5 and 3.1±0.2 ml/min per kg. Urinary excretion was 34±3 and 40±2% of the administered dose. The results demonstrate that drug disposition occurs more via metabolism than via renal excretion, and it is not dependent on the administered dose. Binding of AdoMet to serum proteins is negligible.
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  • 28
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    Quinidine-digoxin interaction: Evidence for involvement of an extrarenal mechanism (1982)
    Springer
    European journal of clinical pharmacology 21 (1982), S. 281-285 
    Details
    ISSN: 1432-1041
    Keywords: quinidine ; digoxin ; anuria ; haemodialysis ; serum digoxin ; plasma quinidine ; protein binding ; extrarenal digoxin clearance
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The influence of quinidine 750 mg per day for one week on serum digoxin concentration (SDC) was evaluated in digitalized anuric patients on chronic haemodialysis. During quinidine administration the SDC increased markedly, from 0.84±0.37 to 1.58±0.72 ng/ml (p〈0.01), a comparable effect to that reported previously in patients with normal renal function. Neither in vitro nor in vivo did quinidine alter the serum protein binding of digoxin. The increase in SDC in anuric patients indicates a decrease in the extrarenal clearance of digoxin, which means that mechanisms other than of renal origin are also involved in the interaction of quinidine and digoxin. There was great interindividual variability in the extent of the quinidine-induced rise in SDC. Regardless of the state of renal function, careful monitoring of digitalized patients seems mandatory once quinidine treatment is initiated.
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  • 29
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    Excretion of paracetamol in human breast milk (1981)
    Springer
    European journal of clinical pharmacology 20 (1981), S. 123-125 
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    ISSN: 1432-1041
    Keywords: paracetamol ; breast milk ; plasma ; drug excretion in breast milk ; protein binding
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Breast milk and plasma levels of paracetamol were monitored in 3 lactating women after ingestion of a single 500 mg dose of paracetamol. The paracetamol concentrations were consistently lower in milk, with a mean milk/plasma AUC ratio of 0.76. This value was in close agreement with the milk/plasma partition ratio of 0.81 foundin vitro, and could be related to quantitative binding differences between the two fluids. The half-lives of paracetamol in plasma and breast milk were almost identical, with an overall mean of 2.7 h. As less than 0.1% of the maternal dose would be present in 100 ml milk, breast feeding need not be discontinued due to paracetamol treatment in conventional dosage.
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  • 30
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    Interaction of sulphinpyrazone with warfarin (1982)
    Springer
    European journal of clinical pharmacology 22 (1982), S. 327-331 
    Details
    ISSN: 1432-1041
    Keywords: Sulphinpyrazone ; warfarin ; drug metabolism ; drug interaction ; protein binding
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The effect of sulphinpyrazone administration on the anticoagulant response was investigated in five patients receiving long-term treatment with warfarin. Sulphinpyrazone caused a rapid increase in prothrombin (PT) ratio in all five patients and warfarin dose had to be reduced by a mean of 46% to maintain the PT ratio in the therapeutic range. PT ratio and daily warfarin requirement returned to previous levels when sulphinpyrazone was ceased. Warfarin protein binding was not altered during sulphinpyrazone administration and sulphinpyrazone added to plasma in vitro did not increase warfarin free fraction. The average racemic plasma warfarin concentration over a dosage interval when adjusted for warfarin dose was not altered by sulphinpyrazone administration. The most likely mechanism for this drug interaction is a stereoselective effect of sulphinpyrazone on the metabolism of the warfarin enantiomers.
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  • 31
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    Serum concentration and protein binding of thioridazine and its metabolites in patients with chronic alcoholism (1982)
    Springer
    European journal of clinical pharmacology 23 (1982), S. 359-363 
    Details
    ISSN: 1432-1041
    Keywords: thioridazine ; alcoholism ; thioridazine metabolites ; serum concentrations ; protein binding ; α1-acid glycoprotein
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The blood chemistry and clinical pharmacokinetics of thioridazine and its metabolites, side-chain sulphoxide, side-chain sulphone and ring sulphoxide, were studied in 31 alcoholics and were compared with values in 17 thioridazine-treated controls without alcoholism. Pathological blood chemistry values, including abnormal liver function and protein concentrations, were common among the alcoholics. In relation to dosage, the majority had a low serum concentration of thioridazine and at a given concentration of thioridazine they had high serum concentrations of its metabolites. Positive intercorrelations were found between pathological liver function tests, prolonged serum half-life and increased serum concentration of thioridazine. The free fractions of thioridazine, side-chain sulphoxide and ring sulphoxide were significantly higher and those of the side-chain sulphone lower in the alcoholics than in the controls. The free fractions of side-chain and ring sulphoxide were significantly increased in patients with a low concentration of α1-acid glycoprotein.
