摘要:

The contribution of cytochrome P450 2D6 (CYP2D6) to the formation of hydrocodone's active metabolite, hydromorphone, was examined in vitro and in vivo. Human liver microsomes prepared from an individual homozygous for the D6‐B mutation of theCYP2D6gene catalyzed this reaction at a negligible rate. Urinary metabolic ratios of hydrocodone/hydromorphone were highly correlated withO‐demethylation ratios for dextromethorphan, an established marker drug of CYP2D6 activity (rs= 0.85;n= 18). The kinetics of hydrocodone after a single oral dose and its partial metabolic clearance to hydromorphone were investigated in five extensive metabolizers of dextromethorphan, six poor metabolizers, and four extensive metabolizers after pretreatment with quinidine, a selective inhibitor of CYP2D6 activity. The mean values for partial metabolic clearance byO‐demethylation in the three groups were 28.1 ± 10.3, 3.4 ± 2.4, and 5.0 ± 3.6 ml/hr/kg, respectively. No statistically significant phenotypic differences in physiologic measures were observed. However, over the first hour after dosing, the extensive metabolizers reported more “good opiate effects” and fewer “bad opiate effects” than poor metabolizers and extensive metabolizers in whom CYP2D6 was inhibited by quinidine. These data establish the importance of CYP2D6 in the formation of hydromorphone from hydrocodone and suggest that the activity of this enzyme may limit the abuse liability of hydrocodone.Clinical Pharmacology and Therapeutics(1993)54,463–472; doi:10

ISSN:0009-9236    

DOI:10.1038/clpt.1993.177

年代:1993

数据来源: WILEY

摘要:

The effect of iron ion on the absorption of cefdinir, a new oral cephalosporin derivative, was evaluated in healthy male volunteers in a randomized three‐way crossover study. The subjects received 200 mg cefdinir alone, 200 mg cefdinir and two tablets of iron ion concomitantly, and two tablets of iron ion preparation 3 hours after 200 mg cefdinir administration. The area under the concentration curve [AUC(0–12)] of cefdinir with concurrent iron was significantly smaller than that with cefdinir alone (mean ± SD, 0.78 ± 0.38 versus 10.3 ± 1.35 µg · hr/ml). While there were no differences in AUC(0–3) between drug alone and drug with iron 3 hours later, the AUC(3‐12) with delayed iron was significantly smaller than that of cefdinir alone (4.60 ± 1.54 versus 8.03 ± 1.72 µg · hr/ml). These findings suggest that the mechanism of interaction between cefdinir and iron ion preparation is the formation of a chelation complex and that this complex probably restricts gastrointestinal absorption.Clinical Pharmacology and Therapeutics(1993)54,473–475; doi:10

ISSN:0009-9236    

DOI:10.1038/clpt.1993.178

年代:1993

数据来源: WILEY

摘要:

The hepatobiliary extraction profile of cefixime, a dianionic cephalosporin antibiotic, was studied in 10 patients, each of whom was provided with T‐tube drainage of his or her common bile duct after cholecystectomy. After a single 200 mg oral dose, cefixime biliary clearance proved to be nonlinear, mostly in its initial phase, which is consistent with a concentrative uptake and intracellular protein binding for the drug. The latter process appears to be saturable and to operate at a rate that correlates with the total amount of cefixime recovered in the 24‐hour bile drainage. Such findings seem to confirm the significant role played in vivo by hepatic ligandin in the hepatobiliary extraction of organic anions. The data also show that a single 200 mg oral dose of cefixime yields drug levels in bile substantially higher than the minimal inhibitory concentrations for the most frequent Enterobacteriaceae in biliary tract infections. Accordingly, this cephalosporin could be an interesting alternative in both prophylaxis and treatment of biliary tract infections.Clinical Pharmacology and Therapeutics(1993)54,476–484; doi:10.1038/clpt.19

ISSN:0009-9236    

DOI:10.1038/clpt.1993.179

年代:1993

数据来源: WILEY

摘要:

Progabide was investigated as a potential inhibitor of microsomal epoxide hydrolase as a result of reports of elevated levels of carbamazepine‐10,11‐epoxide after coadministration of progabide and carbamazepine to patients with epilepsy. The formation clearance of carbamazepine transdihydrodiol after administration of carbamazepine‐10,11‐epoxide to healthy volunteers was decreased 26% by progabide. Therapeutic concentrations of progabide inhibitedS(+)‐styrene oxide hydrolysis in human liver microsomes (inhibition constant [Ki] = 1.9 µmol/L) and purified human liver microsomal epoxide hydrolase (Ki= 4.4 µmol/L). A mixed competitive and noncompetitive mechanism of inhibition best described the effect of progabide on microsomal epoxide hydrolase; the most potent inhibition was competitive. A similar model described the inhibition by the acid metabolite of progabide, although inhibitory concentrations are higher than concentrations observed after progabide therapy. An excellent agreement between the in vivo and in vitro inhibitory potencies of progabide suggests that potential inhibitors of this important detoxification enzyme can be predicted in vitro.Clinical Pharmacology and Therapeutics(1993)54,485–497; doi:10.1038

ISSN:0009-9236    

DOI:10.1038/clpt.1993.180

年代:1993

数据来源: WILEY

摘要:

Dehydroepiandrosterone sulfotransferase (DHEA ST) catalyzes the sulfation of steroid hormones such as DHEA, estrone, and estradiol. As a first step in pharmacogenetic studies of DHEA ST in humans, we measured individual variation in DHEA ST enzymatic activity and thermal stability in 94 samples of human hepatic tissue, 39 of which were from patients with normal liver function studies. Neither level of enzyme activity nor thermal stability were significantly correlated with either time of tissue storage at −80° C or patient age. In addition, there were no gender‐dependent differences in DHEA ST activity in these samples. DHEA ST enzymatic activity varied 4.6‐fold, with a mean value of 317 ± 100 units/gm tissue (mean ± SD) in all samples and 318 ± 104 units/gm in the subset of 39 samples from patients with normal hepatic function studies. Frequency distributions of DHEA ST activity for both the entire group of 94 samples and the subset of 39 were bimodal, with 25% and 21% included in a high activity subgroup, respectively. The presence of this high activity subgroup was confirmed when data for samples from male and female patients were evaluated separately and when only data for white patients were examined. The existence of a subgroup of subjects with a high level of DHEA ST enzymatic activity in liver and a 4.6‐fold range in this activity have implications for individual differences in the sulfate conjugation of endogenous and exogenously administered steroid hormones and raise the possibility of pharmacogenetic regulation of this important enzyme in humans.Clinical Pharmacology and Therapeutics(1993)54,498–506; doi:10.1038

ISSN:0009-9236    

DOI:10.1038/clpt.1993.181

年代:1993

数据来源: WILEY

摘要:

Only recently has attention been focused on the importance of interethnic differences as determinants of interindividual variability in drug response. We compared the pharmacokinetics and pharmacodynamics of morphine in eight Chinese and eight white healthy men after 0.15 mg/kg of morphine intravenously. The clearance of morphine was significantly higher in the Chinese subjects than in the white subjects because of an increase in the partial metabolic clearance by glucuronidation. There was no interethnic difference in the metabolism to normorphine. Morphine depressed the respiratory response to rebreathing carbon dioxide more in white subjects than in Chinese subjects, resulting in a greater reduction in resting ventilation and resting end‐tidal Pco2. The slope of the ventilation/Pco2response curve, a measure of carbon dioxide sensitivity, was reduced more in white subjects than Chinese subjects. As a result, white subjects had a greater depression in ventilation at a Pco2of 55 mm Hg. The morphine‐induced reduction in blood pressure was also greater in white subjects than in Chinese subjects. Thus this study has shown ethnicity to be an important determinant of the disposition and effects of morphine.Clinical Pharmacology and Therapeutics(1993)54,507–513; doi:10.1038/clpt.19

ISSN:0009-9236    

DOI:10.1038/clpt.1993.182

年代:1993

数据来源: WILEY

摘要:

The renal effects of incremental infusions of norepinephrine (placebo, 0.025 µ/kg/min), 0.075 µ/kg/min, phenylephrine (placebo, 0.5 µg/kg/min, 2.5 µg/kg/min), and tyramine (placebo, 2 µg/kg/min, 15 µg/kg/min) were examined in three respective groups (n= 9,8, and 8) of normotensive male subjects undergoing water diuresis. Tyramine is an indirect sympathetic agent that causes neuronal release of endogenous norepinephrine. Increases in mean arterial pressure during each high‐dose infusion were comparable in all three groups. Both norepinephrine and phenylephrine caused a decrease in urinary sodium excretion and effective renal plasma flow, with no changes in glomerular filtration rate. Proximal tubular sodium reabsorption, as assessed by both lithium clearance and solute‐free water clearance methods, was increased by pressor doses of norepinephrine and phenylephrine. In contrast, a similar pressor dose of tyramine was associated with a pressure natriuresis, an increase in effective renal plasma flow, and a decrease in proximal tubular sodium reabsorption. Our data indicate that, in normotensive humans, circulating catecholamines (norepinephrine and phenylephrine) have opposite effects on renal sodium handling from neuronally released norepinephrine (tyramine).Clinical Pharmacology and Therapeutics(1993)54,514–522; doi:10.1038/c

