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  • 1
    Digitale Medien
    Digitale Medien
    Bioavailability and elimination of nitrendipine in liver disease (1987)
    Springer
    European journal of clinical pharmacology 32 (1987), S. 563-568 
    Details
    ISSN: 1432-1041
    Schlagwort(e): nitrendipine ; pharmacokinetics ; hepatitis ; liver cirrhosis ; protein binding
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Chemie und Pharmazie , Medizin
    Notizen: Summary Twenty one patients with liver disease (cirrhosis 11, chronic hepatitis 5 and acute hepatitis 5) and 6 healthy volunteers were given a single i.v. dose of nitrendipine 5 mg. Afterwords nitrendipine 20 mg once daily were administered orally for seven days. With the intravenous injection a significant increase in the AUC and elimination half-life of nitrendipine was found in patients with cirrhosis as compared to the normal volunteers. After chronic oral dosing, the area under the plasma concentration-time curve, AUC (0–24), was 94.5 ng ml−1 h and the plasma clearance CL was 1380.6 ml/min in the healthy controls; in patients with cirrhosis the AUC (0–24) h was significantly greater at 309.4 ng ml−1 h and CL had fallen to 686.6 ml/min. Considerable accumulation of nitrendipine was also found in the patients with chronic hepatitis. Nitrendipine could not be detected in urine from any of the subjects. Blood pressure and heart rate were not significantly influenced by the treatment in the various groups investigated. Antipyrine clearance in the patients with cirrhosis was correlated with the nitrendipine plasma clearance. Thus, accumulation of nitrendipine has been demonstrated in the patients with cirrhosis and chronic hepatitis.
    Materialart: Digitale Medien
    URL: http://dx.doi.org/10.1007/BF02455989
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  • 2
    Digitale Medien
    Digitale Medien
    Binding of teicoplanin to human serum albumin (1987)
    Springer
    European journal of clinical pharmacology 33 (1987), S. 191-195 
    Details
    ISSN: 1432-1041
    Schlagwort(e): teicoplanin ; glycopeptide antibiotic ; protein binding ; serum albumin
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Chemie und Pharmazie , Medizin
    Notizen: Summary The interaction between the main components of the new glycopeptide antibiotic teicoplanin, A2–2, A2–3, A2–4, A2–5 and A3–1, and human serum albumin has been studied in vitro by equilibrium dialysis (pH 7.4, 37°C). From Scatchard analysis of the data, the calculated association constants (Ka) were: A2–2, 2.47×104, A2–3, 2.86×104, A2–4, 2.95×104 and A2–5, 3.87×104 mol·l−1. The number of binding sites per albumin molecule ranged between 1.23 to 1.31. A3–1 had a lower affinity with a Ka of about 5×103 mol·l−1. Extrapolated to the in vivo situation, the data suggested that about 90–95% of A2 components will be bound to serum albumin, and about 68–72% of A3–1. The in vitro findings were confirmed by a pharmacokinetic study in volunteers given [14C] teicoplanin i.v., in whom the fraction of teicoplanin bound to serum protein ranged between 87.6 and 90.8%.
    Materialart: Digitale Medien
    URL: http://dx.doi.org/10.1007/BF00544566
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  • 3
    Digitale Medien
    Digitale Medien
    Plasma free fatty acids and protein binding of disopyramide during haemodialysis (1987)
    Springer
    European journal of clinical pharmacology 33 (1987), S. 327-329 
    Details
    ISSN: 1432-1041
    Schlagwort(e): disopyramide ; protein binding ; intraindividual variability ; haemodialysis ; free fatty acids ; drug monitoring
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Chemie und Pharmazie , Medizin
    Notizen: Summary The binding of disopyramide (DSP) to plasma (or serum) proteins was determined using an ultrafiltration technique in three patients undergoing haemodialysis. An increase in the free fraction (FF) of DSP during dialysis occurred together with elevation of the free fatty acid (FFA) level in plasma. The effect of FFA on protein binding in vitro was examined using DSP- and FFA-spiked solutions containing human α1-acid glycoprotein and serum albumin. The FF of DSP rose in proportion to increasing FFA levels, supporting the in vivo observations. The findings suggest that the free concentration of DSP should be routinely monitored, especially in haemodialysis patients.
    Materialart: Digitale Medien
    URL: http://dx.doi.org/10.1007/BF00637572
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  • 4
    Digitale Medien
    Digitale Medien
    Effect of probenecid on the elimination and protein binding of ceftriaxone (1988)
    Springer
    European journal of clinical pharmacology 34 (1988), S. 151-156 
    Details
    ISSN: 1432-1041
    Schlagwort(e): ceftriaxone ; probenecid ; drug interaction ; protein binding ; pharmacokinetics
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Chemie und Pharmazie , Medizin
    Notizen: Summary The kinetics and binding parameters of ceftriaxone have been characterized in eight normal subjects who received, in sequence, 1.0 g ceftriaxone and 1.0 g ceftriaxone together with 250 and 500 mg probenecid q.i.d. Probenecid increased the total systemic clearance (CL S T ) from 0.244 to 0.312 ml/min/kg, whereas the terminal half-life (t 1/2(β) T ) fell from 8.1 to 6.5 h. In contrast, the renal clearance of free ceftriaxone (CL R F ) was decreased from 2.09 to 1.67 ml/min/kg, confirming a small but significant contribution of tubular secretion to the renal elimination of ceftriaxone. The final value of CL R F was attained with the lower dose probenecid, whereas the non-renal clearance of free ceftriaxone (CL NR F ) fell progressively from 2.78 to 1.90 ml/min/kg with the increasing probenecid dose. The total decrease in the systemic clearance of free ceftriaxone (CL S F ) after the higher dose of probenecid was about 30% (4.87 to 3.57 ml/min/kg). As a consequence of a decreased affinity constant (KA), the average free fraction in plasma (f) was increased by 54% after the low dose and by 74% after the high dose of probenecid. The protein binding interaction between probenecid and ceftriaxone appears to be unique. The results are of limited clinical consequence for ceftriaxone but they emphasise the importance of evaluating the kinetics of the free drug when examining interactions involving probenecid.
    Materialart: Digitale Medien
    URL: http://dx.doi.org/10.1007/BF00614552
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  • 5
    Digitale Medien
    Digitale Medien
    Inhibitory effect of free fatty acids on plasma protein binding of disopyramide in haemodialysis patients (1989)
    Springer
    European journal of clinical pharmacology 36 (1989), S. 175-180 
    Details
    ISSN: 1432-1041
    Schlagwort(e): disopyramide ; haemodialysis ; protein binding ; intraindividual variability ; free fatty acids ; competitive inhibition
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Chemie und Pharmazie , Medizin
    Notizen: Summary The plasma (or serum) protein binding of disopyramide (DSP) in five haemodialysis patients was studied using an ultrafiltration technique. There was an increase in the free fraction of DSP in the plasma on dialysis days in comparison to the levels on interdialysis days, which was associated with an elevation of the free fatty acid levels in the plasma together with the increase of the free fraction of DSP. The inhibitory effect of free fatty acids on DSP binding in an in vitro study was enhanced in proportion to their concentrations, and was shown to be due to competition at one binding site by experiments with oleic acid as a representative displacer. Certain endogenous organic acids, such as indoxyl sulphate, 2-hydroxyhippuric acid and hippuric acid, which are characteristically elevated in chronic renal failure, scarcely affected the protein binding of DSP. The findings indicate that free DSP should be monitored in patients with elevated plasma free fatty acid levels, such as those on haemodialysis therapy.
    Materialart: Digitale Medien
    URL: http://dx.doi.org/10.1007/BF00609191
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  • 6
    Digitale Medien
    Digitale Medien
    Transsynovial distribution and protein binding of pirazolac in patients with rheumatoid arthritis (1986)
    Springer
    European journal of clinical pharmacology 31 (1986), S. 307-311 
    Details
    ISSN: 1432-1041
    Schlagwort(e): pirazolac ; rheumatoid arthritis ; transsynovial distribution ; synovial fluid drug level ; pharmacokinetics ; protein binding
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Chemie und Pharmazie , Medizin
    Notizen: Summary Following a washout period of 7 days, twenty-one patients suffering from rheumatoid arthritis and 3 from osteo-arthritis, who all required articular puncture were given a non-steroidal anti-inflammatory drug pirazolac 450 mg b.d. for 7 days. After discontinuation of the treatment the subjects were divided into 4 groups each of 6 patients. The non protein bound fraction of pirazolac in synovial fluid (0.86%) was significantly higher than that in plasma (0.53%). The average pirazolac concentration in plasma within the dosing interval fluctuated between 30.9 µg/ml and 59 µg/ml, and in synovial fluid between 16.6 µg/ml and 29.9 µg/ml. The half-life of pirazolac calculated from the measured and interpolated data from all patients was 30.9 h in plasma and 66.2 h in synovial fluid. The absolute free concentrations in plasma and synovial fluid (approx. 250 ng/ml) were in the range of the IC50-values for inhibition of cyclooxygenase in mouse peritoneal macrophages.
    Materialart: Digitale Medien
    URL: http://dx.doi.org/10.1007/BF00981129
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  • 7
    Digitale Medien
    Digitale Medien
    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
    Schlagwort(e): aprindine ; moxaprindine ; cirrhosis ; rheumatoid arthritis ; uraemia ; protein binding ; serum protein ; alpha1-acid glycoprotein
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Chemie und Pharmazie , Medizin
    Notizen: 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.
    Materialart: Digitale Medien
    URL: http://dx.doi.org/10.1007/BF00542331
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  • 8
    Digitale Medien
    Digitale Medien
    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
    Schlagwort(e): vinblastine ; protein binding ; Hodgkin's disease
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Chemie und Pharmazie , Medizin
    Notizen: 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.
    Materialart: Digitale Medien
    URL: http://dx.doi.org/10.1007/BF00542223
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  • 9
    Digitale Medien
    Digitale Medien
    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
    Schlagwort(e): haemodialysis ; protein binding ; prednisolone ; clearance ; renal transplant ; free clearance ; dialysate loss
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Chemie und Pharmazie , Medizin
    Notizen: 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.
