Keio University Faculty of Pharmacy.
Drug Metab Pharmacokinet. 2013;28(5):411-5. doi: 10.2133/dmpk.dmpk-12-rg-134. Epub 2013 Mar 19.
Inhibition of cytochrome P450 (CYP) 3A4 is the major cause of drug-drug interactions (DDI). We have previously reported that the genetic variation of CYP3A4 significantly affected the inhibitory profiles of typical competitive inhibitors. In addition to competitive inhibition, some clinically significant DDI are attributable to mechanism-based inhibition (MBI). However, the differences in the MBI kinetics among CYP3A4 genetic variants remain to be characterized. In this study, we quantitatively investigated the inhibition kinetics of MBI inhibitors, erythromycin and clarithromycin, on the CYP3A4 variants CYP3A4.1, 4.2, 4.7, 4.16, and 4.18. The activity of CYP3A4 was assessed using testosterone 6β-hydroxylation with recombinant CYP3A4. Both erythromycin and clarithromycin decreased the activity of CYP3A4 in a time-dependent manner. The maximum inactivation rate constants, k(inact,max), of erythromycin for CYP3A4.2 and CYP3A4.7 were 0.5-fold that for CYP3A4.1, while that for CYP3A4.16 and CYP3A4.18 were similar to that for CYP3A4.1. The K(I) values of erythromycin for CYP3A4.2, 4.7, 4.16, and 4.18 were 1.2-, 0.4-, 2.2- and 0.72-fold those of CYP3A4.1, respectively. Similar results were obtained for clarithromycin. In conclusion, the inhibitory profiles of MBI inhibitors, as well as competitive inhibitors, may possibly differ among CYP3A4 variants. This difference may contribute to interindividual differences in the extent of DDI based on MBI.
细胞色素 P450（CYP）3A4 的抑制是药物-药物相互作用（DDI）的主要原因。我们之前曾报道过，CYP3A4 的遗传变异显著影响典型竞争性抑制剂的抑制谱。除了竞争性抑制外，一些临床上显著的 DDI 归因于基于机制的抑制（MBI）。然而，CYP3A4 遗传变异体之间 MBI 动力学的差异仍有待表征。在这项研究中，我们定量研究了红霉素和克拉霉素这两种 MBI 抑制剂对 CYP3A4 变体 CYP3A4.1、4.2、4.7、4.16 和 4.18 的抑制动力学。使用重组 CYP3A4 进行睾酮 6β-羟化来评估 CYP3A4 的活性。红霉素和克拉霉素均以时间依赖性方式降低 CYP3A4 的活性。红霉素对 CYP3A4.2 和 CYP3A4.7 的最大失活速率常数（k(inact,max)）是 CYP3A4.1 的 0.5 倍，而 CYP3A4.16 和 CYP3A4.18 与 CYP3A4.1 相似。红霉素对 CYP3A4.2、4.7、4.16 和 4.18 的 K(I) 值分别为 CYP3A4.1 的 1.2、0.4、2.2 和 0.72 倍。克拉霉素也得到了类似的结果。总之，MBI 抑制剂以及竞争性抑制剂的抑制谱可能在 CYP3A4 变体之间存在差异。这种差异可能导致基于 MBI 的 DDI 程度在个体之间存在差异。
