Inhibitory effect of vemurafenib on UGT1A1-mediated irinotecan metabolism

doi:10.12092/j.issn.1009-2501.2019.07.008

Abstract

Abstract:

AIM: To study the inhibitory effect of vemurafenib on UDP-glucuronosyltransferases 1A1 (UGT1A1)-mediated irinotecan metabolism, and predict the risk of drug-drug interactions (DDI) by in vitro-in vivo extrapolation (IV-IVE). METHODS: A panel of human liver microsomes (HLMs) and recombinant human UGT1A1 were used to characterize the inhibitory effect of vemurafenib on human UGT1A1-mediated glucuronidation of SN-38, the active metabolite of irinotecan. The half maximum inhibitory concentration (IC50) and the constant of inhibition kinetics (Ki) were obtained, and the potential risk of DDI was predicted based on in vitro parameters. RESULTS:Vemurafenib had strong non-competitive inhibitory effect on UGT1A1, the IC50 value was 4.35 μmol/L, and the inhibition kinetic constant Ki value was 9.77 μmol/L. The area under the curve (AUC) ratio of SN-38 can be increased by 7% to 149% at the oral dose of 960 mg twice daily. CONCLUSION: The strong inhibition of vemurafenib on UGT1A1 leads to reduction of the UGT1A1-mediated irinotecan metabolism, and increases the risk of DDI.

Key words: vemurafenib, irinotecan, UDP-glucuronosyltransferase 1A1, drug-drug interaction

CLC Number:

R28
R965.5

WEN Chunjie, ZHANG Ying, WU Lanxiang, ZHOU Honghao. Inhibitory effect of vemurafenib on UGT1A1-mediated irinotecan metabolism[J]. Chinese Journal of Clinical Pharmacology and Therapeutics, 2019, 24(7): 773-777.

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