    Materialart: Digitale Medien
    URL: http://dx.doi.org/10.1007/BF01061379
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  • 10
    Digitale Medien
    Digitale Medien
    Diffusion of intramuscular ketoprofen into the cerebrospinal fluid (1985)
    Springer
    European journal of clinical pharmacology 29 (1985), S. 319-321 
    Details
    ISSN: 1432-1041
    Schlagwort(e): ketoprofen ; diffusion ; cerebrospinal Fluid ; CSF level ; protein binding
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Chemie und Pharmazie , Medizin
    Notizen: Summary Serum and cerebrospinal fluid (CSF) concentrations of ketoprofen have been measured in 36 patients hospitalised for sciatica. Diagnostic lumbar puncture was done 15 min to 13 h after a single 100 mg intramuscular dose of ketoprofen. Serum and CSF were sampled at the same time. Free serum concentrations were determined by equilibrium dialysis. Total and free concentrations were assayed by a highly sensitive and specific HPLC method. Ketoprofen rapidly crossed the blood-brain barrier and was detected in CSF 15 min after its administration. The rapid diffusion can be explained by the high lipid solubility of the drug. The CSF level was in equilibrium with the free serum concentration from the second to the 13th hours.
    Materialart: Digitale Medien
    URL: http://dx.doi.org/10.1007/BF00544088
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  • 11
    Digitale Medien
    Digitale Medien
    Pharmacokinetics of fluocortolone in man (1986)
    Springer
    European journal of clinical pharmacology 30 (1986), S. 615-617 
    Details
    ISSN: 1432-1041
    Schlagwort(e): fluocortolone ; pharmacokinetics ; protein binding ; synthetic corticoid ; clearance ; volume of distribution
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Chemie und Pharmazie , Medizin
    Notizen: Summary The kinetics of the synthetic corticoid fluocortolone was determined in 9 healthy female volunteers after a single oral dose of 20 mg. The maximal plasma level fluocortolone (Cmax) of 202±70 ng/ml occurred within 85±32 min of oral intake after which it declined monoexponentially. Total plasma clearance was 6.48±2.07 ml/min·kg and the clearance of unbound fluocortolone was 60.38±26.67 ml/min·kg. Plasma protein binding was 83 to 95%. The volume of distribution at steady-state was 1.01±0.34 l/kg for total fluocortolone and 11.21±3.77 l/kg for unbound drug. The results of the study characterize the kinetics of unbound fluocortolone for the first time. In addition, the kinetics of total fluocortolone presented here confirm values calculated previously.
    Materialart: Digitale Medien
    URL: http://dx.doi.org/10.1007/BF00542423
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  • 12
    Digitale Medien
    Digitale Medien
    Non-linear elimination and protein binding of probenecid (1987)
    Springer
    European journal of clinical pharmacology 32 (1987), S. 395-401 
    Details
    ISSN: 1432-1041
    Schlagwort(e): probenecid ; Michaelis-Menten kinetics ; protein binding ; pharmacokinetics ; healthy volunteers
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Chemie und Pharmazie , Medizin
    Notizen: Summary Six healthy volunteers were given probenecid 0.5, 1 and 2 g p.o. and 0.5 g i.v. The protein binding of probenecid at different concentrations in human plasma was estimated by equilibrium dialysis. The free fraction was found to increase nonlinearly with increasing total probenecid concentration, up to a maximum free fraction of 26%. The plasma concentration-time data after the oral doses were described by a one-compartment open model with first-order absorption and Michaelis-Menten elimination. The mean absorption rate constant 0.0072 min−1 was dose-independent, and the maximal rate of elimination (mean 1429 µg/min) did not differ between doses whether calculated from the total or free concentrations. The Michaelis-Menten constant decreased significantly from 67.1 to 55.5 µg/ml as the dose increased from 1 g to 2 g, while the unbound Michaelis-Menten constant remained unchanged. The elimination of probenecid after the 0.5 g dose was in the linear region of the Michaelis-Menten elimination when calculated from the total and the free concentrations. The volume of distribution increased only slightly from 9.5 to 11.4 l as the dose increased from 0.5 to 2 g, but the unbound volume of distribution decreased significantly from 164 to 99 l. Absorption was complete and was independent of the dose administered.
    Materialart: Digitale Medien
    URL: http://dx.doi.org/10.1007/BF00543976
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  • 13
    Digitale Medien
    Digitale Medien
    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
    Schlagwort(e): chlormethiazole ; cirrhosis of the liver ; antipyrine ; protein binding ; pharmacokinetics ; healthy volunteers
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Chemie und Pharmazie , Medizin
    Notizen: 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.
    Materialart: Digitale Medien
    URL: http://dx.doi.org/10.1007/BF00625801
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  • 14
    Digitale Medien
    Digitale Medien
    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
    Schlagwort(e): naproxen ; renal insufficiency ; metabolism ; protein binding ; single dose ; pharmacokinetics
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Chemie und Pharmazie , Medizin
    Notizen: 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.
    Materialart: Digitale Medien
    URL: http://dx.doi.org/10.1007/BF00563009
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  • 15
    Digitale Medien
    Digitale Medien
    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
    Schlagwort(e): maprotiline ; phenytoin ; uraemia ; protein binding ; alpha1-acid glycoprotein ; haemodialysis
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Chemie und Pharmazie , Medizin
    Notizen: 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.
    Materialart: Digitale Medien
    URL: http://dx.doi.org/10.1007/BF00558388
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  • 16
    Digitale Medien
    Digitale Medien
    Pharmacokinetics of intravenous and oral tolmesoxide (1981)
    Springer
    European journal of clinical pharmacology 19 (1981), S. 119-125 
    Details
    ISSN: 1432-1041
    Schlagwort(e): tolmesoxide ; metabolite ; volunteers ; pharmacokinetics ; intravenous ; oral ; protein binding
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Chemie und Pharmazie , Medizin
    Notizen: 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.
    Materialart: Digitale Medien
    URL: http://dx.doi.org/10.1007/BF00568398
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  • 17
    Digitale Medien
    Digitale Medien
    Intravenous quinidine in congestive cardiomyopathy (1981)
    Springer
    European journal of clinical pharmacology 19 (1981), S. 173-176 
    Details
    ISSN: 1432-1041
    Schlagwort(e): cardiomyopathy ; quinidine ; left ventricular performance ; protein binding
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Chemie und Pharmazie , Medizin
    Notizen: 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.
    Materialart: Digitale Medien
    URL: http://dx.doi.org/10.1007/BF00561944
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  • 18
    Digitale Medien
    Digitale Medien
    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
    Schlagwort(e): furosemide ; probenecid ; protein binding ; natriuretic ; interaction ; diuretic effect
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Chemie und Pharmazie , Medizin
    Notizen: 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.
    Materialart: Digitale Medien
    URL: http://dx.doi.org/10.1007/BF00874661
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  • 19
    Digitale Medien
    Digitale Medien
    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
    Schlagwort(e): disopyramide ; protein binding ; vacutainer® ; alpha-1-acid-glycoprotein
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Chemie und Pharmazie , Medizin
    Notizen: 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.
    Materialart: Digitale Medien
    URL: http://dx.doi.org/10.1007/BF00542466
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  • 20
    Digitale Medien
    Digitale Medien
    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
    Schlagwort(e): etidocaine ; protein binding ; pregnancy ; alpha1-acid glycoprotein ; labour ; free fatty acids
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Chemie und Pharmazie , Medizin
    Notizen: 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.
    Materialart: Digitale Medien
    URL: http://dx.doi.org/10.1007/BF00542552
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  • 21
    Digitale Medien
    Digitale Medien
    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
    Schlagwort(e): sulphinpyrazone ; tolbutamide ; drug metabolism ; drug interaction ; protein binding ; elimination of tolbutamide
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Chemie und Pharmazie , Medizin
    Notizen: 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.
    Materialart: Digitale Medien
    URL: http://dx.doi.org/10.1007/BF00548400
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  • 22
    Digitale Medien
    Digitale Medien
    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
    Schlagwort(e): doxorubicin ; 5-fluorouracil ; pharmacokinetics ; parotid saliva ; plasma concentration ; protein binding
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Chemie und Pharmazie , Medizin
    Notizen: 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.
    Materialart: Digitale Medien
    URL: http://dx.doi.org/10.1007/BF00613829
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  • 23
    Digitale Medien
    Digitale Medien
    Cefodizime penetration into skin suction blister fluid following a single intravenous dose (1986)
    Springer
    European journal of clinical pharmacology 30 (1986), S. 295-298 
    Details
    ISSN: 1432-1041
    Schlagwort(e): cefodizime ; skin suction blister fluid ; pharmacokinetics ; protein binding ; healthy subjects
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Chemie und Pharmazie , Medizin
    Notizen: Summary Cefodizime pharmacokinetics was investigated, evaluating drug concentrations in serum, skin suction blister fluid (SBF), saliva and urine in six healthy male subjects who were administered a 1-g dose intravenously. Serum levels in five subjects can be described according to a two-compartment open model; terminal half-life is 181±14 min. Volume of distribution (Vdβ) amounts to 15.3±1.61, serum clearance to 59±6 ml/min, renal clearance to 33±3 ml/min. Of the administered dose, 54% is renally excreted unchanged within 27 h. Unbound drug fraction in serum is 19.0% and in SBF 38.4%. Thus renal clearance of free cefodizime amounts to 172 ml/min, Vdss to 68.91 (free drug). Whereas cefodizime has not been detected in saliva samples, SBF concentration 3–9 h post administration parallel serum levels, amounting to 40% of the respective serum concentration. At 9 h, unbound cefodizime concentrations in SBF amount to 1.4±0.4 µg/ml, this value being well above the MIC90% values of many clinically relevant bacteria.
    Materialart: Digitale Medien
    URL: http://dx.doi.org/10.1007/BF00541531
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  • 24
    Digitale Medien
    Digitale Medien
    Lidocaine protein binding in preeclampsia (1987)
    Springer
    European journal of clinical pharmacology 31 (1987), S. 719-722 
    Details
    ISSN: 1432-1041
    Schlagwort(e): lidocaine ; preeclampsia ; protein binding ; alpha1-acid glycoprotein ; parturients
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Chemie und Pharmazie , Medizin
    Notizen: Summary The effect of preeclampsia on the binding of lidocaine to serum proteins was studied in 25 term parturients with severe preeclampsia and in 21 normal parturients serving as controls. There were no statistically significant differences in mean lidocaine free fraction, binding ratio, or serum AAG levels in the control vs preeclamptic patients, respectively. Binding ratio was strongly correlated with AAG concentration for the control (r=0.91) and preeclamptic (r=0.85) patients. A statistically significant difference was observed in the slopes of the lines relating binding ratio to AAG. Preeclampsia had little affect on serum AAG concentrations and lidocaine binding ratio. Preeclampsia may alter the interaction of lidocaine with binding sites on AAG without a significant change in lidocaine free fraction.