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  • 32
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    Pharmacokinetics and protein binding of prednisolone after oral and intravenous administration (1983)
    Springer
    European journal of clinical pharmacology 24 (1983), S. 415-419 
    Details
    ISSN: 1432-1041
    Keywords: prednisolone ; bioavailability ; non-linear pharmacokinetics ; protein binding
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The pharmacokinetics of prednisolone after oral and intravenous administration of 10 and 20 mg have been studied. Serum protein binding of prednisolone was also measured after the i.v. injections. The bioavailability after oral administration was 84.5% after 10 mg and 77.6% after 20 mg (p〉0.05). Dose dependent pharmacokinetics were found, the VDss and Clt being significantly larger (p〈0.01) after 20 mg i.v. than after 10 mg i.v. The protein binding of prednisolone in all subjects was non-linear, and is the most likely cause of the dose dependent pharmacokinetics, as there was no dose dependent variation in elimination half-time.
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  • 33
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    Effect of low doses of heparin on the plasma binding of phenytoin and prazosin in normal man (1983)
    Springer
    European journal of clinical pharmacology 25 (1983), S. 211-214 
    Details
    ISSN: 1432-1041
    Keywords: heparin ; protein binding ; phenytoin ; prazosin ; lipases ; plasma triglycerides
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The effect of low doses of heparin on the binding of phenytoin and prazosin to plasma proteins was evaluated in four normal subjects. Heparin activates the hydrolysis of triglycerides in plasma. The ensuing increase in non-esterified fatty acids (NEFA) was more marked in vitro than in vivo and increased the free fraction (FF) of phenytoin and prazosin in plasma. The higher FF caused a change in the plasma to whole blood ratio (P/B ratio) of both drugs. The changes in FF and P/B ratio after heparin were small, but could be of significance in pharmacokinetic studies.
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  • 34
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    The metabolic disposition of flucloxacillin in patients with impaired kidney function (1982)
    Springer
    European journal of clinical pharmacology 22 (1982), S. 429-434 
    Details
    ISSN: 1432-1041
    Keywords: uraemia ; hydroxyflucloxacillin ; flucloxacillin ; isoxazolyl penicillins ; protein binding
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The fate of flucloxacillin and its active metabolite hydroxyflucloxacillin was studied in a group of patients with impaired kidney function. Flucloxacillin was administered orally or intravenously. Peak levels of hydroxyflucloxacillin were obtained between 150 and 250 min after the administration of flucloxacillin. The plasma concentrations obtained after a therapeutic dose of flucloxacillin were well above the concentration (i.e. 1–2 µg/ml) generally considered to be the effective minimum for isoxalyl penicillins. The plasma half life of the metabolite was twice as long as that of flucloxacillin (295 min and 154 min, respectively). The nonprotein-bound fraction of hydroxyflucloxacillin in plasma from patients was twice as large as that of its parent compound (16.2 vs. 8.1%). This was also observed in normal human plasma, although protein binding in the latter was higher than in uraemic plasma. Some accumulation of hydroxyflucloxacillin may occur during flucloxacillin therapy with dosage intervals of 6 h.
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  • 35
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    Pharmacokinetics and hypotensive effect in healthy volunteers of pinacidil, a new potent vasodilator (1984)
    Springer
    European journal of clinical pharmacology 26 (1984), S. 603-608 
    Details
    ISSN: 1432-1041
    Keywords: pinacidil ; hypertension ; pinacidil pyridine-N-oxide ; urinary excretion ; protein binding ; pharmacokinetics ; healthy volunteers
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Preliminary investigation in 3 healthy volunteers suggested that intravenous pinacidil in a dose of 0.2 mg/kg had a potent but well-tolerated hypotensive action in the supine position. Facial flushing, uncomfortable chest sensation and distressing postural hypotension occurred at serum concentrations above 300 ng/ml. Pinacidil, 0.2 mg/kg, was given intravenously over 4 min to 15 healthy volunteers in the supine position. Maximum fall in mean arterial pressure (MAP) was 15.7±6.0 mmHg. Maximum rise in heart rate was 23.8±6.6 beats/min. Pinacidil serum distribution half-life ( $${\text{T}}_{{\raise0.7ex\hbox{${\text{1}}$} \!\mathord{\left/ {\vphantom {{\text{1}} {{\text{2}}\alpha }}}\right.\kern-\nulldelimiterspace}\!\lower0.7ex\hbox{${{\text{2}}\alpha }$}}}$$ ) was 13.4±8.5 min and elimination half-life ( $${\text{T}}_{{\raise0.7ex\hbox{${\text{1}}$} \!\mathord{\left/ {\vphantom {{\text{1}} {{\text{2}}\beta }}}\right.\kern-\nulldelimiterspace}\!\lower0.7ex\hbox{${{\text{2}}\beta }$}}}$$ ) was 2.13±0.49 h. The apparent volume of distribution (Vdβ) was 90.3±13.21 and total body clearance was 31.1±9.61/h. Pinacidil was approximately 40% bound to plasma protein over the concentration range 40–400 ng/ml. Urinary excretion of unchanged pinacidil accounted for 5.7 ± 1.3% of the administered dose over 24 hours and urinary excretion of the major metabolite, pinacidil pyridine-N-oxide, was 31.6±9.2% of the administered dose. It was concluded that intravenous pinacidil is a potent vasodilator hypotensive compound, with a duration of action between 1.5 and 2 h.
