Institute of Pharmaceutical Science and Technology and College of Pharmacy, Hanyang University, Ansan-si, Gyeonggi-do, Republic of Korea.
Cancer Chemother Pharmacol. 2013 Sep;72(3):699-702. doi: 10.1007/s00280-013-2230-x. Epub 2013 Jul 23.
This study aimed to assess the potential inhibitory effects of β-lapachone, a new anticancer candidate, on the activities of the cytochrome P450 (CYP450) enzymes in vitro.
Different concentrations of β-lapachone were incubated with human liver microsomes in the presence of CYP isozyme-specific substrates and NADPH, and the formation of the marker metabolites was measured using liquid chromatography-tandem mass spectrometry. In addition, time-dependent inhibition was examined to characterize the mode of the inhibition.
β-Lapachone showed concentration-dependent inhibitory effects on all CYP isozymes tested (CYP1A2, CYP2A6, CYP2C8, CYP2C9, CYPC19, CYP2D6, and CYP3A4), and its half-maximal inhibitory concentration (IC50) values ranged from 2.6 to 9.7 μM. However, β-lapachone did not appear to modulate CYP450 activities as a mechanism-based inactivator.
These results suggest that pharmacological drug-drug interactions might occur between β-lapachone and drugs co-administered with it, which are extensively metabolized by CYP450 enzymes, and thus, careful observation is required in clinical pharmacokinetic studies.
本研究旨在评估β-拉帕醌作为一种新型抗癌候选药物，在体外对细胞色素 P450（CYP450）酶活性的潜在抑制作用。
不同浓度的β-拉帕醌与人肝微粒体在 CYP 同工酶特异性底物和 NADPH 的存在下孵育，并使用液相色谱-串联质谱法测量标记代谢物的形成。此外，还进行了时程抑制试验以表征抑制模式。
β-拉帕醌对所有测试的 CYP 同工酶（CYP1A2、CYP2A6、CYP2C8、CYP2C9、CYP2C19、CYP2D6 和 CYP3A4）均表现出浓度依赖性抑制作用，其半抑制浓度（IC50）值范围为 2.6 至 9.7 μM。然而，β-拉帕醌似乎并未作为一种基于机制的失活剂来调节 CYP450 活性。
这些结果表明，β-拉帕醌与广泛代谢的 CYP450 酶共同给药的药物之间可能发生药物相互作用，因此在临床药代动力学研究中需要仔细观察。
