摘要:

In the sera from 42 patients receiving quinidine, (3S)‐3‐hydroxyquinidine (3‐OH), an active metabolite of quinidine, and quinidine were determined by high‐pressure liquid chromatography with fluorescence detection. These results were added to those of 25 other patients reported previously.4The 3‐OH/quinidine ratio averaged 0.34 ± 0.17 (SD) with a range of 0.10 to 0.90. Eleven patients (16%) had ratios above 0.50. After adjusting for protein binding differences between the 2 compounds, these 16% had 3‐OH concentrations in serum water greater than that of quinidine. An additional 7 patients (10% of the total) had levels of this metabolite in serum water slightly less than that of quinidine. A histogram showing the frequency distribution of 3‐OH/quinidine in serum indicates extensive skewing with possibly a bimodal distribution with the antimode at 0.50. Thus, 3‐OH may make a significant contribution to the effect of quinidine therapy in a fraction of treated patients. The clearance of quinidine decreased with age, indicating the need for, on the average, higher doses of quinidine in the young.Clinical Pharmacology and Therapeutics(1980)27,72–75; doi:1

ISSN:0009-9236    

DOI:10.1038/clpt.1980.11

年代:1980

数据来源: WILEY

摘要:

The protein binding of sodium [carboxy‐14C] valproate has been studied in normal and uremic plasma using the method of equilibrium dialysis. Protein binding was dependent on concentration in both cases but there was a marked reduction in binding capacity in patients with renal dysfunction. Treatment of normal plasma with urea or creatinine to reproduce concentrations observed in uremia induced small decreases in binding. Diffusion dialysis of uremic plasma partially restored the degree of binding. Pretreatment of uremic plasma with activated charcoal at pH 3 raised binding capacity to that of normal plasma.Clinical Pharmacology and Therapeutics(1980)27,76–82; doi:10.1038/clpt.198

ISSN:0009-9236    

DOI:10.1038/clpt.1980.12

年代:1980

数据来源: WILEY

摘要:

Autoinduction of carbamazepine (CBZ) metabolism was investigated in 3 children (10 to 13 yr old) using tetradeuterium‐labeled CBZ (CBZ‐D4). Prior to treatment, CBZ and CBZ‐D4given as a mixture had almost identical kinetics in each patient. During maintenance therapy with CBZ, part of the CBZ was exchanged for CBZ‐D4on 3 occasions. The clearance of CBZ‐D4given on the second day of therapy was 0.036 ± 0.003 1 · kg−1· hr−1, whereas it had been 0.028 ± 0.003 before treatment. After 17 to 32 days of treatment, clearance doubled (0.056 ± 0.010) but during the next 4 mo there was no further increase, indicating that the autoinduction was complete within 1 mo. As a corollary there was a decrease in steady‐state plasma levels.Clinical Pharmacology and Therapeutics(1980)27,83–88; d

ISSN:0009-9236    

DOI:10.1038/clpt.1980.13

年代:1980

数据来源: WILEY

摘要:

Our study underlines the importance of performing protein binding interaction studies in vivo. Predictions from in vitro studies may be misleading because they may not take into account the kinetics of the drug in the whole animal. Probably the most important clinical implication of these findings is that total serum phenytoin levels may fall when sodium valproate is added to therapy and this may lead to an increase in dose under the mistaken belief that the effect of the drug has been reduced. Since it is the bound and not the free drug which is reduced, phenytoin intoxication may result from this misguided action.Clinical Pharmacology and Therapeutics(1980)27,89–95; doi:10.1038/clpt.1980.

ISSN:0009-9236    

DOI:10.1038/clpt.1980.14

年代:1980

数据来源: WILEY

摘要:

