Division of Clinical Pharmacology (C.X., Z.D.), Department of Obstetrics and Gynecology (S.K.Q.) and Center for Computational Biology and Bioinformatics (L.L.), Indiana University School of Medicine, Indianapolis, Indiana; and Department of Drug Disposition, Lilly Research Laboratories, Eli Lilly and Co., Indianapolis, Indiana (Y.G., S.D.H.).
Drug Metab Dispos. 2013 Dec;41(12):2004-11. doi: 10.1124/dmd.113.051755. Epub 2013 Jul 11.
Efavirenz is mainly cleared by CYP2B6. The CYP2B66 allele is associated with lower efavirenz clearance. Efavirenz clearance was predictable using in vitro data for carriers of the CYP2B61/1 genotype, but the prediction in carriers of the CYP2B66 allele was poor. To test the hypothesis that incorporation of mechanism of reduced efavirenz metabolism by the CYP2B66 allele can predict the genetic effect on efavirenz pharmacokinetics, in vitro-in vivo extrapolation of efavirenz clearance was performed by physiologically based pharmacokinetic modeling (Simcyp Simulator; Simcyp Ltd., Sheffield, UK) using data obtained from expressed CYP2B6.1 and CYP2B6.6 as well as human liver microsomes (HLMs) with CYP2B61/*1, *1/6, and 6/6 genotypes. Simulated pharmacokinetics of a single 600-mg oral dose of efavirenz for individuals with each genotype was compared with data observed in healthy subjects genotyped for the CYP2B66 allele (n = 20). Efavirenz clearance for carriers of the CYP2B61/1 genotype was predicted reasonably well using HLM data, but the clearance in carriers of the CYP2B66 allele was underpredicted using both expressed and HLM systems. Improved prediction of efavirenz clearance was obtained from expressed CYP2B6 after recalculating intersystem extrapolation factors for CYP2B6.1 and CYP2B6.6 based on in vitro intrinsic clearance of bupropion 4-hydroxylation. These findings suggest that genetic effect on both CYP2B6 protein expression and catalytic efficiency needs to be taken into account for the prediction of pharmacokinetics in individuals carrying the CYP2B66/6 genotype. Expressed CYP2B6 proteins may be a reliable in vitro system to predict effect of the CYP2B66 allele on the metabolism of CYP2B6 substrates.
依非韦伦主要通过 CYP2B6 清除。CYP2B66 等位基因与依非韦伦清除率降低相关。对于 CYP2B61/1 基因型携带者，使用体外数据可以预测依非韦伦清除率，但对于 CYP2B66 等位基因携带者的预测效果不佳。为了验证 CYP2B66 等位基因降低依非韦伦代谢的机制纳入可以预测其对依非韦伦药代动力学遗传效应的假设，采用基于生理学的药代动力学模型（Simcyp Simulator；Simcyp Ltd.，Sheffield，UK），通过表达 CYP2B6.1 和 CYP2B6.6 以及具有 CYP2B61/1、1/6 和6/6 基因型的人肝微粒体（HLMs），进行依非韦伦清除的体外-体内外推。将具有每种基因型的个体单次 600mg 口服依非韦伦的模拟药代动力学与 CYP2B66 等位基因基因分型的健康受试者观察到的数据进行比较（n=20）。使用 HLMs 数据可以很好地预测 CYP2B61/1 基因型携带者的依非韦伦清除率，但使用表达和 HLMs 系统均低估了 CYP2B66 等位基因携带者的清除率。在基于体外内在清除率重新计算 CYP2B6.1 和 CYP2B6.6 系统间外推因子后，从表达 CYP2B6 中获得了对依非韦伦清除率的改善预测。这表明，对于携带 CYP2B66/6 基因型的个体，需要考虑对 CYP2B6 蛋白表达和催化效率的遗传效应，以预测其药代动力学。表达的 CYP2B6 蛋白可能是预测 CYP2B66 等位基因对 CYP2B6 底物代谢影响的可靠体外系统。