    Materialart: Digitale Medien
    URL: http://dx.doi.org/10.1007/BF00541302
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  • 25
    Digitale Medien
    Digitale Medien
    Salicylate protein binding in serum from young and elderly subjects as measured by diafiltration (1985)
    Springer
    European journal of clinical pharmacology 28 (1985), S. 339-345 
    Details
    ISSN: 1432-1041
    Schlagwort(e): salicylate ; protein binding ; elderly ; diafiltration ; binding constants
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Chemie und Pharmazie , Medizin
    Notizen: Summary The protein binding of salicylate was measured by continuous ultrafiltration (diafiltration) at 22°C in serum obtained from 5 healthy young (mean age: 27 years) and 5 healthy elderly (mean age: 73 years) male volunteers. Unbound salicylate increased disproportionately with increasing total salicylate concentration, up to 7000 µmol, in all sera. The fraction bound of salicylate was significantly lower in sera from elderly but this was not due to decreased albumin or total protein concentrations. The binding of salicylate to serum proteins was characterized by two classes of binding sites. The high affinity site had an association constant of either 94901/mol (young) or 75601/mol (elderly) and the number of binding sites was either 4.7 (young) or 3.7 (elderly). The total binding capacity of the low affinity site, 1121/mol, in sera from elderly was significantly less than the binding capacity, 631l/mol, in sera from young. Differences in binding capacity of the low affinity site partially accounted for a two to three-fold increase in the salicylate free fraction in elderly sera. These data suggest that age-related differences in serum protein binding may influence salicylate pharmacokinetics.
    Materialart: Digitale Medien
    URL: http://dx.doi.org/10.1007/BF00543334
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  • 26
    Digitale Medien
    Digitale Medien
    Plasma protein binding of imipramine in patients with rheumatoid arthritis (1985)
    Springer
    European journal of clinical pharmacology 28 (1985), S. 693-696 
    Details
    ISSN: 1432-1041
    Schlagwort(e): imipramine ; rheumatoid arthritis ; protein binding ; acute phase proteins
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Chemie und Pharmazie , Medizin
    Notizen: Summary In 23 patients with rheumatoid arthritis the plasma protein binding of3H-imipramine and the plasma levels of 13 proteins were measured in order to examine the significance of the proteins for the binding of imipramine. The degree of3H-imipramine binding did not differ significantly from that in healthy controls. It was positively correlated with the concentrations of fibrinogen, α1-acid-glycoprotein, ceruloplasmin, complement C3c, haptoglobin and hemopexin. Erythrocyte sedimentation rate was also highly positively correlated with binding. The concentration of several of the proteins showed a significant covariation. The3H-imipramine binding was negatively correlated with the concentration of albumin and the latter was negatively correlated with some of the proteins mentioned-above. No correlation with the levels of apolipoproteins A and B was found. There appears to be more a qualitative than a quantitative change in3H-imipramine binding in patients with rheumatoid arthritis.
    Materialart: Digitale Medien
    URL: http://dx.doi.org/10.1007/BF00607918
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  • 27
    Digitale Medien
    Digitale Medien
    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
    Schlagwort(e): bromocriptine ; Parkinson's disease ; plasma level ; salivary level ; protein binding ; pharmacokinetics
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Chemie und Pharmazie , Medizin
    Notizen: 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.
    Materialart: Digitale Medien
    URL: http://dx.doi.org/10.1007/BF00561586
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  • 28
    Digitale Medien
    Digitale Medien
    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
    Schlagwort(e): piretanide ; uraemia ; protein binding
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Chemie und Pharmazie , Medizin
    Notizen: 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.
    Materialart: Digitale Medien
    URL: http://dx.doi.org/10.1007/BF00637619
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  • 29
    Digitale Medien
    Digitale Medien
    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
    Schlagwort(e): cephalosporin ; ceftriaxone ; protein binding ; non-linear pharmacokinetics ; intravenous injection ; plasma levels
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Chemie und Pharmazie , Medizin
    Notizen: 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).
    Materialart: Digitale Medien
    URL: http://dx.doi.org/10.1007/BF00606428
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  • 30
    Digitale Medien
    Digitale Medien
    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
    Schlagwort(e): benserazide ; carbidopa ; serotonin ; 5HTP-treatment ; metabolism ; decarboxylase inhibitors ; cerebrospinal fluid metabolites ; protein binding
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Chemie und Pharmazie , Medizin
    Notizen: 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.
    Materialart: Digitale Medien
    URL: http://dx.doi.org/10.1007/BF01061381
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  • 31
    Digitale Medien
    Digitale Medien
    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
    Schlagwort(e): hypertensive crisis ; diazoxide ; protein binding ; dose response ; diazoxide assay ; plasma half-life ; individual variation
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Chemie und Pharmazie , Medizin
    Notizen: 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.
    Materialart: Digitale Medien
    URL: http://dx.doi.org/10.1007/BF00613809
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  • 32
    Digitale Medien
    Digitale Medien
    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
    Schlagwort(e): propranolol ; protein binding ; genetic factors ; environmental factors ; plasma orosomucoid ; plasma albumin
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Chemie und Pharmazie , Medizin
    Notizen: 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.
    Materialart: Digitale Medien
    URL: http://dx.doi.org/10.1007/BF00542107
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  • 33
    Digitale Medien
    Digitale Medien
    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
    Schlagwort(e): mexiletine ; myocardial infarction ; pharmacokinetics ; gastro-intestinal absorption ; protein binding
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Chemie und Pharmazie , Medizin
    Notizen: 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.
    Materialart: Digitale Medien
    URL: http://dx.doi.org/10.1007/BF00542518
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  • 34
    Digitale Medien
    Digitale Medien
    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
    Schlagwort(e): piroxicam ; rheumatoid arthritis ; protein binding ; synovial fluid ; plasma
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Chemie und Pharmazie , Medizin
    Notizen: 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.
    Materialart: Digitale Medien
    URL: http://dx.doi.org/10.1007/BF00542141
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  • 35
    Digitale Medien
    Digitale Medien
    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
    Schlagwort(e): mebendazole ; haemodialysis ; echinococcosis ; pharmacokinetics ; protein binding
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Chemie und Pharmazie , Medizin
    Notizen: 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).
    Materialart: Digitale Medien
    URL: http://dx.doi.org/10.1007/BF00544053
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  • 36
    Digitale Medien
    Digitale Medien
    Naproxen disposition in patients with alcoholic cirrhosis (1984)
    Springer
    European journal of clinical pharmacology 27 (1984), S. 291-296 
    Details
    ISSN: 1432-1041
    Schlagwort(e): naproxen ; cirrhosis ; pharmacokinetics ; protein binding ; nonsteroidal antiinflammatory drugs
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Chemie und Pharmazie , Medizin
    Notizen: 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.
    Materialart: Digitale Medien
    URL: http://dx.doi.org/10.1007/BF00542162
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  • 37
    Digitale Medien
    Digitale Medien
    Pharmacokinetics of ketanserin in man (1983)
    Springer
    European journal of clinical pharmacology 25 (1983), S. 73-76 
    Details
    ISSN: 1432-1041
    Schlagwort(e): ketanserin ; pharmacokinetics ; protein binding ; excretion ; oral dosing ; i.v. injection ; first-pass effect ; antihypertensive drug ; serotonin antagonist
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Chemie und Pharmazie , Medizin
    Notizen: 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.
    Materialart: Digitale Medien
    URL: http://dx.doi.org/10.1007/BF00544018
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  • 38
    Digitale Medien
    Digitale Medien
    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
    Schlagwort(e): lidocaine ; alpha1-acid glycoprotein ; protein binding ; free fraction ; displacement ; basic drug interaction
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Chemie und Pharmazie , Medizin
    Notizen: 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.
    Materialart: Digitale Medien
    URL: http://dx.doi.org/10.1007/BF01037957
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  • 39
    Digitale Medien
    Digitale Medien
    Protein binding of enprofylline (1983)
    Springer
    European journal of clinical pharmacology 25 (1983), S. 703-708 
    Details
    ISSN: 1432-1041
    Schlagwort(e): enprofylline ; 3-propylxanthine ; protein binding ; equilibrium dialysis ; theophylline ; ultrafiltration ; pH effect ; species differences
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Chemie und Pharmazie , Medizin
    Notizen: 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).
    Materialart: Digitale Medien
    URL: http://dx.doi.org/10.1007/BF00542362
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  • 40
    Digitale Medien
    Digitale Medien
    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
    Schlagwort(e): S-adenosyl-L-methionine ; pharmacokinetics ; protein binding ; dose-dependent kinetics ; healthy volunteers ; urinary excretion
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Chemie und Pharmazie , Medizin
    Notizen: 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.
    Materialart: Digitale Medien
    URL: http://dx.doi.org/10.1007/BF02395218
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  • 41
    Digitale Medien
    Digitale Medien
    Pharmacokinetics and distribution of flucloxacillin in pacemaker patients (1985)
    Springer
    European journal of clinical pharmacology 27 (1985), S. 713-719 
    Details
    ISSN: 1432-1041
    Schlagwort(e): flucloxacillin ; cardiac pacemaker ; pharmacokinetics ; protein binding ; tissue fluid ; elderly patients
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Chemie und Pharmazie , Medizin
    Notizen: Summary The pharmacokinetics of flucloxacillin in plasma and tissue fluid after i.v. infusion of 1 g was analyzed according to an open two-compartment model in 19 patients with bradyarrhythmias (mean age 70.8 years) admitted for implantation or replacement of a permanent pacemaker system. After the first infusion of flucloxacillin (5 min), the distribution phase was rapid (t1/2α=0.13 h). The plasma half-life of elimination (t1/2β) was 1.51 h, which is almost twice as long as reported in healthy volunteers. Total plasma clearance (93.1 ml/min) was also lower than is usually found in healthy individuals, due to low renal clearance of flucloxacillin (60.2 ml/min). The total apparent volume of distribution during the β-phase (Vdarea) was 0.172 l/kg and distribution in the central compartment (Vc) 0.064 l/kg. In each patient plasma protein binding and drug distribution to plasma water, proteins and blood cells in whole blood were determined. Binding in plasma to proteins was 91.0% and distribution to blood cells in whole blood 13.8%. The mean distribution volume of free flucloxacillin during the β-phase (Vdβ free) was 2.18 l/kg, which exceeds total body water, suggesting possible intracellular distribution and substantial tissue binding. Plasma concentrations of flucloxacillin after the fourth dose (1 g t.i.d.) were very similar to those obtained after the first infusion and those predicted from the single dose kinetics. The concentration of flucloxacillin in fluid from the pacemaker pockets in 5 patients averaged 12.1 µg/ml and 9.5 µg/ml at 1 and 5 h, respectively, which was more than ten times the MIC-values for Staphylococcus aureus and S. epidermidis. The average concentration ratio (tissue fluid/plasma) was 0.57. Thus the pharmacokinetics of flucloxacillin in these elderly patients exhibited marked differences from what has been found in healthy volunteers. Despite the high degree of plasma protein binding, flucloxacillin appears to distribute rapidly and efficiently to extravascular compartments, such as a pacemaker pocket.
