摘要:

Clinical Pharmacology and Therapeutics(1994)56,355; doi:10.1038/clpt.1994.148

ISSN:0009-9236    

DOI:10.1038/clpt.1994.148

年代:1994

数据来源: WILEY

摘要:

Clinical Pharmacology and Therapeutics(1994)56,356–358; doi:10.1038/clpt.1994.1

ISSN:0009-9236    

DOI:10.1038/clpt.1994.149

年代:1994

数据来源: WILEY

摘要:

Background and ObjectivesThe hepatic 6‐hydroxylation of chlorzoxazone in vitro is mediated primarily by CYP2E1, and measurement of this metabolic pathway may provide an in vivo probe of the enzyme. In animals, such as the rat, levels of CYP2E1 are induced by both fasting and obesity. This study investigated whether these two physiologic factors are determinants of the metabolism and disposition of chlorzoxazone in humans.MethodsThe plasma concentration‐time profiles of chlorzoxazone and its 6‐hydroxy metabolite were determined after oral administration of parent drug (250 mg). The urinary excretion of the metabolite was also determined. In one study, the disposition profiles were obtained in six healthy white men, first after an overnight fast, and on a separate occasion after a 38‐hour fast. The second study investigated the disposition of chlorzoxazone in nine obese women and in nine age‐matched women.ResultsProlonged fasting produced a significant increase in circulating ketone bodies. This was associated with a reduction in the oral clearance of chlorzoxazone (mean ± SD, 5.79 ± 1.04 to 3.69 ± 1.54 ml min−1kg−1;p<0.03). The 0‐ to 24‐hour urinary recovery of the 6‐hydroxy metabolite was extensive (50% to 80%), and the reduced clearance reflected a lower 6‐hydroxylating ability after fasting. The elimination half‐life of the drug was increased by a similar extent to clearance (1.00 ± 0.09 versus 1.50 ± 0.42 hours; p<0.004), whereas its apparent volume of distribution was unaffected by fasting. By contrast, obesity resulted in significant increases in the oral clearance and distribution of chlorzoxazone on both an absolute and weight‐normalized basis; for example, 4.15 ± 0.81 versus 6.23 ± 1.72 ml min−1kg−1and 0.50 ± 0.28 versus 0.82 ± 0.19 L · kg−1. Half‐life of elimination was similar in both groups of subjects. Estimation of the fractional clearance to 6‐hydroxychlorzoxazone showed that obesity increased this parameter to a similar extent as oral clearance. The difference in the oral clearance and 6‐hydroxylating ability of nonobese men and women was also statistically different.ConclusionsA discordancy was observed between the reported effect of fasting in rodents and that observed in humans. This may reflect an interspecies difference in CYP2E1 regulation or, more likely, destruction of the enzyme by lipid peroxidation resulting from the prolonged period of fasting. However, serious to morbid obesity in humans is associated with increased 6‐hydroxylation of chlorzoxazone, consistent with induction of CYP2E1. Accordingly, such individuals may be at increased risk of CYP2E1‐mediated toxicities and adverse effects caused by the formation of CYP2E1‐mediated metabolites of environmental agents. In addition, the efficacy of an active drug that is a CYP2E1 substrate may be reduced in obese patients.Clinical Pharmacology and T

ISSN:0009-9236    

DOI:10.1038/clpt.1994.150

年代:1994

数据来源: WILEY

摘要:

Aging decreases elimination of racemic verapamil but reports vary regarding effects of aging on clearance of individual verapamil enantiomers. To determine effects of aging on elimination ofS‐ andR‐verapamil, racemic verapamil was infused to steady‐state concentrations of ~30, 60, and 120 ng/ml in 27 healthy subjects ranging in age from 23 to 81 years (young, 20 to 39 years; middle aged, 40 to 59 years; old, 60 to 81 years), and enantiomer concentrations were measured at each steady‐state and after infusions.S‐Verapamil clearance was greater thanR‐verapamil clearance in all age groups (p<0.001), and aging decreasedS‐verapamil (p<0.05) and R‐verapamil (p<0.008) clearance (average ± SD,S‐verapamil clearance was 14.3 ± 4.7, 13.4 ± 5.2, and 11.7 ± 5.2 ml/min/kg;R‐verapamil clearance was 6.5 ± 3.3, 5.6 ± 2.8, and 4.5 ± 1.6 ml/min/kg in young, middle‐aged, and older subjects, respectively). Enantiomer clearance was not effected by verapamil concentration. A trend toward an age effect on elimination half‐lives was seen (S‐verapamil half‐life, 281 ± 116 versus 234 ± 89 minutes in elderly versus young;R‐verapamil half‐life, 253 ± 56 versus 199 ± 58 minutes in elderly versus young,p= 0.08).R‐but not S‐verapamil clearance during multistage infusions of racemic verapamil was lower than previously reported clearance after single intravenous enantiomer doses (p<0.0001). In summary, aging decreases clearance of bothS‐andR‐verapamil during steady‐state intravenous dosing of racemic verapamil with preserved stereoselective clearance of verapamil with aging.Clinical Pharmacology and Th