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    Pharmacokinetics of S-adenosyl-L-methionine in healthy volunteers (1984)
    Springer
    European journal of clinical pharmacology 27 (1984), S. 119-121 
    Details
    ISSN: 1432-1041
    Keywords: S-adenosyl-L-methionine ; pharmacokinetics ; protein binding ; dose-dependent kinetics ; healthy volunteers ; urinary excretion
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary S-Adenosyl-L-methionine (AdoMet) kinetics was studied in 6 male subjects given 100 and 500 mg i. v. Drug concentrations in plasma and urine were assayed using a radioenzymatic method. Pharmacokinetic parameters were estimated according to an open two-compartment model. The apparent volumes of distribution after the 100 and 500 mg doses were 407±27 and 443±36 ml/kg (mean±SEM), terminal half-lives 81±8 and 101±7 min and body clearances 3.7±0.5 and 3.1±0.2 ml/min per kg. Urinary excretion was 34±3 and 40±2% of the administered dose. The results demonstrate that drug disposition occurs more via metabolism than via renal excretion, and it is not dependent on the administered dose. Binding of AdoMet to serum proteins is negligible.
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    Comparison of the disposition of total and unbound sulfisoxazole after single and multiple dosing (1982)
    Springer
    Journal of pharmacokinetics and pharmacodynamics 10 (1982), S. 157-172 
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    ISSN: 1573-8744
    Keywords: sulfisoxazole ; pharmacokinetics—unbound drug ; pharmacokinetics—total drug ; bioavailability ; healthy volunteers ; protein binding
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract Plasma concentrations of total and unbound sulfisoxazole were followed after single intravenous and oral doses of 1 g sulfisoxazole and during a 500-mg, four-time-a-day dosing regimen in six healthy males, using a specific high pressure liquid Chromatographic assay method. Saturable plasma protein binding was observed at total concentrations above 80–100 mg/liter. The clearance of sulfisoxazole was 18.7±3.9ml/min for total drug and 232±64ml/min for unbound drug. Renal elimination, on the average, accounted for 49% of the clearance of sulfisoxazole. The apparent volume of distribution for total drug was 10.9±2.0 liters and 136±36 liters for unbound drug, indicating that sulfisoxazole is primarily distributed extracellularly. Accumulation of N4-acetyl-sulfisoxazole during multiple dosing did not affect the disposition of sulfisoxazole. Adjusting for variable renal clearances between oral and intravenous administration and using the unbound plasma concentrations, the bioavailability for an oral dose of sulfisoxazole was found to be 0.95±0.04.
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    Clinical pharmacokinetics of disopyramide (1982)
    Springer
    Journal of pharmacokinetics and pharmacodynamics 10 (1982), S. 465-494 
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    ISSN: 1573-8744
    Keywords: disopyramide ; pharmacokinetics ; bioavailability ; metabolite ; half-life ; protein binding ; disease states ; drug-drug interaction
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract Current information on the pharmacokinetics of disopyramide is reviewed with emphasis on the implications for antiarrhythmic therapy. The absolute bioavailability, the disposition half-life, the plasma clearance, and the renal clearance for normal subjects and patients are discussed. Drug-drug interactions are discussed, and a new flexible intravenous dosing schedule is proposed.
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    Pharmacokinetics of triamterene and its metabolite in man (1982)
    Springer
    Journal of pharmacokinetics and pharmacodynamics 10 (1982), S. 507-523 
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    ISSN: 1573-8744
    Keywords: triamterene ; sulfate conjugate ; protein binding ; blood/plasma ratio ; renal clearance ; HPLC
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract The pharmacokinetic profiles of triamterene and hydroxytriamterene sulfuric acid ester, the major metabolite of triamterene, were studied in six normal male volunteers using a newly developed specific HPLC analytical method. Following a 100 mg oral dose of triamterene, the plasma concentration time course of the sulfate conjugate parallels that of triamterene in all subjects, but concentrations of the metabolite were more than 10 times higher than unchanged triamterene concentrations at identical sampling times. Interestingly, the renal clearance of the sulfate conjugate was less than that of triamterene. These characteristic features of triamterene disposition were fitted to a compartment model incorporating a first-pass metabolic process. Unbound fractions of triamterene and metabolite in plasma were 0.39 and 0.10 (mean of 6 subjects), respectively. The low unbound fraction of the metabolite in plasma most probably accounts for the low renal clearance of the sulfate conjugate as compared with triamterene.