    Materialart: Digitale Medien
    URL: http://dx.doi.org/10.1007/BF00547055
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  • 42
    Digitale Medien
    Digitale Medien
    Human plasma and skin blister fluid levels of griseofulvin following a single oral dose (1985)
    Springer
    European journal of clinical pharmacology 29 (1985), S. 109-113 
    Details
    ISSN: 1432-1041
    Schlagwort(e): griseofulvin ; skin blister fluid levels ; pharmacokinetics ; healthy subjects ; bioavailability ; protein binding
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Chemie und Pharmazie , Medizin
    Notizen: Summary Griseofulvin and 6-demethylgriseofulvin (6-DMG) in plasma, suction blister fluid (SBF) and cantharides blister fluid (CBF) and urinary excretion of 6-DMG, were evaluated following administration of single oral doses of an ultramicrosize and a microsize formulation of griseofulvin to 6 healthy volunteers. The bioavailability of griseofulvin was higher following the ultramicrosize formulation when 64% of the dose was recovered (via metabolites) versus 52% after the microsize preparation. Penetration into skin blister fluid was delayed as compared to plasma levels; the peak concentration in plasma was observed at 3–4 h, whereas griseofulvin in CBF increased up to 6 h. The terminal half-live was calculated from plasma levels to 9.3 h. The half-lives calculated from SBF and CBF concentrations were 9.2 and 9.8 h, respectively, (n=5). In plasma 84% of griseofulvin was bound to proteins, predominantly to albumin; binding in SBF and CBF was 72 and 82%, respectively. 3 h after drug administration the free concentration in plasma significantly exceeded the free concentrations in SBF and CBF. Distribution equilibrium between plasma and skin blister fluid was observed after 27 h. Thus, during chronic administration, the plasma griseofulvin level should reflect its concentration in the target organ.
    Materialart: Digitale Medien
    URL: http://dx.doi.org/10.1007/BF00547378
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  • 43
    Digitale Medien
    Digitale Medien
    Disopyramide pharmacokinetics in patients with acute myocardial infarction (1985)
    Springer
    European journal of clinical pharmacology 28 (1985), S. 45-51 
    Details
    ISSN: 1432-1041
    Schlagwort(e): disopyramide ; myocardial infarction ; antiarrhythmic agent ; pharmacokinetics ; protein binding ; intravenous administration ; oral administration ; gastro-intestinal absorption
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Chemie und Pharmazie , Medizin
    Notizen: Summary To study the effects of acute myocardial infarction on the pharmacokinetics of disopyramide a single oral dose of disopyramide base (200 mg) was administered to 6 patients with myocardial infarction both in the acute (Study I) and recovery (Study II) phases. An intravenous tracer dose of14C-disopyramide (2.5 µg/0.3 mg) was given simultaneously with the oral dose. On the basis of the intravenous tracer data, the volume of distribution, binding to plasma proteins, total plasma clearance, renal clearance and elimination half-life of disopyramide and mono-N-dealkyl disopyramide were the same in Studies I and II. The peak serum concentrations of disopyramide after oral dosing in Studies I and II were 2.6±1.2 (SEM) and 6.4±1.9 µg/ml, respectively (p〈0.05), the peak times 3.29±1.22 and 1.21±0.39 h (N.S.) and the AUCINF 38.0±7.7 and 60.7±9.9 µg·h·ml−1 (p〈0.05). The recovery of disopyramide in urine over 3 days averaged 46% and 47% of dose, and that of mono-N-dealkyl disopyramide 22% and 16% of the dose, respectively. Thus, the gastrointestinal absorption of disopyramide was disturbed, resulting in low plasma concentrations after oral dosing, whereas the elimination of disopyramide was unaltered in the acute phase of myocardial infarction.
    Materialart: Digitale Medien
    URL: http://dx.doi.org/10.1007/BF00635707
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  • 44
    Digitale Medien
    Digitale Medien
    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
    Schlagwort(e): quinidine ; digoxin ; anuria ; haemodialysis ; serum digoxin ; plasma quinidine ; protein binding ; extrarenal digoxin clearance
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Chemie und Pharmazie , Medizin
    Notizen: 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.
    Materialart: Digitale Medien
    URL: http://dx.doi.org/10.1007/BF00637614
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  • 45
    Digitale Medien
    Digitale Medien
    Excretion of paracetamol in human breast milk (1981)
    Springer
    European journal of clinical pharmacology 20 (1981), S. 123-125 
    Details
    ISSN: 1432-1041
    Schlagwort(e): paracetamol ; breast milk ; plasma ; drug excretion in breast milk ; protein binding
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Chemie und Pharmazie , Medizin
    Notizen: 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.
    Materialart: Digitale Medien
    URL: http://dx.doi.org/10.1007/BF00607148
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  • 46
    Digitale Medien
    Digitale Medien
    Interaction of sulphinpyrazone with warfarin (1982)
    Springer
    European journal of clinical pharmacology 22 (1982), S. 327-331 
    Details
    ISSN: 1432-1041
    Schlagwort(e): Sulphinpyrazone ; warfarin ; drug metabolism ; drug interaction ; protein binding
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Chemie und Pharmazie , Medizin
    Notizen: 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.
    Materialart: Digitale Medien
    URL: http://dx.doi.org/10.1007/BF00548401
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  • 47
    Digitale Medien
    Digitale Medien
    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
    Schlagwort(e): thioridazine ; alcoholism ; thioridazine metabolites ; serum concentrations ; protein binding ; α1-acid glycoprotein
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Chemie und Pharmazie , Medizin
    Notizen: 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.
    Materialart: Digitale Medien
    URL: http://dx.doi.org/10.1007/BF00613621
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  • 48
    Digitale Medien
    Digitale Medien
    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
    Schlagwort(e): prednisolone ; bioavailability ; non-linear pharmacokinetics ; protein binding
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Chemie und Pharmazie , Medizin
    Notizen: 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.
    Materialart: Digitale Medien
    URL: http://dx.doi.org/10.1007/BF00610064
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  • 49
    Digitale Medien
    Digitale Medien
    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
    Schlagwort(e): heparin ; protein binding ; phenytoin ; prazosin ; lipases ; plasma triglycerides
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Chemie und Pharmazie , Medizin
    Notizen: 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.
    Materialart: Digitale Medien
    URL: http://dx.doi.org/10.1007/BF00543793
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  • 50
    Digitale Medien
    Digitale Medien
    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
    Schlagwort(e): uraemia ; hydroxyflucloxacillin ; flucloxacillin ; isoxazolyl penicillins ; protein binding
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Chemie und Pharmazie , Medizin
    Notizen: 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.
    Materialart: Digitale Medien
    URL: http://dx.doi.org/10.1007/BF00542548
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  • 51
    Digitale Medien
    Digitale Medien
    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
    Schlagwort(e): pinacidil ; hypertension ; pinacidil pyridine-N-oxide ; urinary excretion ; protein binding ; pharmacokinetics ; healthy volunteers
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Chemie und Pharmazie , Medizin
    Notizen: 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.
    Materialart: Digitale Medien
    URL: http://dx.doi.org/10.1007/BF00543493
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  • 52
    Digitale Medien
    Digitale Medien
    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
    Schlagwort(e): S-adenosyl-L-methionine ; pharmacokinetics ; protein binding ; dose-dependent kinetics ; healthy volunteers ; urinary excretion
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Chemie und Pharmazie , Medizin
    Notizen: 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.
    Materialart: Digitale Medien
    URL: http://dx.doi.org/10.1007/BF00553166
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  • 53
    Digitale Medien
    Digitale Medien
    Melphalan concentration dependent plasma protein binding in healthy humans and rats (1987)
    Springer
    European journal of clinical pharmacology 32 (1987), S. 179-185 
    Details
    ISSN: 1432-1041
    Schlagwort(e): melphalan ; protein binding ; plasma ; humans ; rats ; pharmacokinetics
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Chemie und Pharmazie , Medizin
    Notizen: Summary The binding of melphalan to plasma proteins from four healthy humans and from rats was measured by centrifugal ultrafiltration. Melphalan concentrations were determined by HPLC and by measuring 14C-melphalan activity. In whole blood, melphalan was distributed preferentially in plasma. However, a constant fraction, 37%, which was independent of the total melphalan concentration in whole blood, was present within the red blood cells. The binding of melphalan to plasma proteins from humans was less than that from rats. In both, however, the fraction bound was constant throughout the concentration range (0.1 to 9.0 µM) that is achieved during standard-dose melphalan therapy. Albumin was the primary binding protein. At concentrations equal to or in excess of 33 µM, which have been achieved during high-dose melphalan therapy, free plasma melphalan concentrations were no longer linearly related to total drug concentrations, and the plasma protein binding of melphalan in the human became concentration dependent. This occurred at concentrations of 70 µM in the rat. Scatchard analysis of the data indicated the presence of 2 groups of binding sites. Class I sites had 0.03 and 0.4 binding sites per albumin molecule in humans and rats, with respective association constants of 4.43 × 104M−1 and 1.92 × 104M−1. Class II sites had 5.18 and 2.60 binding sites per molecule, with repective association constants of 3.82 × 102M−1 and 2.01 × 102M−1.
    Materialart: Digitale Medien
    URL: http://dx.doi.org/10.1007/BF00542192
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  • 54
    Digitale Medien
    Digitale Medien
    Plasma and synovial fluid meclofenamic acid concentrations in patients with rheumatoid arthritis of the knee (1988)
    Springer
    European journal of clinical pharmacology 35 (1988), S. 199-202 
    Details
    ISSN: 1432-1041
    Schlagwort(e): meclofenamic acid ; synovial fluid ; rheumatoid arthritis ; pharmacokinetics ; protein binding
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Chemie und Pharmazie , Medizin
    Notizen: Summary We have measured plasma and synovial fluid concentrations of meclofenamic acid at 2, 4, 8, and 12 h during steady-state administration (100 mg three times daily for 4–7 days). Paired plasma and synovial samples were obtained pre-treatment and at one of the above times in twelve patients with a diagnosis of rheumatoid arthritis. In addition, the extent of protein binding of meclofenamic acid was assessed in vitro in the pre-treatment plasma and synovial fluid specimens. Peak total concentrations of 1.73 and 0.86 µg·ml−1 were observed in plasma (at 2 h) and synovial fluid (at 4 h) respectively. The extent of protein binding was 99.7 and 99.6% (not significantly different) in plasma and synovial fluid respectively. The results of this study are compared to those from similar reported studies of other nonsteroidal anti-inflamatory compounds.
