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Indexed by:Journal Papers

Date of Publication:2019-11-05

Journal:Cancer chemotherapy and pharmacology

Included Journals:PubMed

ISSN No.:1432-0843

Key Words:Irinotecan,Pharmacokinetic interaction,SN-38,Sunitinib

Abstract:The previous clinical trials found that the co-administration of irinotecan with sunitinib exhibited a synergistic antitumor effect. In the current study, we aimed to investigate whether the synergistic effect is related to a potential pharmacokinetic interaction between sunitinib and irinotecan. The inhibitory effects of sunitinib on SN-38 glucuronidation were determined by measuring the formation rates for SN38 glucuronide using recombinant human UGT isoforms and human liver microsomes (HLMs) in the absence or presence of sunitinib. Our data indicated that sunitinib exhibited competitive inhibition against SN-38 glucuronidation by UGT1A1, but inhibitory effects of sunitinib were weak in pooled human liver microsomes (HLMs) (Ki = 119.00 μM) and recombinant UGT1A1 (Ki = 42.71 μM). Our further prediction study partly explains the possible mechanism of synergistic antitumor activity of sunitinib and irinotecan in the combined treatment and provides a basis for design of clinical studies for the development and optimization of this combination.