ISSN:0009-9236    

DOI:10.1038/clpt.1993.183

年代:1993

数据来源: WILEY

摘要:

Angiotensin converting enzyme inhibitors have been proposed to have a prostaglandin‐dependent component to their hypotensive action. The aim of this study was to assess whether the structurally dissimilar angiotensin converting enzyme inhibitors captopril and enalapril stimulate the synthesis of prostacyclin, whether their hypotensive action is blunted by indomethacin, and whether these biochemical or physiologic parameters differ for the two drugs, in white subjects with essential hypertension. Twelve patients were enrolled and 11 finished the study. The study consisted of a double blind, randomized, double‐crossover design. All patients received either placebo or 50 mg indomethacin twice a day for 3 weeks; after 1 week of placebo or indomethacin either 50 mg captopril or 10 mg enalapril twice a day was added and continued for 2 weeks. Each patient received every possible combination. Neither captopril nor enalapril stimulated prostacyclin production as determined by measurement of the urinary excretion rate of its main enzymatic metabolite, 2,3‐dinor‐6‐keto‐prostaglandinF1α. Although indomethacin reduced the urinary excretion of the enzymatic metabolite of prostacyclin by more than 50%, it did not influence the hypotensive effect of captopril or enalapril. We conclude that neither captopril nor enalapril have a significant prostacyclin‐dependent component to their hypotensive action.Clinical Pharmacology and Therapeutics(1993)54,523–532; doi:10.1

ISSN:0009-9236    

DOI:10.1038/clpt.1993.184

年代:1993

数据来源: WILEY

摘要:

We investigated the effect of a novel gastrin—cholecystokinin‐B receptor antagonist, L‐365,260 [(3R)‐3(N′‐3‐methylphenyl)ureido)‐1,3‐dihydro‐5‐phenyl‐2H‐1,4‐benzodiazepin‐2‐one], on gastric acid secretion in humans. In a double‐blind, four‐period crossover study, eight subjects received single oral doses of placebo or of 2.5, 10, or 50 mg L‐365,260, followed by an intravenous infusion of pentagastrin at doses of 0.05, 0.4, and 2 µg/kg/hr for successive 30‐minute periods. L‐365,260 caused a dose‐dependent inhibition of pentagastrin‐stimulated gastric acid secretion. A single oral dose of 50 mg L‐365,260 produced 50% inhibition of the gastric acid output response to pentagastrin (0.4 µg/kg/hr) when the mean (±SD) plasma L‐365,260 concentration was 502 ± 108 ng/ml. Plasma L‐365,260 concentrations (all doses combined) and the inhibition of gastric acid output were correlated with a correlation coefficient ofr= 0.45 (p<0.05). Single oral doses of L‐365,260 up to 50 mg did not inhibit basal gastric acid output or alter plasma gastrin concentrations. L‐365,260 was well tolerated at oral doses up to 50 mg. These findings show that L‐365,260 is an orally active antagonist at gastrin—cholecystokinin‐B receptors in humans.Clinical Pharma

ISSN:0009-9236    

DOI:10.1038/clpt.1993.185

年代:1993

数据来源: WILEY

摘要:

The objective of this multicenter randomized clinical trial was to compare the efficacy, acceptability, and occurrence of side effects associated with the oral versus vaginal route of administration of contraceptive pills. Eight hundred nineteen healthy, parous women of reproductive age were recruited at family planning clinics and research centers, members of the South to South Cooperation in Reproductive Health, in seven countries of the developing world. These women were randomly assigned to use either oral or vaginal administration of the same contraceptive pill, which contained 250 µg levonorgestrel and 50 µg ethinyl estradiol. No statistically significant differences were found in discontinuation rates between the two groups after 1 year. Involuntary pregnancy rates after 1 year were not statistically significantly different between the two groups. The vaginal route of administration appears to be as acceptable and efficacious as the oral route.Clinical Pharmacology and Therapeutics(1993)54,540–545; doi:10.1038/clpt.1993

ISSN:0009-9236    

DOI:10.1038/clpt.1993.186

年代:1993

数据来源: WILEY