    Materialart: Digitale Medien
    URL: http://dx.doi.org/10.1007/BF00609253
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  • 55
    Digitale Medien
    Digitale Medien
    Pharmacokinetics of nitrendipine in terminal renal failure (1989)
    Springer
    European journal of clinical pharmacology 36 (1989), S. 467-471 
    Details
    ISSN: 1432-1041
    Schlagwort(e): nitrendipine ; renal failure ; pharmacokinetics ; protein binding
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Chemie und Pharmazie , Medizin
    Notizen: Summary The pharmacokinetics and plasma protein binding of nitrendipine in patients with terminal renal failure have been compared with those in subjects with normal renal function. Kinetic parameters were calculated after a single 40 mg oral dose, an i.v. injection of 3 mg and after a 15 mg i.v. infusion of nitrendipine. Steady-state plasma levels were determined after 5 days of oral treatment with 20 mg b.d. Pharmacokinetic parameters and steady-state plasma levels in patients with renal failure did not differ from those in subjects with normal renal function. Nitrendipine was as highly bound to plasma proteins in patients with renal failure, as in subjects with normal renal function. The plasma protein did not differ between the two. The dosage of nitrendipine need not be modified for kinetic reasons in patients with renal failure.
    Materialart: Digitale Medien
    URL: http://dx.doi.org/10.1007/BF00558071
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  • 56
    Digitale Medien
    Digitale Medien
    Pharmacokinetics of chlorpropamide in epileptic patients: Effects of enzyme induction and urine pH on chlorpropamide elimination (1987)
    Springer
    European journal of clinical pharmacology 32 (1987), S. 297-301 
    Details
    ISSN: 1432-1041
    Schlagwort(e): chlorpropamide ; epileptics ; pharmacokinetics ; antiepileptic drug ; protein binding ; antipyrine test ; urine pH ; excretion
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Chemie und Pharmazie , Medizin
    Notizen: Summary The effects of liver enzyme induction and of urine pH on the pharmacokinetics of chlorpropamide have been studied. A single oral dose of chlorpropamide 250 mg was administered to 8 patients on antiepileptic drugs (phenytoin, carbamazepine) and to 8 healthy volunteers. The half-life of chlorpropamide was significantly shorter in the patients (34.4 h) than in the healthy volunteers (50.2 h), but the difference between the groups in the half-life of antipyrine was even more pronounced (5.1 vs 11.4 h). The clearance and volume of distribution of total chlorpropamide were significantly higher in the patients (2.99 ml·h−1·kg−1 and 126 ml·kg−1) than in the healthy volunteers (1.60 ml·h−1·kg−1 and 106 ml·kg−1). The unbound fraction of chlorpropamide in serum was also higher in the patients (5.7%) than in the healthy subjects (4.4%). Neither the volume of distribution nor the clearance of the free fraction of chlorpropamide differed significantly between the groups. There was a significant correlation between the half-lifes of chlorpropamide and antipyrine, and the half-life of chlorpropamide also had at least as good an inverse correlation with the urinary excretion of unchanged chlorpropamide. The renal clearance of chlorpropamide correlated well with urine pH and was almost 100-fold higher at pH 7 than at pH 5. Both the metabolic and renal clearances of chlorpropamide are important in its elimination. At urine pH higher than 6.5–7, the renal clearance of chlorpropamide represents more than half its total clearance regardless the degree of induction of liver enzymes.
    Materialart: Digitale Medien
    URL: http://dx.doi.org/10.1007/BF00607578
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  • 57
    Digitale Medien
    Digitale Medien
    Total and free steady-state plasma levels and pharmacokinetics of nifedipine in patients with terminal renal failure (1989)
    Springer
    European journal of clinical pharmacology 37 (1989), S. 185-189 
    Details
    ISSN: 1432-1041
    Schlagwort(e): nifedipine ; renal failure ; pharmacokinetics ; protein binding ; blood pressure
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Chemie und Pharmazie , Medizin
    Notizen: Summary The total and free steady-state plasma levels of nifedipine in patients with renal failure have been compared with those in subjects with normal renal function. Studies were done after administration of nifedipine 10 mg t.d.s. p.o. for 5 days, after i.v. infusion of 4·4 mg, and after a single 10 mg oral dose. The systemic clearance of nifedipine after a single i.v.-dose was higher in subjects with renal insufficiency (854 ml/min) than in those with normal renal function (468 ml/min). After the single oral dose the AUC (6100 ng·min·ml−1) and maximum plasma concentration (75.0 ng·ml−1) were lower than in subjects with normal renal function (19300 ng·ml−1; 122 ng·ml−1). The plasma protein binding of nifedipine averaged 95.5% in normal subjects and 94.8% in patients with renal failure. Although free and total steady-state plasma levels of nifedipine tended to be somewhat lower than normal in renal failure, the changes in pharmacokinetics and decreased protein binding of nifedipine did not result in a significantly different steady-state plasma level of the drug. The blood pressure response to a given plasma nifedipine level appeared to be enhanced in renal failure.
    Materialart: Digitale Medien
    URL: http://dx.doi.org/10.1007/BF00558229
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  • 58
    Digitale Medien
    Digitale Medien
    The effect of prednisone and hydrocortisone on the plasma protein binding of prednisolone in man (1986)
    Springer
    European journal of clinical pharmacology 30 (1986), S. 51-55 
    Details
    ISSN: 1432-1041
    Schlagwort(e): prednisolone ; protein binding ; prednisone ; hydrocortisone ; transcortin
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Chemie und Pharmazie , Medizin
    Notizen: Summary The protein binding of prednisolone was studied in plasma obtained from healthy volunteers in the presence of added amounts of prednisone and hydrocortisone. The plasma protein binding was determined using in vitro equilibrium dialysis for 16 h at 37°C against isotonic Krebs-Ringer buffer using radioactive prednisolone. Prednisone appeared to have no effect on prednisolone binding. This surprising result was observed even when prednisone concentrations were more than 35 fold greater than prednisolone concentrations. In contrast, a marked competition between hydrocortisone and prednisolone was observed. These binding data were fit using a nonlinear least squares regression computer program and the capacity and affinity constants for the binding of prednisolone to transcortin and albumin were estimated including the competition for binding sites between prednisolone and hydrocortisone. The results from these studies compare favorably with recent parameter calculations, and our previous work where differences in binding were noted between cushingoid and noncushingoid patients.
    Materialart: Digitale Medien
    URL: http://dx.doi.org/10.1007/BF00614195
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  • 59
    Digitale Medien
    Digitale Medien
    Cirrhosis of the liver markedly impairs the elimination of mexiletine (1986)
    Springer
    European journal of clinical pharmacology 30 (1986), S. 83-88 
    Details
    ISSN: 1432-1041
    Schlagwort(e): mexiletine ; cirrhosis of the liver ; antiarrhythmic agents ; pharmacokinetics ; intravenous administration ; protein binding
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Chemie und Pharmazie , Medizin
    Notizen: Summary To study the effects of cirrhosis of the liver on the pharmacokinetics of mexiletine a single i.v. dose of 200 mg was administered to six cirrhotic patients and to six healthy controls. The distribution of mexiletine in both study groups was similar, as indicated by similar values of V1 and Vss, but it tended to occur more slowly in the cirrhotics. The plasma protein binding of mexiletine was unchanged in the patients with cirrhosis. The elimination of mexiletine was markedly retarded in the cirrhotics, as indicated by its lower total clearance (2.31 vs. 8.27 ml/kg/h,) lower total elimination rate constant (0.059 vs 0.353 h−1), and longer elimination half-life (28.7 vs 9.9 h). The antipyrine half-life was 38.3 h in the patients and 14.7 h in the controls. One healthy volunteer had a Morgagni-Stokes-Adams type of syncopal attack 5 min after administration of mexiletine due to disturbance of AV conduction induced by the drug. Thus, on a pharmacokinetic basis the loading dose of mexiletine need not be modified in cirrhotic patients, whereas the maintenance dosage should be reduced to one fourth — one third of the usual dose.
    Materialart: Digitale Medien
    URL: http://dx.doi.org/10.1007/BF00614201
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  • 60
    Digitale Medien
    Digitale Medien
    Pharmacokinetics of tenoxicam in patients with impaired renal function (1986)
    Springer
    European journal of clinical pharmacology 29 (1986), S. 697-701 
    Details
    ISSN: 1432-1041
    Schlagwort(e): tenoxicam ; renal insufficiency ; non-steroidal antiinflammatory agents ; protein binding ; metabolism ; pharmacokinetics
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Chemie und Pharmazie , Medizin
    Notizen: Summary The pharmacokinetics of tenoxicam after a single oral dose of 20 mg has been studied in 12 patients with various degrees of decreased renal function. Unchanged tenoxicam and its 5′OH-metabolite in plasma and urine were determined by HPLC. The mean areas under the plasma concentration-time curve (138±53 µg/ml·h) and terminal half-lives in patients with impaired renal function did not differ from values previously reported in normal volunteers, nor did the peak concentration of tenoxicam. The half-life of 5′OH-tenoxicam and unchanged tenoxicam where the same. The urinary excretion of 5′OH-tenoxicam fell with decreasing renal function. Thus no dosage adjustment should be necessary and the usual daily dose of tenoxicam may be administered once daily also to patients with renal failure.
    Materialart: Digitale Medien
    URL: http://dx.doi.org/10.1007/BF00615961
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  • 61
    Digitale Medien
    Digitale Medien
    Use of saliva for monitoring oxcarbazepine therapy in epileptic patients (1986)
    Springer
    European journal of clinical pharmacology 31 (1986), S. 91-94 
    Details
    ISSN: 1432-1041
    Schlagwort(e): oxcarbazepine ; epilepsy ; saliva ; protein binding ; drug monitoring ; 10-OH-carbazepine
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Chemie und Pharmazie , Medizin
    Notizen: Summary The utility of saliva sampling in monitoring oxcarbazepine therapy has been assessed in 17 epileptic outpatients treated with a mean dose 22.7 mg/kg/d for 19–411 days, i. e. at steady-state. Blood was collected before the morning dose measurement of the plasma 10-OH-carbazepine concentration and determination of the protein bound fraction. Immediately after blood sampling resting saliva and saliva produced after a masticatory stimulus were collected. Using equilibrium dialysis and an ultrafiltration technique the protein binding of 10-OH-carbazepine was found to be 40% and 45%, respectively. When the degree of protein binding was expressed as the ratio between the corresponding saliva and plasma concentrations of 10-OH-carbazepine, the concentration in resting saliva indicated that no drug was bound to plasma protein, whereas the use of stimulated saliva suggested a protein-bound fraction of 35%. The concentration in stimulated saliva reflects the free fraction of 10-OH-carbazepine, but regression analysis of paired salivary and plasma values showed that the prediction of plasma concentrations from levels in saliva is uncertain. This, together with the low degree of plasma protein binding, leads to the conclusion that it would be preferable to monitor total plasma concentrations if therapeutic drug monitoring of oxcarbazepine were to prove essential in epileptic patients.