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    Comparative pharmacokinetics of benzodiazepines in dog and man (1982)
    Springer
    Journal of pharmacokinetics and pharmacodynamics 10 (1982), S. 411-426 
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    ISSN: 1573-8744
    Keywords: benzodiazepines ; interspecies variation ; half-life ; metabolic clearance ; volume of distribution ; protein binding
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract The pharmacokinetic parameters disposition half-life, metabolic clearance, volume of distribution, intrinsic clearance of unbound drug, and (distributive tissue volume/unbound fraction in tissue) were compared for 12 benzodiazepines in dog and man. With the exception of volume of distribution, statistically significant correlations were obtained when parameters were plotted on a double logarithmic grid. In general, benzodiazepines were metabolized more rapidly and exhibited greater tissue distribution in dog than in man. The variability in parameters was such, however, as to make extrapolations from one species to another subject to considerable error.
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    Pharmacokinetic-pharmacodynamic analysis of unbound disopyramide directly measured in serial plasma samples in man (1984)
    Springer
    Journal of pharmacokinetics and pharmacodynamics 12 (1984), S. 559-573 
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    ISSN: 1573-8744
    Keywords: disopyramide ; pharmacokinetics ; pharmacodynamics ; electrophysiology ; protein binding ; modelling
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract The pharmacokinetics and pharmacodynamics of the antiarrhythmic drug, disopyramide, were investigated in 12 volunteers who took 300 mg doses of 3 different capsule preparations and an aqueous oral solution of the drug at 1-week intervals. Concentrations of drug unbound to plasma proteins were measured by a sensitive immunoenzyme assay after ultrafiltration of plasma samples taken serially after dosing. QT interval was measured on serial ECG recordings with correction for changes in heart rate. Unbound concentrations of disopyramide were modelled by an open one-compartment pharmacokinetic model with a zero-order absorption rate and a lag time. There was no significant difference in parameter estimates between the four preparations, except for the lag time, which was significantly shorter for the solution preparation. The saturable protein binding of disopyramide was described by a hyperbolic model including a specific binding site and additional nonspecific binding. The pharmacodynamic relationship between unbound drug concentration and QT prolongation was fit by a simple linear model. This fit was better using unbound concentration of the drug than using total concentrations.
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    Pharmacokinetics and bioavailability of intravenous, oral, and rectal nitrazepam in humans (1982)
    Springer
    Journal of pharmacokinetics and pharmacodynamics 10 (1982), S. 231-245 
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    ISSN: 1573-8744
    Keywords: nitrazepam ; i.v. ; oral ; rectal administration ; protein binding ; pharmacokinetics ; bioavailability
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract The pharmacokinetics and bioavailability of nitrazepam following intravenous, oral (tablet), and rectal (solution) administration were studied in seven healthy, young male volunteers. Nitrazepam plasma concentrations were determined by electron-capture GLC; pharmacokinetic evaluations were made by compartmental analysis (NONLIN) and compared with the results obtained by a less stringent modelling of the data. The plasma concentration-time profile was similar for all three routes of administration. Mean kinetic parameters as obtained by compartmental analysis of i.v. nitrazepam were: distribution half-life 17 min; volume of distribution after equilibrium 2.14 liters/kg; total plasma clearance 61.6 ml/min; elimination half-life 29.0 h. The mean protein unbound fraction of nitrazepam in plasma was 12.3% and the clearance of the unbound fraction was 506 ml/min. Absorption of oral nitrazepam started after the elapse of a lag time (mean value 12 min) and occurred as an apparent first-order process in all but one subject, with a mean absorption half-life of 16 min. Distribution and elimination half-lives were comparable with those following i.v. administration. Following rectal administration of the nitrazepam solution, rapid first-order absorption occurred with a mean lag time of 4 min and a mean absorption half-life of 9 min. Peak times (median 18 min) were significantly shorter than following oral administration (median 38 min), but there was little difference in peak concentrations. The distribution half-life was similar to i.v. and oral administration, but the elimination half-lives were longer with a mean value of 33.1 h. Following i.v. administration a good agreement was found between the results obtained by compartmental analysis using NONLIN and those obtained by a less stringent modelling of the data. Following oral and rectal administration, a good agreement between the two procedures was found for the elimination half-life; estimation of bioavailability, however, was higher by compartmental analysis. The mean bioavailability data showed that absorption is complete when nitrazepam is given orally and almost 20% lower when it is given rectally, but considerable interindividual differences were observed.
