title: Effects of β-lapachone, a new anticancer candidate, on cytochrome P450-mediated drug metabolism.
abstract: OBJECTIVE
  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.
  
  
  METHODS
  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.
  
  
  RESULTS
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Institute of Pharmaceutical Science and Technology and College of Pharmacy, Hanyang University, Ansan-si, Gyeonggi-do, Republic of Korea.
authors.forename: In Sook
authors.initials: IS
authors.lastname: Kim
authors.forename: Yun
authors.initials: Y
authors.lastname: Kim
authors.forename: Tae Hwan
authors.initials: TH
authors.lastname: Kwak
authors.forename: Hye Hyun
authors.initials: HH
authors.lastname: Yoo
mesh_terms: D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000494:pharmacology*; D002853:Chromatography, Liquid; D065607:Cytochrome P-450 Enzyme Inhibitors; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D006801:Humans; D020128:Inhibitory Concentration 50; D008862:Microsomes, Liver / Q000378:metabolism*; D009285:Naphthoquinones / Q000008:administration & dosage / Q000494:pharmacology*; D053719:Tandem Mass Spectrometry; D013997:Time Factors
chemical_list: D000970:Antineoplastic Agents; D065607:Cytochrome P-450 Enzyme Inhibitors; D009285:Naphthoquinones; C014638:beta-lapachone; D003577:Cytochrome P-450 Enzyme System