Keio University Faculty of Pharmacy, Tokyo, Japan.
Drug Metab Dispos. 2011 Apr;39(4):724-8. doi: 10.1124/dmd.110.036780. Epub 2011 Jan 6.
CYP3A4, an important drug-metabolizing enzyme, is known to have genetic variants. We have previously reported that CYP3A4 variants such as CYP3A4.2, 7, 16, and 18 show different enzymatic kinetics from CYP3A4.1 (wild type). In this study, we quantitatively investigated the inhibition kinetics of two typical inhibitors, itraconazole (ITCZ) and cimetidine (CMD), on CYP3A4 variants and evaluated whether the genetic variation leads to interindividual differences in the extent of CYP3A4-mediated drug interactions. The inhibitory profiles of ITCZ and CMD on the metabolism of testosterone (TST) were analyzed by using recombinant CYP3A4 variants. The genetic variation of CYP3A4 significantly affected the inhibition profiles of the two inhibitors. In CYP3A4.7, the K(i) value for ITCZ was 2.4-fold higher than that for the wild-type enzyme, whereas the K(i) value for CMD was 0.64-fold lower. In CYP3A4.16, the K(i) value for ITCZ was 0.54-fold lower than that for wild-type CYP3A4, whereas the K(i) value for CMD was 3.2-fold higher. The influence of other genetic variations also differed between the two inhibitors. Docking simulations could explain the changes in the K(i) values, based on the accessibility of TST and inhibitors to the heme moiety of the CYP3A4 molecule. In conclusion, the inhibitory effects of an inhibitor differ among CYP3A4 variants, suggesting that the genetic variation of CYP3A4 may contribute, at least in part, to interindividual differences in drug interactions mediated by CYP3A4 inhibition, and the pattern of the influences of genetic variation differs among inhibitors as well as substrates.
CYP3A4 是一种重要的药物代谢酶，已知其存在遗传变异。我们之前曾报道过，CYP3A4 变体（如 CYP3A4.2、7、16 和 18）与 CYP3A4.1（野生型）相比，表现出不同的酶动力学特性。在这项研究中，我们定量研究了两种典型抑制剂伊曲康唑（ITCZ）和西咪替丁（CMD）对 CYP3A4 变体的抑制动力学，并评估了遗传变异是否导致 CYP3A4 介导的药物相互作用程度的个体间差异。使用重组 CYP3A4 变体分析了 ITCZ 和 CMD 对睾酮（TST）代谢的抑制谱。CYP3A4 的遗传变异显著影响了两种抑制剂的抑制谱。在 CYP3A4.7 中，ITCZ 的 K(i)值比野生型酶高 2.4 倍，而 CMD 的 K(i)值低 0.64 倍。在 CYP3A4.16 中，ITCZ 的 K(i)值比野生型 CYP3A4 低 0.54 倍，而 CMD 的 K(i)值高 3.2 倍。两种抑制剂对其他遗传变异的影响也不同。基于 TST 和抑制剂与 CYP3A4 分子血红素部分的可及性，对接模拟可以解释 K(i)值的变化。总之，抑制剂对 CYP3A4 变体的抑制作用不同，这表明 CYP3A4 的遗传变异至少部分导致了 CYP3A4 抑制介导的药物相互作用的个体间差异，遗传变异的影响模式在抑制剂和底物之间也存在差异。