ISSN:0009-9236    

DOI:10.1038/clpt.1994.151

年代:1994

数据来源: WILEY

摘要:

MK‐383 (L‐tyrosine, N‐n‐butylsulfonyl)‐O‐[4‐butyl(4‐piperidinyl)], monohydrochloride monohydrate) is a potent and specific platelet fibrinogen receptor antagonist that may be useful in preventing processes that lead to occlusive thrombus formation in the lumen of the blood vessel. Two placebo‐controlled phase I trials were completed in 56 healthy volunteers to investigate the safety, tolerability, pharmacokinetics, and pharmacodynamics of MK‐383 administered as 1‐ and 4‐hour infusions in the presence and absence of aspirin. When administered to healthy male subjects by constant infusions up to 0.4 µg/kg/min over 1 hour or up to 0.2 µg/min over 4 hours, it provided a well‐tolerated reversible means of inhibiting platelet function. At infusion rates of 0.25 and 0.15 µg/kg/min for 1 and 4 hours, respectively, MK‐383 extended baseline bleeding time by 2.0‐ to 2.5‐fold and inhibited adenosine diphosphate (ADP)‐induced platelet aggregation by at least 80%. The pharmacokinetics of MK‐383 include a mean plasma clearance of 329 ml/min, steady‐state volume of distribution of 76 L, and half‐life of 1.6 hours. The percentage of dose excreted in the urine was 37%. Correlations between MK‐383 plasma concentration (C) and inhibition of platelet aggregation were examined by fitting with a sigmoid maximum‐effect model. The plasma concentration yielding 50% inhibition (C50) for MK‐383 in healthy volunteers is approximately 13 ng/ml, with a Hill coefficient>5. Based on a naive pooled analysis, an exponential empirical model best describes the MK‐383 C–extension of template bleeding time (BTE) relationship. The model indicates that the MK‐383 plasma concentration necessary to double BTE is approximately 30 ng/ml (i.e., 2.5‐fold greater than the C50for ADP‐induced inhibition of platelet aggregation). The pharmacokinetics of MK‐383 was unaffected by pretreatment with 325 mg aspirin 1 day before and 1 hour before infusion. Conversely, aspirin pretreatment reduced C50and increased bleeding time extension, suggesting that aspirin may have an additive effect with respect to inhibition of platelet function. Based on the putative role of the fibrinogen receptor in thrombotic processes and an acceptable human pharmacokinetic‐pharmacodynamic profile, MK‐383 should be evaluated in patients with unstable angina.Clinical Pharmac

ISSN:0009-9236    

DOI:10.1038/clpt.1994.152

年代:1994

数据来源: WILEY

摘要:

The pharmacokinetic interaction between phenytoin and tirilazad was studied in 12 healthy men who received 200 mg phenytoin orally every 8 hours for 11 doses and 100 mg for the remaining 5 doses in one period of a two‐way crossover study. In both periods, 1.5 mg/kg tirilazad mesylate was administered (as 10‐minute intravenous infusions) every 6 hours for 21 doses (5 days). Plasma tirilazad mesylate and U‐89678 (an active metabolite) were quantified by HPLC. After dose 21, area under the plasma concentration‐time curve [AUC(0–6)] for tirilazad mesylate was significantly lower (p= 0.0061) after phenytoin treatment (3029 ± 982 ng · hr/ml) than after tirilazad mesylate alone (4647 ± 1562 ng · hr/ml). AUC(0–6) for U‐89,678 after dose 21 was reduced from 1485 ± 1173 ng · hr/ml after tirilazad mesylate alone to 195 ± 223 ng · hr/ml after phenytoin coadministration. U‐89678 normally accumulates during multiple dosing, but mean U‐89678 trough concentrations decreased after 24 hours during tirilazad and phenytoin coadministration. No clinically significant interactions of tirilazad mesylate and phenytoin for medical events, vital signs, or laboratory parameters were identified. These results suggest that phenytoin rapidly induces tirilazad mesylate metabolism; it may also induce the metabolism of U‐89678 or shunt tirilazad mesylate metabolism through other pathways.Clinical Pharmacology and Therapeutics(1994)56,389–

