Effects of beta-lapachone, a new anticancer candidate, on cytochrome P450-mediated drug metabolism

Abstract

This study aimed to assess the potential inhibitory effects of beta-lapachone, a new anticancer candidate, on the activities of the cytochrome P450 (CYP450) enzymes in vitro. Different concentrations of beta-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. beta-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 mu M. However, beta-lapachone did not appear to modulate CYP450 activities as a mechanism-based inactivator. These results suggest that pharmacological drug-drug interactions might occur between beta-lapachone and drugs co-administered with it, which are extensively metabolized by CYP450 enzymes, and thus, careful observation is required in clinical pharmacokinetic studies.