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    Plasma protein binding of furosemide in kidney transplant patients (1982)
    Springer
    Journal of pharmacokinetics and pharmacodynamics 10 (1982), S. 663-674 
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    ISSN: 1573-8744
    Keywords: furosemide ; protein binding ; kidney transplant ; renal transplant
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract The present investigation was undertaken in order to determine the in vivo plasma protein binding of furosemide in kidney transplant patients and its possible consequence on furosemide effect. Using an equilibrium dialysis technique, serial plasma samples of furosemide taken after intravenous administration were dialyzed against an equal volume of isotonic Krebs Ringer bicarbonate buffer (pH7.4). Dialysis was performed at 37°C for 5 hr, and furosemide concentrations (total as well as free) were analyzed by HPLC using fluorescence detection. It was observed that kidney transplant patients on concomitant sulfisoxazole treatment (KT+) had a significantly greater value for percent free of furosemide as compared to transplant patients not on sulfisoxazole (KT-) (4.4±0.8 for KT+ vs. 1.7±0.3% for KT-;p〈0.01) as well as to healthy volunteers (4.4±0.8 for KT+ vs. 1.2±0.2% for controls;p〈0.01). In addition, kidney transplant patients not on concomitant sulfisoxazole treatment had a significantly higher value for percent free of furosemide with respect to healthy volunteers (p〈0.05). Nonlinear plasma protein binding was also observed for one patient, who had values for percent free of furosemide ranging from 1.3 to 12.9%. However, no significant correlation was found between the fraction of the dose excreted unchanged in the urine and percent free of furosemide.
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    Disopyramide pharmacokinetics and bioavailability following the simultaneous administration of disopyramide and14C-disopyramide (1984)
    Springer
    Journal of pharmacokinetics and pharmacodynamics 12 (1984), S. 289-313 
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    ISSN: 1573-8744
    Keywords: protein binding ; pharmacokinetics ; bioavailability ; disopyramide ; heart failure
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract The pharmacokinetics and bioavailability of total (bound plus unbound) and unbound disopyramide were compared following the simultaneous administration of an oral dose of disopyramide and an intravenous dose of14C-disopyramide in five normal volunteers and in 11 patients with congestive heart failure. The binding of disopyramide varied between 60 and 92% in patients and between 81 and 88% in normal subjects at postequilibrium drug concentrations of 10−7M. The binding of disopyramide to serum protein was concentration-dependent in all study subjects at serum concentrations achieved following drug administration. The association constant for the first binding site in serum from normal subjects and patients averaged 8.7X105 M−1 and 4.4X10 5 M−1, respectively (p 〈 0.05). The unbound clearance of disopyramide averaged 277ml/min and 209 ml/min in normal subjects and in patients (p 〈 0.05). When normalized for body weight, the unbound clearance between patients and normal subjects was not significantly different. The elimination half-life of unbound concentrations in normal subjects and in patients averaged 4.9 and 6.1 h, respectively (p 〈 0.05). The clearance and elimination half-life of total disopyramide was the same in both groups. Although the bioavailability of disopyramide averaged 0.85 in both groups, it was more variable in patients owing to the variability in the fraction of the dose absorbed. The unbound renal clearance and volume of distribution at steady state of disopyramide was related to cardiac index. The ratio of elimination half-lives of total and unbound disopyramide was related to the extent of serum protein binding.
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    In vitro binding of14C-labeled acidic compounds to serum albumin and their tissue distribution in the rat (1980)
    Springer
    Journal of pharmacokinetics and pharmacodynamics 8 (1980), S. 583-597 
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    ISSN: 1573-8744
    Keywords: protein binding ; organic acids ; tissue distribution ; species effects
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract The acidic compounds, such as phenoxyacetic acids, substituted benzoic acids, or acetylsalicylic acid, were found to bind to bovine serum albumin (BSA). Among phenoxyacetic acids, the binding affinity to BSA was highest for 2,4,5-trichlorophenoxyacetic acid (2,4,5-T), which was approximately 4-, 24-, and 160-fold greater than those for 2,4-dichlorophenoxyacetic acid (2,4-D), o-chlorophenoxyacetic acid (CPA), and phenoxyacetic acid (PAA), respectively. There were two binding sites in BSA for 2,4,5-T and 2,4-D, and one site for others. These acidic compounds also bound to serum albumins of other mammalian species. The binding affinity varied among species and also depended on the chemicals. However, the order of binding affinity in the albumin of each species remained the same as observed in BSA with few exceptions. Blood/tissue ratios of14C from rats dosed with these14C-labeled acids were highly correlated with the logarithm of the binding affinity constants.
