Dorne J L C M, Walton K, Renwick A G
Clinical Pharmacology Group, University of Southampton, Biomedical Sciences Building, Bassett Crescent East, Southampton SO16 7PX, UK.
Food Chem Toxicol. 2003 Feb;41(2):225-45. doi: 10.1016/s0278-6915(02)00210-7.
CYP2C19-mediated oxidation and N-acetylation constitute major phase I and phase II polymorphic pathways of xenobiotic metabolism in humans. Analysis of human variability in kinetics for these pathways has been carried out for compounds metabolised extensively (>60%) by these routes. Data for minor substrates for CYP2C19 metabolism (10-60%) have also been analysed. Published pharmacokinetic studies (after oral and intravenous dosing) in CYP2C19 non-phenotyped healthy adults (NPs), and phenotyped extensive (EMs), slow-extensive (SEMs) and poor metabolisers (PMs) have been analysed using data for parameters that relate primarily to chronic exposure (metabolic and total clearances, area under the plasma concentration-time curve) and primarily to acute exposure (peak concentration). Similar analyses were performed for the N-acetylation pathway using data for fast acetylators (FA) and slow acetylators (SA). Interindividual variability in the kinetics of CYP2C19 substrates after oral dosage was greater in EMs than in NPs (60 vs 43% for clearances and 54 vs 45% for Cmax). Lower variability was found for N-acetylation for both phenotypes (32 and 22% for FA and SA, respectively). The internal dose of CYP2C19 substrates in PM subjects would be 31-fold higher than in EMs, while for N-acetylated substrates there was a three-fold difference between SA and FA subjects. Pathway-related uncertainty factors were above the default safety factor of 3.16 for most subgroups and values of 52 and 5.2 would be necessary to cover to the 99th centile of the poor metaboliser phenotype for CYP2C19 and N-acetylation, respectively. An exponential relationship (R(2)=0.86) was found between the extent of CYP2C19 metabolism and the difference in internal dose between EMs and PMs. The kinetic default factor (3.16) would cover PMs for substrates for which CYP2C19 was responsible for up to 20-30% of the metabolism in EMs.
细胞色素P450 2C19（CYP2C19）介导的氧化作用和N - 乙酰化作用构成了人体对外源物质代谢的主要I相和II相多态性途径。对于通过这些途径大量代谢（>60%）的化合物，已对这些途径的人体动力学变异性进行了分析。也分析了CYP2C19代谢的次要底物（10 - 60%）的数据。已使用主要与慢性暴露（代谢清除率和总清除率、血浆浓度 - 时间曲线下面积）以及主要与急性暴露（峰浓度）相关的参数数据，对CYP2C19未分型的健康成年人（NPs）以及已分型的广泛代谢者（EMs）、慢广泛代谢者（SEMs）和代谢不良者（PMs）进行了口服和静脉给药后的已发表药代动力学研究分析。使用快速乙酰化者（FA）和慢乙酰化者（SA）的数据，对N - 乙酰化途径进行了类似分析。口服给药后，CYP2C19底物动力学的个体间变异性在EMs中比在NPs中更大（清除率分别为60%对43%，Cmax分别为54%对45%）。两种表型的N - 乙酰化变异性较低（FA和SA分别为32%和22%）。PM受试者中CYP2C19底物的体内剂量比EMs高31倍，而对于N - 乙酰化底物，SA和FA受试者之间存在3倍差异。对于大多数亚组，途径相关的不确定因素高于默认安全系数3.16，分别需要52和5.2的值才能涵盖CYP2C19和N - 乙酰化代谢不良者表型的第99百分位数。在CYP2C19代谢程度与EMs和PMs之间的体内剂量差异之间发现了指数关系（R² = 0.86）。动力学默认因子（3.16）将涵盖CYP2C19在EMs中负责高达20 - 30%代谢的底物的PMs。