ISSN:0009-9236    

DOI:10.1038/clpt.1994.153

年代:1994

数据来源: WILEY

摘要:

This study tested the hypothesis that patterns of xenobiotic metabolism in patients with eosinophiliamyalgia syndrome (EMS) differed from healthy control subjects. We determined the genotypes of 27 EMS patients with EMS and 114 control subjects for the cytochrome P450 CYP2D6 polymorphism. The metabolic phenotypes of patients with EMS forS‐mephenytoin hydroxylation(n= 17) and dapsone acetylation(n= 19) were determined and compared with 29 healthy control subjects. The incidence of theCYP2D6poor metabolizer genotype (mutant/mutant) was 0.185 in patients with EMS and 0.061 in control subjects (Mantel‐Haenszel, χ2= 7.213,p= 0.007). The mephenytoin S/R ratios were 0.39 ± 0.23 in patients with EMS versus 0.18 ± 0.13 in control subjects (p≤ 0.005). There was no difference in dapsone acetylation between the two groups. A pattern of xenobiotic metabolism may play a role in the pathogenesis of EMS, but the precise role that it plays remains unclear.Clinical Pharmacology and Therapeutics(1994)56,398–405; doi:10.1038/cl

ISSN:0009-9236    

DOI:10.1038/clpt.1994.154

年代:1994

数据来源: WILEY

摘要:

A family of four basic physiologic indirect response models has been proposed to account for the pharmacodynamics of drugs that act by way of inhibition or stimulation of the production or loss of endogenous substances or mediators. Such models were applied previously to account for the anticoagulant effects of warfarin, adrenal suppression by corticosteroids, cell trafficking effects of corticosteroids, antipyretic effects of Ibuprofen, and aldose reductase inhibition. Additional responses that can be readily characterized with such models include muscular contraction from pyridostigmine, diuresis from furosemide, bronchodilation from terbutaline, prolactin secretion after Cimetidine, and potassium suppression by terbutaline. This report shows that indirect response models, rather than “link” or “hypothetical effect compartment” models, may be more appropriate for diverse drugs when time lags exist between plasma or biophase drug concentrations and the time course of pharmacodynamic responses.Clinical Pharmacology and Therapeutics(1994)56,406–419; doi:10.1038/clp

ISSN:0009-9236    

DOI:10.1038/clpt.1994.155

年代:1994

数据来源: WILEY

摘要:

Ethoxyidazoxan, a potent and highly selective α2‐adrenergic receptor antagonist, was administered intravenously to six healthy male volunteers in a double‐blind, placebo‐controlled, dose‐rising design. Doses of 6 µg/kg and 8 µg/kg infused intravenously over 30 minutes produced significant elevations of plasma norepinephrine and body temperature and inhibited norepinephrine‐induced platelet aggregation. Central activity was shown by reversal of the slowing of saccadic eye movements and an increase in saccade peak velocity at the higher dose. Modest increases in blood pressure were produced without change in heart rate. Ethoxyidazoxan was well tolerated, with slight changes in subjective alertness and sedation.Clinical Pharmacology and Therapeutics(1994)56,420–429; doi:10.103

ISSN:0009-9236    

DOI:10.1038/clpt.1994.156

年代:1994

数据来源: WILEY

摘要:

Zolpidem is a new imidazopyridine‐hypnotic that selectively binds to the central ω1‐receptor subtype. A double‐blind, randomized, three‐way, crossover placebo‐controlled study was carried out in nine healthy male volunteers to assess the possible antagonism of central nervous system–depressant effects of Zolpidem by flumazenil. Subjects received Zolpidem (0.21 mg/kg) or placebo, intravenously, followed 17 minutes later by flumazenil (0.04 mg/kg) or placebo. Vigilance and performance were assessed by a trained anesthetist with use of ciliary reflex, response to a verbal instruction, subjective sedation, a tracking task, and a free recall task. Zolpidem produced a clinically relevant hypnotic effect in five subjects and significantly impaired performance in all nine subjects up to 90 minutes after dosing. Flumazenil rapidly antagonized clinical sedation in the five subjects who were asleep and significantly reversed the performance decrement within 3 minutes, without any escape phenomenon. Flumazenil did not change Zolpidem plasma concentrations, confirming the pharmacodynamic nature of the interaction. Flumazenil may thus be a safe and effective antidote in patients with Zolpidem overdosage.Clinical Pharmacology and Therapeutics(1994)56,430–436; doi:10.103

ISSN:0009-9236    

DOI:10.1038/clpt.1994.157

年代:1994

数据来源: WILEY