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    Evidence that cannabidiol does not significantly alter the pharmacokinetics of tetrahydrocannabinol in man (1981)
    Springer
    Journal of pharmacokinetics and pharmacodynamics 9 (1981), S. 245-260 
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    ISSN: 1573-8744
    Keywords: cannabidiol ; tetrahydrocannabinol ; pharmacokinetics ; cannabinoids ; pharmacodynamics ; metabolism ; renal clearance ; protein binding
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract The pharmacokinetics of Δ 9 -tetrahydrocannabinol (THC) administered intravenously was evaluated in four subjects after oral administration of placebo and 1500 mg of cannabidiol (CBD) according to a crossover design. The cannabidiol pretreatment had no apparent effect on THC pharmacokinetics, yet there may have been minimal effect on the formation and excretion of metabolites. The total (metabolic) blood clearance of THC averaged 17.4 ml/min/kg without CBD and 20.9 ml/min/kg with CBD, and was probably hepatic blood flow limited. The apparent steady-state volume of distribution averaged 9.86 (with CBD, 10.54) liters/kg. Irrespective of CBD pretreatment, the renal clearance of THC metabolites ranged from 17 ml/min after approximately 1 hr to 1.13 ml/min 3.5days after dosing with THC. The apparent terminal half life for metabolites averaged 8.2 days.
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    Pharmacokinetics of intravenously administered bumetanide in man (1980)
    Springer
    Journal of pharmacokinetics and pharmacodynamics 8 (1980), S. 219-228 
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    ISSN: 1573-8744
    Keywords: bumetanide ; diuretics ; pharmacokinetics ; three-compartment model ; protein binding
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract Disposition of [ 14C] bumetanide administered intravenously to four healthy volunteers could be described by a triexponential equation. The mean half-lives associated with each exponent were 5.9 min, 46 min, and 3.1 hr, respectively. The largest fraction of dose was eliminated during the second phase; only 17% was eliminated during the last phase. The total plasma clearance averaged 228 ml/min, with renal clearance about one-half of this value. The recovery of unchanged bumetanide in urine over 2 days was 47% of the dose, while the total recovery of radioactivity in urine averaged 82% of dose. In plasma 93% of bumetanide was bound to proteins. Thus bumetanide is rapidly eliminated by both renal and nonrenal mechanisms. The elimination kinetics resembled those described for furosemide.
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    Dose dependent pharmacokinetics of prednisone and prednisolone in man (1981)
    Springer
    Journal of pharmacokinetics and pharmacodynamics 9 (1981), S. 389-417 
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    ISSN: 1573-8744
    Keywords: Prednisone ; prednisolone ; dose-dependent ; pharmacokinetics ; biotransformation ; protein binding ; bioavailability ; transcortin binding ; interconversion ; renal clearance
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract Six healthy male volunteers were given 5, 20, and 50 mg of oral prednisone and 5, 20, and 40 mg doses of intravenous prednisolone. Plasma and urine concentrations of prednisone and prednisolone were determined by HPLC, and the binding of prednisolone to plasma proteins was measured by radioisotopic and equilibrium dialysis techniques. The pharmacokinetics of both oral prednisone and intravenous prednisolone were dose-dependent. The mean oral dose plasma clearances of prednisone ranged from 572 ml/min/ 1.73 m 2 for the 5mg dose to 2271 ml/min/1.73 m 2 for the 50 mg dose. Changes in prednisone half-life were insignificant, but increases in the half-life of its metabolite were dose-dependent. The systemic plasma clearance of i.v. prednisolone was dose-dependent and increased from 111 to 194 ml/min/1.73 m 2 over the 5 to 40 mg i.v. dosage range. The steady-state volume of distribution also increased, but little change in mean transit time and half-life was found. The binding of prednisolone to plasma proteins was markedly concentration-dependent, and a two compartment, nonlinear equation was used to characterize the effective binding of prednisolone to transcortin and albumin. The apparent pharmacokinetic parameters of protein-free and transcortin-free prednisolone were relatively constant with dose. The interconversion of prednisone and prednisolone varied with time and dose, although prednisolone concentrations dominated by 4-to 10-fold over prednisone. In urine, 2–5% of either administered drug was excreted as prednisone and 11–24% as prednisolone. The apparent renal clearances of both steroids were also nonlinear and unrelated to protein binding. These studies indicate that the pharmacokinetics of prednisone and prednisolone are dose-dependent and that protein binding does not fully explain their apparent nonlinear distribution and disposition.
