Division of Medicinal Safety Science, National Institute of Health Sciences, 1-18-1 Kamiyoga, Setagaya-ku, Tokyo 158-8501, Japan.
Drug Metab Dispos. 2010 Dec;38(12):2100-4. doi: 10.1124/dmd.110.034140. Epub 2010 Sep 16.
CYP3A4, the major form of cytochrome P450 (P450) expressed in the adult human liver, is involved in the metabolism of approximately 50% of commonly prescribed drugs. Several genetic polymorphisms in CYP3A4 are known to affect its catalytic activity and to contribute in part to interindividual differences in the pharmacokinetics and pharmacodynamics of CYP3A4 substrate drugs. In this study, catalytic activities of the two alleles found in East Asians, CYP3A416 (T185S) and CYP3A418 (L293P), were assessed using the following seven substrates: midazolam, carbamazepine, atorvastatin, paclitaxel, docetaxel, irinotecan, and terfenadine. The holoprotein levels of CYP3A4.16 and CYP3A4.18 were significantly higher and lower, respectively, than that of CYP3A4.1 when expressed in Sf21 insect cell microsomes together with human NADPH-P450 reductase. CYP3A4.16 exhibited intrinsic clearances (V(max)/K(m)) that were lowered considerably (by 84-60%) for metabolism of midazolam, carbamazepine, atorvastatin, paclitaxel, and irinotecan compared with CYP3A4.1 due to increased K(m) with or without decreased V(max) values, whereas no apparent decrease in intrinsic clearance was observed for docetaxel. On the other hand, K(m) values for CYP3A4.18 were comparable to those for CYP3A4.1 for all substrates except terfenadine; but V(max) values were lower for midazolam, paclitaxel, docetaxel, and irinotecan, resulting in partially reduced intrinsic clearance values (by 34-52%). These results demonstrated that the impacts of both alleles on CYP3A4 catalytic activities depend on the substrates used. Thus, to evaluate the influences of both alleles on the pharmacokinetics of CYP3A4-metabolized drugs and their drug-drug interactions, substrate drug-dependent characteristics should be considered for each drug.
CYP3A4 是成人肝脏中表达的细胞色素 P450（P450）的主要形式，参与约 50%常用药物的代谢。已知 CYP3A4 中的几种遗传多态性会影响其催化活性，并部分导致 CYP3A4 底物药物的药代动力学和药效动力学的个体间差异。在这项研究中，使用以下七种底物评估了在东亚人中发现的两种等位基因 CYP3A416（T185S）和 CYP3A418（L293P）的催化活性：咪达唑仑、卡马西平、阿托伐他汀、紫杉醇、多西他赛、伊立替康和特非那定。当与人类 NADPH-P450 还原酶一起在 Sf21 昆虫细胞微粒体中表达时，CYP3A4.16 和 CYP3A4.18 的全蛋白水平分别明显高于 CYP3A4.1，而 CYP3A4.18 的全蛋白水平则明显低于 CYP3A4.1。与 CYP3A4.1 相比，CYP3A4.16 对咪达唑仑、卡马西平、阿托伐他汀、紫杉醇和伊立替康代谢的内在清除率（V(max)/K(m)）明显降低（84-60%），这是由于 K(m)增加，而 V(max)值降低或不变，而对于多西他赛，没有观察到内在清除率的明显降低。另一方面，对于除特非那定以外的所有底物，CYP3A4.18 的 K(m)值与 CYP3A4.1 相当；但对于咪达唑仑、紫杉醇、多西他赛和伊立替康，V(max)值较低，导致部分降低的内在清除率（34-52%）。这些结果表明，两种等位基因对 CYP3A4 催化活性的影响取决于所用的底物。因此，为了评估两种等位基因对 CYP3A4 代谢药物的药代动力学及其药物相互作用的影响，应考虑每种药物的底物药物依赖性特征。
