Pazopanib interacts with irinotecan by inhibiting UGT1A1-mediated glucuronidation, but not OATP1B1-mediated hepatic uptake, of an active metabolite SN-38

Cancer Chemotherapy and Pharmacology
Mariko IwaseYuji Kiuchi

Abstract

Pazopanib is an orally active, multi-targeted tyrosine kinase inhibitor. A previous phase I study demonstrated that coadministration of pazopanib with irinotecan increases the area under the plasma concentration-time curve (AUC) for SN-38, an active metabolite of irinotecan. To clarify the possible mechanism underlying that drug-drug interaction, we investigated the potential for pazopanib to inhibit UDP-glucuronosyltransferase (UGT)1A1 and organic anion-transporting polypeptide (OATP)1B1, which are involved in detoxification and hepatic uptake of SN-38, respectively. Human liver microsomes (HLMs) and recombinant human UGT1A1, and HEK293 cells stably transfected with OATP1B1 were used to evaluate the inhibitory effects of pazopanib against glucuronidation, and hepatic uptake of SN-38, respectively. Kinetic analysis was performed to estimate inhibition constants, which were corrected for non-specific binding to enzyme sources (Ki,u values). Concentration-dependent inhibition of SN-38 glucuronidation was observed in the HLMs and recombinant human UGT1A1 experiments: Pazopanib noncompetitively inhibited SN-38 glucuronidation by HLMs (Ki,u = 1.6 ± 0.05 µM) and recombinant human UGT1A1 (Ki,u = 0.69 ± 0.02 µM). Pazopanib-induced incr...Continue Reading

References

Apr 8, 2014·Cancer Chemotherapy and Pharmacology·Diane-Charlotte ImbsEtienne Chatelut
Oct 8, 2015·Drug Metabolism and Disposition : the Biological Fate of Chemicals·Kushari BurnsJohn O Miners
Apr 24, 2018·Japanese Journal of Clinical Oncology·Shingo MiyamotoAkira Ishikawa
Jun 27, 2018·Cancer Chemotherapy and Pharmacology·John P FruehaufJames G Jakowatz

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Citations

Jul 4, 2020·Drug Metabolism and Disposition : the Biological Fate of Chemicals·Takayuki TaguchiYukio Kato
Sep 13, 2020·Pharmaceutics·Dominique A GarrisonSharyn D Baker
Aug 16, 2019·Pharmacological Research : the Official Journal of the Italian Pharmacological Society·Christian Bailly

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