Possible roles of intestinal P-glycoprotein and cytochrome P450 3A on the limited oral absorption of irinotecan.

Autor:	Yamasaki K; Faculty of Pharmaceutical Sciences, Sojo University, Kumamoto, Japan.; DDS Research Institute, Sojo University, Kumamoto, Japan.; Department of Pharmacy, University of Miyazaki Hospital, Miyazaki, Japan., Hidaka M; Department of Pharmacy, University of Miyazaki Hospital, Miyazaki, Japan.; Department of Clinical Pharmacy, Graduate School of Clinical Pharmacy, Kyushu University of Health and Welfare, Nobeoka, Japan., Kawano Y; Department of Pharmacy, University of Miyazaki Hospital, Miyazaki, Japan.; Faculty of Pharmaceutical Sciences, Tokyo University of Science, Chiba, Japan., Furuya Y; Department of Pharmacy, University of Miyazaki Hospital, Miyazaki, Japan., Ono H; Department of Pharmacy, University of Miyazaki Hospital, Miyazaki, Japan.; Faculty of Pharmaceutical Sciences, Sanyo-Onoda City University, Sanyo-Onoda, Japan., Arimori K; Department of Pharmacy, University of Miyazaki Hospital, Miyazaki, Japan.
Jazyk:	angličtina
Zdroj:	The Journal of pharmacy and pharmacology [J Pharm Pharmacol] 2021 Mar 04; Vol. 73 (2), pp. 178-184.
DOI:	10.1093/jpp/rgaa009
Abstrakt:	Objectives: Irinotecan is a widely intravenously used drug for the treatment of certain types of solid tumours. The oral administration of irinotecan has recently been recognized as being a more effective method for the treatment than intravenous administration. However, the limited oral bioavailability of irinotecan poses a problem for its oral delivery. In this study, we report on an investigation of the mechanism responsible for the limited oral absorption of irinotecan using rats as models. Methods: The intestinal absorption of irinotecan in the absence and presence of several compounds was examined using intestinal loop method. The pharmacokinetics of irinotecan was investigated when verapamil, an inhibitor of the P-glycoprotein (P-gp) and cytochrome P450 3A (CYP3A) was pre-administered. Key Findings: The intestinal absorption of irinotecan was enhanced in the presence of verapamil, indicating that efflux by intestinal P-gp contributes to its limited oral absorption. Indeed, the oral bioavailability of irinotecan was increased when verapamil was orally pre-administered. This increased oral bioavailability was accompanied by a slight but significant decrease in the formation of a metabolite produced by the action of CYP3A. Conclusion: The findings presented herein suggest that intestinal efflux by P-gp is mainly and intestinal metabolism by CYP3A is partially responsible for the limited oral absorption of irinotecan. (© The Author(s) 2020. Published by Oxford University Press on behalf of Royal Pharmaceutical Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)
Databáze:	MEDLINE
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