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):201-24. doi: 10.1016/s0278-6915(02)00209-0.
CYP3A4 constitutes the major liver cytochrome P450 isoenzyme and is responsible for the oxidation of more than 50% of all known drugs. Human variability in kinetics for this pathway has been quantified using a database of 15 compounds metabolised extensively (>60%) by this CYP isoform in order to develop CYP3A4-related uncertainty factors for the risk assessment of environmental contaminants handled via this route. Data were analysed from published pharmacokinetic studies (after oral and intravenous dosing) in healthy adults and other subgroups using parameters relating primarily to chronic exposure [metabolic and total clearances, area under the plasma concentration-time curve (AUC)] and acute exposure (Cmax). Interindividual variability in kinetics was greater for the oral route (46%, 12 compounds) than for the intravenous route (32%, 14 compounds). The physiological and molecular basis for the difference between these two routes of exposure is discussed. In relation to the uncertainty factors used for risk assessment, the default kinetic factor of 3.16 would be adequate for adults, whereas a CYP3A4-related factor of 12 would be required to cover up to 99% of neonates, which have lower CYP3A4 activity.
CYP3A4是肝脏中主要的细胞色素P450同工酶，已知超过50%的药物都是由它氧化代谢的。为了确定与CYP3A4相关的不确定性因素，以便对通过该途径处理的环境污染物进行风险评估，研究人员利用一个包含15种化合物的数据库对该途径的人体动力学变异性进行了量化，这些化合物在很大程度上（>60%）由这种CYP亚型代谢。研究人员分析了已发表的健康成年人及其他亚组的药代动力学研究数据（口服和静脉给药后），主要使用与慢性暴露相关的参数[代谢清除率和总清除率、血浆浓度-时间曲线下面积（AUC）]和急性暴露参数（Cmax）。口服途径的个体间动力学变异性（46%，12种化合物）大于静脉途径（32%，14种化合物）。本文讨论了这两种暴露途径差异的生理和分子基础。关于风险评估中使用的不确定性因素，默认的动力学因子3.16对成年人来说足够了，而对于CYP3A4活性较低的新生儿，需要一个与CYP3A4相关的因子12才能涵盖高达99%的新生儿。