    Materialart: Digitale Medien
    URL: http://dx.doi.org/10.1007/BF00870993
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  • 62
    Digitale Medien
    Digitale Medien
    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 
    Details
    ISSN: 1573-8744
    Schlagwort(e): sulfisoxazole ; pharmacokinetics—unbound drug ; pharmacokinetics—total drug ; bioavailability ; healthy volunteers ; protein binding
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Chemie und Pharmazie
    Notizen: 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.
    Materialart: Digitale Medien
    URL: http://dx.doi.org/10.1007/BF01062333
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  • 63
    Digitale Medien
    Digitale Medien
    Clinical pharmacokinetics of disopyramide (1982)
    Springer
    Journal of pharmacokinetics and pharmacodynamics 10 (1982), S. 465-494 
    Details
    ISSN: 1573-8744
    Schlagwort(e): disopyramide ; pharmacokinetics ; bioavailability ; metabolite ; half-life ; protein binding ; disease states ; drug-drug interaction
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Chemie und Pharmazie
    Notizen: 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.
    Materialart: Digitale Medien
    URL: http://dx.doi.org/10.1007/BF01059032
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  • 64
    Digitale Medien
    Digitale Medien
    Pharmacokinetics of triamterene and its metabolite in man (1982)
    Springer
    Journal of pharmacokinetics and pharmacodynamics 10 (1982), S. 507-523 
    Details
    ISSN: 1573-8744
    Schlagwort(e): triamterene ; sulfate conjugate ; protein binding ; blood/plasma ratio ; renal clearance ; HPLC
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Chemie und Pharmazie
    Notizen: 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.
    Materialart: Digitale Medien
    URL: http://dx.doi.org/10.1007/BF01059034
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  • 65
    Digitale Medien
    Digitale Medien
    Comparative pharmacokinetics of benzodiazepines in dog and man (1982)
    Springer
    Journal of pharmacokinetics and pharmacodynamics 10 (1982), S. 411-426 
    Details
    ISSN: 1573-8744
    Schlagwort(e): benzodiazepines ; interspecies variation ; half-life ; metabolic clearance ; volume of distribution ; protein binding
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Chemie und Pharmazie
    Notizen: 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.
    Materialart: Digitale Medien
    URL: http://dx.doi.org/10.1007/BF01065172
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  • 66
    Digitale Medien
    Digitale Medien
    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 
    Details
    ISSN: 1573-8744
    Schlagwort(e): disopyramide ; pharmacokinetics ; pharmacodynamics ; electrophysiology ; protein binding ; modelling
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Chemie und Pharmazie
    Notizen: 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.
    Materialart: Digitale Medien
    URL: http://dx.doi.org/10.1007/BF01059552
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  • 67
    Digitale Medien
    Digitale Medien
    The impact of neglecting nonlinear plasma-protein binding on disopyramide bioavailability studies (1986)
    Springer
    Journal of pharmacokinetics and pharmacodynamics 14 (1986), S. 365-379 
    Details
    ISSN: 1573-8744
    Schlagwort(e): disopyramide ; bioavailability ; protein binding ; nonlinear ; sustained release ; pharmacokinetics ; ultrafiltration ; immunoassay
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Chemie und Pharmazie
    Notizen: Abstract Disopyramide has nonlinear protein binding and thus the relationship between the extent of its bioavailability and AUC,the area under the plasma concentration-time curve, is (1) nonlinear and (2) absorption rate-dependent. The unbound species follows linear pharmacokinetics. A solution of disopyramide, the innovator's product, and two generic formulations were found to be statistically indistinguishable in their bioavailability of disopyramide, whether comparison was based upon AUCor area under the plasma unbound concentration-time curve (AUCu).The AUCand AUCugave similar results because of truly similar bioavailability, coupled with sufficiently similar release rates, among the four preparations chosen for study. The concentration dependence of disopyramide protein binding and the time course of unbound plasma concentrations were fit by models which then allowed prediction of AUCunder various biopharmaceutical scenarios. Nonlinear binding of disopyramide to plasma proteins renders AUCan insensitive parameter for the discrimination of products with different extents of bioavailability; immediate release products allowing bioavailabilities of 75 or 125% relative to the solution can generate AUCs86 and 112%, respectively, of that from the solution. Nonlinear binding, furthermore, leads to a tendency for AUC tooverestimate the bioavailability of slower release products in single-dose studies; if AUCwere the index of bioavailability, products permitting the same bioavailability as the solution but releasing over 12 hr could appear to allow 114% relative bioavailability. Moreover, in some situations the bias arising from the insensitivity of AUCto product differences can be reinforced by the dependence of AUCon release rate; an apparent relative bioavailability of 80% can be achieved by a 12-hr release product allowing a true relative bioavailability of a mere 58%. While multiple-dose studies appear largely to avoid the tendency to overestimate low bioavailability in slow-release products, in these studies AUCappears to be even more insensitive in resolving discrepancies between products. Assay technology now available makes AUCua feasible and more reliable index of bioavailability than AUCwhen plasma protein binding of drugs is nonlinear.
    Materialart: Digitale Medien
    URL: http://dx.doi.org/10.1007/BF01059197
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  • 68
    Digitale Medien
    Digitale Medien
    Protein binding of glycopeptide antibiotics with diverse physical-chemical properties in mouse, rat, and human serum (1987)
    Springer
    Journal of pharmacokinetics and pharmacodynamics 15 (1987), S. 5-13 
    Details
    ISSN: 1573-8744
    Schlagwort(e): Structure-activity relationships ; pharmacokinetics ; protein binding ; glycopeptide antibiotics ; charge ; lipophilicity
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Chemie und Pharmazie
    Notizen: Abstract In previous studies of the pharmacokinetics and urinary excretion of nine glycopeptides with diverse isoelectric points (pI),as pIdecreases, the total systemic and renal clearance, urinary recovery, and volume of distribution decrease, whereas the half-life increases. With glycopeptides of similar pI,clearance decreases and half-life increases with increasing lipophilicity. The present study examines the serum protein binding of these glycopeptide antibiotics in mouse, rat, and human serum and calculates the previously reported pharmacokinetic parameters for these drugs based on unbound concentration. Increased negative charge and lipophilicity increase serum protein binding (90-fold, fu 83% to 0.96%), which decreases the renal clearance and total systemic clearance (90-fold, 16.4 to 0.18 ml/min/kg) of these drugs. Increased serum protein binding also decreases the volume of distribution of these compounds, but this change is relatively small (sixfold, 755 to 131 ml/kg) compared with the change in total systemic clearance causing an increase in elimination half-life (25-fold, 20 to 492 min). The results demonstrate that the large differences in the total systemic clearance and half-life of these glycopeptide antibiotics are primarily due to dramatic differences in serum protein binding and notto differences in the intrinsic elimination processes (enzymes or transport proteins). It appears that the same physical-chemical properties that govern the protein binding and pharmacokinetics of small organic molecules govern the disposition of these high-molecular weight glycopeptide antibiotics.
    Materialart: Digitale Medien
    URL: http://dx.doi.org/10.1007/BF01062935
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  • 69
    Digitale Medien
    Digitale Medien
    Pharmacokinetics and bioavailability of intravenous, oral, and rectal nitrazepam in humans (1982)
    Springer
    Journal of pharmacokinetics and pharmacodynamics 10 (1982), S. 231-245 
    Details
    ISSN: 1573-8744
    Schlagwort(e): nitrazepam ; i.v. ; oral ; rectal administration ; protein binding ; pharmacokinetics ; bioavailability
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Chemie und Pharmazie
    Notizen: 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.
    Materialart: Digitale Medien
    URL: http://dx.doi.org/10.1007/BF01059259
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  • 70
    Digitale Medien
    Digitale Medien
    Plasma protein binding of furosemide in kidney transplant patients (1982)
    Springer
    Journal of pharmacokinetics and pharmacodynamics 10 (1982), S. 663-674 
    Details
    ISSN: 1573-8744
    Schlagwort(e): furosemide ; protein binding ; kidney transplant ; renal transplant
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Chemie und Pharmazie
    Notizen: 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.
    Materialart: Digitale Medien
    URL: http://dx.doi.org/10.1007/BF01062547
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  • 71
    Digitale Medien
    Digitale Medien
    Disopyramide pharmacokinetics and bioavailability following the simultaneous administration of disopyramide and14C-disopyramide (1984)
    Springer
    Journal of pharmacokinetics and pharmacodynamics 12 (1984), S. 289-313 
    Details
    ISSN: 1573-8744
    Schlagwort(e): protein binding ; pharmacokinetics ; bioavailability ; disopyramide ; heart failure
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Chemie und Pharmazie
    Notizen: 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.
    Materialart: Digitale Medien
    URL: http://dx.doi.org/10.1007/BF01061722
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  • 72
    Digitale Medien
    Digitale Medien
    The macromolecular binding of prednisone in plasma of healthy volunteers including pregnant women and oral contraceptive users (1985)
    Springer
    Journal of pharmacokinetics and pharmacodynamics 13 (1985), S. 561-569 
    Details
    ISSN: 1573-8744
    Schlagwort(e): prednisone ; prednisolone ; protein binding ; pregnancy ; oral contraceptives ; transcortin ; albumin
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Chemie und Pharmazie
    Notizen: Abstract The macromolecular binding of prednisone has been studied in the plasma of eight healthy human volunteers. The subjects included two control males, two control females, two females taking estrogen-containing oral contraceptives, and two females in the third trimester of pregnancy. All volunteers exhibited the expected nonlinear plasma binding of prednisolone with free fraction increasing as the total prednisolone concentration was increased. Both the oral contraceptive and pregnant subjects had increased transcortin binding capacity over the control volunteers as evidenced by their increased binding of prednisolone. Prednisone macromolecular binding, however, was not altered by either changing total prednisone concentration or transcortin binding capacity. The mean prednisone free fraction was 0.250 ± 0.027 in the eight subjects over the concentration range 0–2500 ng/ml. The addition of prednisolone in up to a 25- fold excess did not alter prednisone's free fraction. Prednisone apparently does not bind to transcortin with the same strong affinity that characterizes prednisolone's binding, and due to albumin's extensive binding capacity, prednisone macromolecular binding is not saturable over the pharmacological drug concentration range.