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    Disposition of sulfadimethoxine in swine: Inclusion of protein binding factors in a pharmacokinetic model (1982)
    Springer
    Journal of pharmacokinetics and pharmacodynamics 10 (1982), S. 539-550 
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    ISSN: 1573-8744
    Keywords: Sulfadimethoxine ; swine ; pharmacokinetic modelling ; protein binding
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract Sulfadimethoxine was administered intravenously and orally to five swine. More than 75% of the dose was excreted into urine as the acetyl metabolite with 4–6% excreted unchanged. Plasma and urine data were not consistent when a linear pharmacokinetic model was used to describe the data. Sulfadimethoxine has a high affinity for plasma protein, and the data were subsequently fitted to a nonlinear model, which included saturable protein binding. The choice of a nonlinear model was further supported by a minimum value for the Akaike information criteria. The protein binding constant obtained was 2.8× 104 M−1 and the total protein binding site concentration in plasma was 4.6×10−4 m. Both values are comparable with in vitrodata. This result suggests that the nonlinear model involving protein binding can be successfully applied to pharmacokinetic data. The apparent biological half-life of Sulfadimethoxine (free and bound) in plasma was 14 hr; however, the half-life of elimination of free drug was 1.25 hr. Following oral administration, all of the dose was absorbed with an apparent absorption half-life of 2.9 hr.
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    Evaluation of equilibrium dialysis volume shifts: A comment (1984)
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    Journal of pharmacokinetics and pharmacodynamics 12 (1984), S. 463-465 
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    ISSN: 1573-8744
    Keywords: equilibrium dialysis ; volume shift ; protein binding
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract Previous authors have presented in this journal an equation defining the fractional shift in volume (fs)as a general equation implying applicability to a wide variety of circumstances. The equation concerned actually applies only when the starting volumes before dialysis are equal. A better general definition is given by fs=(volume shift)/(starting volume of protein solution).
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    Effect of serum protein binding on pharmacokinetics and anticoagulant activity of phenprocoumon in rats (1980)
    Springer
    Journal of pharmacokinetics and pharmacodynamics 8 (1980), S. 177-191 
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    ISSN: 1573-8744
    Keywords: protein binding ; tissue binding ; anticoagulant drugs ; tolbutamide ; drug interactions
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract The relationship among serum protein binding, kinetics of elimination, distribution, and anticoagulant activity of phenprocoumon was investigated in 25 selected outbred Sprague-Dawley rats which differed in the extent of serum protein binding of this drug. In addition, the serum protein binding of phenprocoumon was altered in inbred Lewis rats by continuous treatment with tolbutamide. This drug was found to displace phenprocoumon from serum proteins without affecting its intrinsic clearance. The serum free fraction values (fs)of the selected Sprague-Dawley rats ranged from 0.0053 to 0.0145. There were positive and linear correlations between fs and the first-order elimination rate constant (k), fs and total clearance (CL total ),and fs and the liver/plasma concentration ratio (L/P ratio) of phenprocoumon. The free fraction values in the liver tissue (f I )showed twofold variations and were not related to fs.The half-effective plasma concentrations (C p50% )of total phenprocoumon (i.e., the concentrations necessary to inhibit the prothrombin complex synthesis rate by 50%) decreased with increasing fs.The Cp50% values of total drug varied eightfold between the animals but those of free drug only 3.5- fold. The total anticoagulant effect per dose (AE/dose), as reflected by the magnitude of the area above the prothrombin complex activity vs. time curve in the plasma, varied only 1.5- fold between the rats and was not related to fs.Continuous treatment of inbred Lewis rats with tolbutamide led to an increase of fs (twofold), k (1.3-fold), Vd (1.5-fold), and CLtotal (twofold). The intrinsic clearance (CL intr )remained unaffected. There was no significant increase of fL but a twofold increase of the L/P ratio. AE/dose and the Cp50% values of free drug in tolbutamide-treated rats were not significantly different from those of control rats. Thus an increase of the free fraction of phenprocoumon in the serum of rats is followed by a proportional increase of the total clearance. This prevents a concomitant rise of the free drug concentration. Consequently, the total anticoagulant effect per dose remains almost unaffected by about threefold variations in the serum free fraction values of this drug.
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    Influence of volume shifts on drug binding during equilibrium dialysis: Correction and attenuation (1983)
    Springer
    Journal of pharmacokinetics and pharmacodynamics 11 (1983), S. 483-498 
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    ISSN: 1573-8744
    Keywords: volume-shift ; protein binding ; dextran ; disopyramide ; lidocaine ; propranolol ; diazepam ; clofibrate
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract A time-dependent volume shift from buffer to plasma, which occurs during equilibrium dialysis, decreased the protein binding of disopyramide and its capacity constant, and had no effect on the binding association constant. The volume-dependent decrease in disopyramidine binding may be corrected for by use of a derived equation. Inclusion of dextran, 2.5% (w/v), and use of a thick, low molecular weight cutoff membrane was the most effective technique in attenuating the volume shift. The plasma (serum) protein binding of the basic drugs lidocaine, disopyramide,propranolol, and diazepam was decreased when protein was diluted to 88 % or less of its undiluted concentration as a consequence of the volume shift. The protein binding of clofibrate, a highly bound acid drug, was more sensitive to volume shifts than the four basic drugs. Correction of drug binding for volume shifts was reasonably successful for most drugs. The highest binding measured for all drugs was associated with the lowest volume shift.
