O'Shea D, Kim R B, Wilkinson G R
Department of Pharmacology, Vanderbilt University, Nashville, TN 37232-6600, USA.
Br J Clin Pharmacol. 1997 Jan;43(1):99-103. doi: 10.1111/j.1365-2125.1997.tb00039.x.
An investigation was undertaken to compare the effects of isoniazid pretreatment on the CYP2E1-mediated 6-hydroxylation of chlorzoxazone in healthy subjects of known N-acetylator phenotype.
CYP2E1 activity was estimated based on the 6-hydroxylation of chlorzoxazone following single dose (250 mg) oral administration to seven slow and eight rapid N-acetylators who were in good health. Separate studies were performed prior to and 14 days after the subjects received 300 mg isoniazid daily. Additional investigations were undertaken 2 and 16 days after discontinuing treatment with the antitubercular agent.
Concomitant administration of chlorzoxazone with the final dose of isoniazid resulted in reduced metabolism in both phenotypes; however, the extent of inhibition of 6-hydroxylation was greater in the slow N-acetylators-about 80% vs 60%. Two days after stopping isoniazid administration, chlorzoxazone's pharmacokinetic parameters had returned to their baseline values and remained constant for a further 14 days in the rapid acetylators. In contrast, chlorzoxazone's 6-hydroxylation in slow acetylators was increased by about 60% compared with baseline at 2 days after discontinuing isoniazid but had returned to its initial value 14 days later.
The interphenotypic difference in the time-dependent interactions of isoniazid with CYP2E1 probably reflect a higher drug exposure in slow acetylators. Inhibition of CYP2E1 activity occurs in both N-acetylator phenotypes but is less extensive in fast acetylators, during the time that effective levels of isoniazid are present in the body. Increased CYP2E1 activity reflective of enzyme induction, on the other hand, is only observable following isoniazid's elimination and is more extensive in slow than rapid acetylators. Even then, however, such induction is relatively modest and of short duration.
开展一项研究，比较异烟肼预处理对已知N - 乙酰化酶表型的健康受试者中细胞色素P450 2E1（CYP2E1）介导的氯唑沙宗6 - 羟化作用的影响。
对7名慢乙酰化者和8名快乙酰化且身体健康的受试者口服单剂量（250毫克）氯唑沙宗后，根据其6 - 羟化作用来评估CYP2E1活性。在受试者每日服用300毫克异烟肼之前和之后14天分别进行研究。在停用抗结核药物后第2天和第16天进行了额外调查。
氯唑沙宗与最后一剂异烟肼同时给药导致两种表型的代谢均降低；然而，慢乙酰化者中6 - 羟化作用的抑制程度更大——约80%对60%。停用异烟肼给药后2天，氯唑沙宗的药代动力学参数已恢复至基线值，并且在快乙酰化者中在接下来的14天内保持恒定。相比之下，慢乙酰化者中氯唑沙宗的6 - 羟化作用在停用异烟肼后第2天比基线增加了约60%，但在14天后恢复到初始值。
异烟肼与CYP2E1的时间依赖性相互作用中的表型间差异可能反映了慢乙酰化者中更高的药物暴露。在体内存在有效水平异烟肼的时间段内，两种N - 乙酰化酶表型中均发生CYP