    Materialart: Digitale Medien
    URL: http://dx.doi.org/10.1007/BF01058901
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  • 73
    Digitale Medien
    Digitale Medien
    Theoretical study of the influence of the circadian rhythm of plasma protein binding on cisplatin area under the curve (1986)
    Springer
    Journal of pharmacokinetics and pharmacodynamics 14 (1986), S. 79-93 
    Details
    ISSN: 1573-8744
    Schlagwort(e): protein binding ; cisplatin ; circadian rhythm ; AUC ; model
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Chemie und Pharmazie
    Notizen: Abstract A mathematical model for area under the curve (AUC)determination is proposed taking into account the circadian variation of cisplatin protein binding. The main theoretical result obtained with the model is that early morning drug administration (2–4 AM) promotes the highest AUC.The model predicts a maximum AUCvariation, due to the binding variation, ranging between 2.4 and 15%. The minimum of AUCbetween 2.45 and 3.30 PM is in agreement with the minimum nephrotoxicity observed when cisplatin is injected in the afternoon.The model can be applied to other drugs that are irreversively bound to proteins or irreversively bound to other plasma components if the binding rate depends on the time of day. The variation intensity of AUC wasdemonstrated to depend on drug characteristics, but can never be higher than the circadian variation of the protein binding rate.
    Materialart: Digitale Medien
    URL: http://dx.doi.org/10.1007/BF01059285
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  • 74
    Digitale Medien
    Digitale Medien
    Effect of caffeine on ceftriaxone disposition and plasma protein binding in the rat (1986)
    Springer
    Journal of pharmacokinetics and pharmacodynamics 14 (1986), S. 397-408 
    Details
    ISSN: 1573-8744
    Schlagwort(e): caffeine ; ceftriaxone ; plasma ; tissue ; pharmacokinetics ; compartment model ; protein binding
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Chemie und Pharmazie
    Notizen: Abstract Previous studies have shown that caffeine can affect drug kinetics by altering drug binding to plasma protein, drug absorption, or drug distribution. In this study, the effect of caffeine on the in vivoprotein binding and the disposition of ceftriaxone (a highly protein-bound cephalosporin) were investigated in the rat. Ceftriaxone 100mg/kg and caffeine 20mg/kg were i.v. injected via the tail vein and ceftriaxone in plasma, plasma filtrate, urine, feces, and tissues (brain, heart, kidney, liver, gut, lung, and muscle) was assayed by HPLC with UV detection. The fraction of free ceftriaxone in plasma ranged from 5.6 to 32.8% of total ceftriaxone (3–347 μg/ml) without caffeine and showed no alteration by caffeine. The total amount of ceftriaxone excreted in urine and feces was increased significantly (p〈0.05)from 13.1±1.8mg (mean±SD, 54.6% of total) to 15.3 ±1.1 mg (63.8% of total) by caffeine coadministration. The terminal half-life of ceftriaxone in plasma was shortened from 59 to 47 min, and the area under the plasma drug concentration-time curve (AUC)was reduced from 612 to 516 μg hr/ml Although the peak drug concentrations and the times of peak concentration of ceftriaxone in tissues were not altered by caffeine administration, the elimination of ceftriaxone was increased, as indicated by generally shorter half-lives (decreases ranged from 17.5% in liver to 34.2% in brain) and lower AUCvalues (from 9.0% in heart to 54.5% in brain). These results suggest that caffeine does not alter the protein binding of ceftriaxone, but enhances the elimination of ceftriaxone in the rat.
    Materialart: Digitale Medien
    URL: http://dx.doi.org/10.1007/BF01059199
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  • 75
    Digitale Medien
    Digitale Medien
    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 
    Details
    ISSN: 1573-8744
    Schlagwort(e): protein binding ; organic acids ; tissue distribution ; species effects
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Chemie und Pharmazie
    Notizen: 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.
    Materialart: Digitale Medien
    URL: http://dx.doi.org/10.1007/BF01060055
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  • 76
    Digitale Medien
    Digitale Medien
    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 
    Details
    ISSN: 1573-8744
    Schlagwort(e): cannabidiol ; tetrahydrocannabinol ; pharmacokinetics ; cannabinoids ; pharmacodynamics ; metabolism ; renal clearance ; protein binding
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Chemie und Pharmazie
    Notizen: 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.
    Materialart: Digitale Medien
    URL: http://dx.doi.org/10.1007/BF01059266
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  • 77
    Digitale Medien
    Digitale Medien
    Pharmacokinetics of intravenously administered bumetanide in man (1980)
    Springer
    Journal of pharmacokinetics and pharmacodynamics 8 (1980), S. 219-228 
    Details
    ISSN: 1573-8744
    Schlagwort(e): bumetanide ; diuretics ; pharmacokinetics ; three-compartment model ; protein binding
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Chemie und Pharmazie
    Notizen: 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.
    Materialart: Digitale Medien
    URL: http://dx.doi.org/10.1007/BF01059643
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  • 78
    Digitale Medien
    Digitale Medien
    Dose dependent pharmacokinetics of prednisone and prednisolone in man (1981)
    Springer
    Journal of pharmacokinetics and pharmacodynamics 9 (1981), S. 389-417 
    Details
    ISSN: 1573-8744
    Schlagwort(e): Prednisone ; prednisolone ; dose-dependent ; pharmacokinetics ; biotransformation ; protein binding ; bioavailability ; transcortin binding ; interconversion ; renal clearance
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Chemie und Pharmazie
    Notizen: 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.
    Materialart: Digitale Medien
    URL: http://dx.doi.org/10.1007/BF01060885
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  • 79
    Digitale Medien
    Digitale Medien
    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 
    Details
    ISSN: 1573-8744
    Schlagwort(e): Sulfadimethoxine ; swine ; pharmacokinetic modelling ; protein binding
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Chemie und Pharmazie
    Notizen: 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.
    Materialart: Digitale Medien
    URL: http://dx.doi.org/10.1007/BF01059036
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  • 80
    Digitale Medien
    Digitale Medien
    Evaluation of equilibrium dialysis volume shifts: A comment (1984)
    Springer
    Journal of pharmacokinetics and pharmacodynamics 12 (1984), S. 463-465 
    Details
    ISSN: 1573-8744
    Schlagwort(e): equilibrium dialysis ; volume shift ; protein binding
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Chemie und Pharmazie
    Notizen: 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).
    Materialart: Digitale Medien
    URL: http://dx.doi.org/10.1007/BF01062669
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  • 81
    Digitale Medien
    Digitale Medien
    Pharmacokinetics of diminazene in sheep (1985)
    Springer
    Journal of pharmacokinetics and pharmacodynamics 13 (1985), S. 173-184 
    Details
    ISSN: 1573-8744
    Schlagwort(e): diminazene ; pharmacokinetics ; protein binding ; plasma/rbc partition
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Chemie und Pharmazie
    Notizen: Abstract The pharmacokinetic behavior of diminazene in plasma after administration of 2 mg/kg i.v. and 3.5 mg/kg i.m. was studied in four healthy Dala × Ryggja rams. Following i.v. injection, the data were satisfactorily described by a triexponential equation; the apparent volume of distribution at the steady-state was 0.56±0.04 L/Kg (X±sd; n=4); total body clearance averaged 1.1±0.09 ml/kg/min and elimination half-life was 9.30±1.40 hr. After intramuscular administration peak plasma levels of 6.30–7.57 μg/ml were reached in 20 to 45 min and the mean absorption time averaged 5.83±1.61 hr. Systemic availability relative to the intravenous dose was 95.10±23.21% and mean residence time averaged 14.16±1.55hr. The partition of diminazene between erythrocytes and plasma averaged 0.64±0.10; plasma protein binding was high (65–85%) and concentration-dependent. Based on the experimental data obtained, an initial i.m. dose of 2.5 mg/kg followed by 2 mg/kg 24 hr later should be safe and effective in cases of babesiosis and trypanosomiasis sensitive to diminazene. A preslaughter withdrawal period of 14–26 days was estimated.
    Materialart: Digitale Medien
    URL: http://dx.doi.org/10.1007/BF01059397
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  • 82
    Digitale Medien
    Digitale Medien
    Effect of protein binding on steady-state equations (1985)
    Springer
    Journal of pharmacokinetics and pharmacodynamics 13 (1985), S. 559-560 
    Details
    ISSN: 1573-8744
    Schlagwort(e): protein binding ; steady-state ; physiological pharmacokinetics
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Chemie und Pharmazie
    Notizen: Abstract Previously published steady-state equations assumed elimination of total drug. The equations have been derived to cover the case where only free (unbound) drug is eliminated. The equation for oral administration is the same in both cases. The equation for intravenous administration has the same form, but the interpretation of Km is different.
    Materialart: Digitale Medien
    URL: http://dx.doi.org/10.1007/BF01059338
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  • 83
    Digitale Medien
    Digitale Medien
    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 
    Details
    ISSN: 1573-8744
    Schlagwort(e): protein binding ; tissue binding ; anticoagulant drugs ; tolbutamide ; drug interactions
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Chemie und Pharmazie
    Notizen: 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.
    Materialart: Digitale Medien
    URL: http://dx.doi.org/10.1007/BF01065192
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  • 84
    Digitale Medien
    Digitale Medien
    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 
    Details
    ISSN: 1573-8744
    Schlagwort(e): volume-shift ; protein binding ; dextran ; disopyramide ; lidocaine ; propranolol ; diazepam ; clofibrate
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Chemie und Pharmazie
    Notizen: 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.
    Materialart: Digitale Medien
    URL: http://dx.doi.org/10.1007/BF01062207
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  • 85
    Digitale Medien
    Digitale Medien
    Induction of quinidine metabolism and plasma protein binding by phenobarbital in dogs (1984)
    Springer
    Journal of pharmacokinetics and pharmacodynamics 12 (1984), S. 495-515 
    Details
    ISSN: 1573-8744
    Schlagwort(e): quinidine ; phenobarbital ; induction ; protein binding ; metabolism ; dogs
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Chemie und Pharmazie
    Notizen: 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.
    Materialart: Digitale Medien
    URL: http://dx.doi.org/10.1007/BF01060128
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  • 86
    Digitale Medien
    Digitale Medien
    Renal transport kinetics of furosemide in the isolated perfused rat kidney (1986)
    Springer
    Journal of pharmacokinetics and pharmacodynamics 14 (1986), S. 157-174 
    Details
    ISSN: 1573-8744
    Schlagwort(e): furosemide ; protein binding ; renal and secretion clearances ; excretion ratio
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Chemie und Pharmazie
    Notizen: Abstract Direct quantitative data and corresponding theory are provided for the effect of protein binding on the renal transport of furosemide. Drug studies were performed with various combinations of bovine serum albumin and dextran. This resulted in a percent unbound (fu) of furosemide ranging from 0.785 to 85.8%. The corrected renal (CLr/GFR) and secretion (CLs/GFR) clearances of furosemide were observed to increase with percent free, but in a nonproportional manner. Plots ofCLr/GFR orCLs/GFR vs.fu appeared to have a prominenty intercept as well as a convex ascending curve. In addition, the excretion ratio [ER=CLr/ (fu · GFR)] was reduced from 60.8 to 8.72 asfu increased. Overall, the data were best fitted to a model in which two Michaelis-Menten terms wre used to describe renal tubular transport, and secretion was dependent upon free drug concentrations in the perfusate. The results demonstrate that the renal mechanisms of furosemide excretion are more complex than previously reported and that active secretion may involve two different transport systems over the concentration range studied.