To determine whether the slowp‐hydroxylation of phenytoin (PHT) is an inherited train, we studied its kinetics in members of a single family in which the trait was observed and in nonfamily control subjects. Each subject was given 5 mg/kg PHT intravenously; plasma and urine samples collected at various intervals after administration were analyzed for PHT or its major metabolite, 5‐(p‐hydroxyphenyl)‐5‐phenylhydantoin (HPPH). Initially, 1 member of the family was observed for 6 mo on oral PHT. The subject became clinically intoxicated on 4.6 mg/kg/day PHT with a plasma level of 52 μg/ml; less than 50% of the dose was excreted as the major metabolite and after 3 mg/kg PHT intravenously, half‐life (t½) was 30.6 hr. The results in all subjects were used to determine t½ and volume of distribution (Vd). The mean t½ for the control population was 18.6 ± 3.4 hr and for the family was 24.2 ± 4.2 hr. Individual members of each population were sufficiently far from the mean to suggest a bimodal t½ distribution. Three members of the kinship had t½ for intravenous PHT more than 2 standard deviations longer than the control population mean. HPPH excretion was extremely low in the 3 family members with long t½ as well as 1 child with a t½ somewhat longer than the mean adult values. Other members of the kinship had normal t½s and normal excretion. Vd for all family members was in the normal range. Since hypometabolism was seen in 3 of 4 generations of the kinship and since a bimodal distribution was observed for PHT metabolism, we conclude that it is an inherited trait. The mode of inheritance is not known at this time.Clinical Pharmacology and Therapeutics(1980)27,96–103;

ISSN:0009-9236    

DOI:10.1038/clpt.1980.15

年代:1980

数据来源: WILEY

摘要:

The relationship between sulfamethazine disposition kinetics and acetylator phenotype was studied in 19 healthy subjects. Various kinetic parameters for sulfamethazine and itsN4‐acetylated metabolite were determined after a dose of a rapidly absorbed oral solution. When plotted on a frequency distribution histogram, the results exhibited a well‐defined trimodal pattern for acetylation clearance values and overall elimination or metabolic rate constants. These data were consistent with the well‐recognized acetylation polymorphism for sulfamethazine, except that they clearly subdivided the previously acknowledged “fast” acetylator mode into intermediate and rapid acetylator groups. The apparent distribution volume and renal clearance for sulfamethazine and acetylsulfamethazine did not differ significantly among the 3 phenotypes. Of special interest was the observation that rapid acetylators initially produce much greater amounts of acetyl metabolite than intermediate acetylators. The potential clinical implications of identifying rapid and intermediate acetylators are discussed in view of evidence showing that acetyl metabolites may be pharmacologically active or function as intermediates in toxic metabolic pathways.Clinical Pharmacology and Therapeutics(1980)27,104–113; doi:10.1038/

ISSN:0009-9236    

DOI:10.1038/clpt.1980.16

年代:1980

数据来源: WILEY

摘要:

Ethanol (0.6 gm/kg) was given orally as a cocktail to 6 healthy fasted volunteers (3 men and 3 women) on 4 separate occasions at 2300 hr. Subjects were recumbent and remained awake in 2 sessions while sleep was allowed in the other 2. An indwelling forearm venous catheter was used to allow blood sampling without disturbance of sleep, and 20 serial blood samples (2 ml) were drawn at appropriate intervals in the 8 hr after the cocktail. Blood ethanol concentration was determined by a head‐space gas chromatographic technique and Michaelis‐Menten parameters (Vmand Km) were estimated from data in the terminal elimination phase. Mean estimates were Vmawake = 0.214 ± 0.009 mg/ml/hr (SEM), Vmasleep = 0.221 ± 0.017, Kmawake = 0.069 ± 0.009 mg/ml, and Kmasleep = 0.085 ± 0.016. These values were slightly lower than literature reports for elimination in ambulant patients during the daytime. Mean differences in Vmand Kmbetween the awake and asleep groups and between sexes were not significant (p>0.05).Clinical Pharmacology and Therapeutics(1980)27,114–119; doi:10.1038/cl

ISSN:0009-9236    

DOI:10.1038/clpt.1980.17

年代:1980

数据来源: WILEY

摘要:

Clinical Pharmacology and Therapeutics(1980)27,120–130; doi:10.1038/clpt.1980.

ISSN:0009-9236    

DOI:10.1038/clpt.1980.18

年代:1980

数据来源: WILEY

摘要:

Clinical Pharmacology and Therapeutics(1980)27,131–131; doi:10.1038/clpt.1980.

ISSN:0009-9236    

DOI:10.1038/clpt.1980.19

年代:1980

数据来源: WILEY

摘要:

Clinical Pharmacology and Therapeutics(1980)27,132–146; doi:10.1038/clpt.1980.

ISSN:0009-9236    

DOI:10.1038/clpt.1980.20

年代:1980

数据来源: WILEY