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    Induction of quinidine metabolism and plasma protein binding by phenobarbital in dogs (1984)
    Springer
    Journal of pharmacokinetics and pharmacodynamics 12 (1984), S. 495-515 
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    ISSN: 1573-8744
    Keywords: quinidine ; phenobarbital ; induction ; protein binding ; metabolism ; dogs
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract Two porta-caval transposed mongrel dogs were studied for phenobarbital (PB) induction of quinidine disposition after separate quinidine infusions via normal intravenous route and via portal vein. The plasma concentrations of quinidine and of three metabolites measured (3-OH quinidine, quinidine N-oxide, quinidine 10,11-dihydrodiol) were quite similar between i.v. and portal vein infusions, suggesting that the liver extraction ratio for quinidine in dogs is very low. After PB pretreatment plasma quinidine concentrations at the end of a 10 hr infusion increased about two-fold while the half-life decreased from a control value of about 16 hr to 6 hr. Plasma concentrations of the three major metabolites measured were also increased following PB treatment. Plasma protein binding for quinidine and two of its three measured metabolites (3-hydroxy quinidine and quinidine N-oxide) were increased after PB treatment. Pharmacokinetic analysis of the data showed a decrease in steady-state volume of distribution (Vdss)of quinidine from an average value of 153 L to 54 L after PB treatment, while the total clearance did not change (6.6 vs. 5.6L/hr). This decrease in Vdss could be explained by an increase in plasma protein binding of quinidine after PB treatment. The unbound nonrenal clearance of quinidine was induced by PB treatment. The decrease in fraction free in plasma and increase in unbound nonrenal (hence total) clearance resulted in little or no change in total plasma clearance for quinidine. The formation rate constants calculated for two quinidine metabolites, 3-hydroxy quinidine and quinidine N-oxide, were increased after PB treatment, suggesting an induction in these two metabolic pathways. Only quinidine 10,11-dihydrodiol was found in the bile after quinidine infusion, and the biliary clearance of this metabolite was also induced after PB treatment.
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    Kinetics of d-tubocurarine disposition and pharmacologic response in rats (1983)
    Springer
    Journal of pharmacokinetics and pharmacodynamics 11 (1983), S. 47-61 
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    ISSN: 1573-8744
    Keywords: d-tubocurarine ; pharmacokinetics ; pharmacodynamics ; multicompartrnent model ; Hill equation ; plasma ; tibialis anterior muscle ; protein binding ; rats
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract After bolus intravenous dosing of d-tubocurarine (d-TC) to rats, the twitch heights of the tibialis anterior muscle indirectly stimulated were followed, and its decrease was defined as pharmacologic response of d-TC. The relation between dose and response intensity was found to be well described with Hill's equation. According to a theory proposed by Smolen, Hill's equation was also applicable to the biophase d-TC concentration-response relation; the time courses of the relative biophase d-TC concentration indicated linear kinetics with dose levels ≤0.15 mg/kg and the occurrence of dose-dependent disposition with 0.30 mg/kg. After bolus i.v. dosing of3H-d-TC, plasma d-TC concentration obeyed a dose-independent two compartment model with doses ≤0.15mg/kg, but not with 0.30 mg/kg. This finding matched the above estimated with pharmacologic data. The active metabolite was not found in plasma and urine. The extent of d-TC plasma protein binding was independent of the wide range of plasma levels and its mean (±SD) value was 30.5 (±3.8). Plasma d-TC levels and pharmacologie response intensity were well correlated by Hill's equation and a three compartment model (the general two and the biophase compartments) in the dose range ≤0.15 mg/kg.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF01061767
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  • 55
    Electronic Resource
    Electronic Resource
    Protein binding and hepatic clearance: Discrimination between models of hepatic clearance with diazepam, a drug of high intrinsic clearance, in the isolated perfused rat liver preparation (1984)
    Springer
    Journal of pharmacokinetics and pharmacodynamics 12 (1984), S. 129-147 
    Details
    ISSN: 1573-8744
    Keywords: diazepam ; protein binding ; models of hepatic elimination ; hepatic clearance ; rat ; isolated perfused liver
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract The influence of protein binding on the extraction ratio, and availability, of diazepam has been examined in the single-pass isolated perfused rat liver preparation. Binding of diazepam was varied by adjusting the concentration of albumin in the perfusate. In the absence of binding the extraction ratio of diazepam was high, 0.93–0.995. Extraction decreased dramatically as the degree of binding was increased. The data are more consistent with the “parallel-tube” model than with the “well-stirred” model, two perfusion models that have been used to describe hepatic drug elimination.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF01059274
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