    Materialart: Digitale Medien
    URL: http://dx.doi.org/10.1007/BF01065259
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  • 87
    Digitale Medien
    Digitale Medien
    A dispersion model of hepatic elimination: 1. Formulation of the model and bolus considerations (1986)
    Springer
    Journal of pharmacokinetics and pharmacodynamics 14 (1986), S. 227-260 
    Details
    ISSN: 1573-8744
    Schlagwort(e): dispersion model ; hepatic elimination ; bolus ; well-stirred model ; parallel-tube model ; distributed model ; protein binding ; hepatic cellular activity ; cellular permeability ; blood flow ; bioavailability
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Chemie und Pharmazie
    Notizen: Abstract A dispersion model of hepatic elimination, based on the residence time distribution of blood elements within the liver, is presented. The general rate equations appropriate for describing the hepatic output concentration of a tracer solute are derived. Particular consideration is given to events following a bolus input dose of a tracer. The model is shown to be compatible with the known hepatic architecture and hepatic physiology. The model has been fitted to hepatic outflow data for red blood cells, albumin, and other noneliminated solutes. The experimental data suggest a high degree of dispersion of blood elements within the liver. The model has also been used to evaluate the effects of changes in enzyme activity, hepatic cell permeability, blood flow, and protein binding on the outflow concentration vs. time profiles of solutes.
    Materialart: Digitale Medien
    URL: http://dx.doi.org/10.1007/BF01106706
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  • 88
    Digitale Medien
    Digitale Medien
    Relationship between the ocular and systemic disposition of flurbiprofen: The effect of altered protein dynamics at steady state (1987)
    Springer
    Journal of pharmacokinetics and pharmacodynamics 15 (1987), S. 387-397 
    Details
    ISSN: 1573-8744
    Schlagwort(e): flurbiprofen ; protein binding ; plasmapheresis ; aqueous humor disposition ; systemic disposition ; ocular-systemic relationship
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Chemie und Pharmazie
    Notizen: Abstract The differences in flurbiprofen disposition in the aqueous humor and the plasma were examined after systemic doses. Steady state plasma concentrations of flurbiprofen (20–60 Μg/mL) were achieved via intravenous infusion to albino rabbits. Flurbiprofen demonstrated linear systemic kinetics throughout the dosing range, with constant body clearance and unbound fraction in plasma. At steady state, aqueous humor drug concentrations depended on the corresponding plasma drug concentration. Two clearance terms—CLs→o, the systemic clearance to ocular tissues, and CLo→s, the ocular clearance to systemic circulation—were used. After systemic doses, the drug concentration in the aqueous humor was related to that in the plasma as well as to the ratio of these two clearances. Flurbiprofen was extensively bound to plasma proteins and showed limited ocular distribution; its CLs→o to CLs→o tratio was very small. Thus, the concentration of flurbiprofen in the aqueous humor after systemic doses was lower than that obtained after ophthalmic doses. A plasmapheresis technique was utilized to lower the plasma protein concentrations to 60% of normal levels. As a consequence, flurbiprofen demonstrated reduced aqueous humor protein concentrations, increased unbound fractions in the plasma and the aqueous humor, elevated aqueous humor drug concentrations, and elevated total body clearance. The unbound body clearance stayed unchanged. Our study indicated that a drug should present a significant CLs→o/CLo→s ratio in order to achieve therapeutic concentrations in the eye via systemic doses. The drug-protein binding kinetics can be different between the plasma and the aqueous humor circulations. Because the ocular compariment is very small compared to the overall systemic distribution of flurbiprofen, it has little effect on the steady state systemic concentrations.
    Materialart: Digitale Medien
    URL: http://dx.doi.org/10.1007/BF01066520
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  • 89
    Digitale Medien
    Digitale Medien
    Kinetics of d-tubocurarine disposition and pharmacologic response in rats (1983)
    Springer
    Journal of pharmacokinetics and pharmacodynamics 11 (1983), S. 47-61 
    Details
    ISSN: 1573-8744
    Schlagwort(e): d-tubocurarine ; pharmacokinetics ; pharmacodynamics ; multicompartrnent model ; Hill equation ; plasma ; tibialis anterior muscle ; protein binding ; rats
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Chemie und Pharmazie
    Notizen: 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.
    Materialart: Digitale Medien
    URL: http://dx.doi.org/10.1007/BF01061767
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  • 90
    Digitale Medien
    Digitale Medien
    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
    Schlagwort(e): diazepam ; protein binding ; models of hepatic elimination ; hepatic clearance ; rat ; isolated perfused liver
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Chemie und Pharmazie
    Notizen: 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.
    Materialart: Digitale Medien
    URL: http://dx.doi.org/10.1007/BF01059274
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  • 91
    Digitale Medien
    Digitale Medien
    Serum Protein Binding of AL01576, a New Aldose Reductase Inhibitor (1988)
    Springer
    Pharmaceutical research 5 (1988), S. 319-321 
    Details
    ISSN: 1573-904X
    Schlagwort(e): aldose reductase ; AL01576 ; protein binding ; pH-dependent binding
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Chemie und Pharmazie
    Materialart: Digitale Medien
    URL: http://dx.doi.org/10.1023/A:1015939023465
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  • 92
    Digitale Medien
    Digitale Medien
    Protein Binding of Cocaine in Human Serum (1988)
    Springer
    Pharmaceutical research 5 (1988), S. 440-442 
    Details
    ISSN: 1573-904X
    Schlagwort(e): cocaine ; protein binding ; albumin ; alpha-1-acid glycoprotein
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Chemie und Pharmazie
    Notizen: Abstract The protein binding characteristics of cocaine have not been extensively studied. Since cocaine is related to other local anesthetic compounds which are highly protein bound, we examined the binding of cocaine in human serum using an ultrafiltration method. The free fraction averaged 0.083 ± 0.018 in the serum of 12 healthy volunteers. Binding was studied at concentrations ranging from 0.1 to 500 µg/ml and was concentration dependent, with increases being most pronounced at concentrations above 5 µg/ml. Two classes of binding sites were identified with affinity and capacity constants consistent with binding to alpha-1-acid glycoprotein (AAG) and albumin. The addition of AAG to serum resulted in a decrease in the free fraction from 0.079 to 0.041, while tris(butoxyethyl)phosphate increased the free fraction to 0.233. The binding ratio was found to be highly correlated with the AAG concentration (r = 0.89). In addition, the predicted free fraction in the absence of AAG (0.67) was in good agreement with the observed value of 0.647 in a solution of human serum albumin (4.5 g/dl). Of the metabolites of cocaine, only norcocaine displaced the parent drug from serum binding sites. These results indicate that cocaine is highly bound to serum proteins, primarily albumin and AAG. The significance of concentration-dependent binding to cocaine toxicity remains to be established.
    Materialart: Digitale Medien
    URL: http://dx.doi.org/10.1023/A:1015992502509
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  • 93
    Digitale Medien
    Digitale Medien
    Influence of Unbound Fraction and Perfusate Flow Rate on Taurocholate Elimination by Perfused Rat Liver: Applicability of Three Distributed Models (1989)
    Springer
    Pharmaceutical research 6 (1989), S. 874-876 
    Details
    ISSN: 1573-904X
    Schlagwort(e): distributed model ; isolated perfused rat liver ; protein binding ; hepatic blood flow rate ; taurocholate
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Chemie und Pharmazie
    Notizen: Abstract The applicability of three different distributed models to the kinetics of elimination of taurocholate by isolated perfused rat liver was examined by fitting each model to literature data. Each of the models was able to predict the effect of changing hepatic blood flow on elimination, but only the model which incorporates separate density functions describing the degree of sinusoidal heterogeneity of blood flow and intrinsic clearance was able to predict the effect of changing unbound fraction on elimination.
    Materialart: Digitale Medien
    URL: http://dx.doi.org/10.1023/A:1015912606260
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  • 94
    Digitale Medien
    Digitale Medien
    The Protein Binding of Phenytoin, Propranolol, Diazepam, and AL01576 (an Aldose Reductase Inhibitor) in Human and Rat Diabetic Serum (1988)
    Springer
    Pharmaceutical research 5 (1988), S. 261-265 
    Details
    ISSN: 1573-904X
    Schlagwort(e): protein binding ; diabetes ; streptozotocin-treated rats ; glucosylated albumin ; AL01576 ; phenytoin ; diazepam ; propranolol
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Chemie und Pharmazie
    Notizen: Abstract The extent of serum protein binding of AL01576, phenytoin (DPH), diazepam (DIAZ), and propranolol (PRO) was evaluated in a group of nondiabetic and a group of insulin-dependent diabetic subjects, as well as in streptozotocin-treated rats. Both serum glucose and glucosylated protein levels were elevated in the diabetic patient population (179 and 150% of control values, respectively). The mean free fractions (f p) of AL01576, DPH, and PRO were not statistically different for the two human groups. The DIAZ f p was slightly elevated (P 〈 0.05) in the diabetic patients (mean = 0.016) compared to the control group (mean f p = 0.014). An acute (〈3 days) and chronic (〉20 days) diabetic rodent model was evaluated using Sprague–Dawley rats following streptozotocin administration (60 mg/kg i.p.). Both diabetic rat groups exhibited substantial increases in serum glucose, free fatty acids (FFA), and protein glucosylation compared to controls. The f p of AL01576 was increased in both the acute (mean = 0.248) and the chronic (mean = 0.202) condition compared to controls (mean = 0.163). The f p of DPH was also markedly increased in the acute (mean = 0.348) and the chronic (mean = 0.280) models compared to untreated controls (mean = 0.207). DIAZ and PRO binding was largely unaffected by the streptozotocin treatment. In vitro studies of purified human albumin suggest that a considerable degree of glucosylation would need to be present in diabetic serum before it would effectively alter drug binding. Our data suggest that only minor drug–serum binding changes occur in diabetic patients who are otherwise healthy and whose disease is well controlled.
    Materialart: Digitale Medien
    URL: http://dx.doi.org/10.1023/A:1015966402084
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