Possible roles of intestinal P-glycoprotein and cytochrome P450 3A on the limited oral absorption of irinotecan
| Autor: | Kazuhiko Arimori, Keishi Yamasaki, Muneaki Hidaka, Yumiko Furuya, Hiroshige Ono, Yohei Kawano |
|---|---|
| Rok vydání: | 2020 |
| Předmět: |
Male
CYP3A Pharmaceutical Science Administration Oral Biological Availability Pharmacology Irinotecan 030226 pharmacology & pharmacy Intestinal absorption 03 medical and health sciences 0302 clinical medicine Pharmacokinetics Oral administration medicine Animals Cytochrome P-450 CYP3A ATP Binding Cassette Transporter Subfamily B Member 1 Rats Wistar P-glycoprotein biology Chemistry Bioavailability Rats stomatognathic diseases Intestinal Absorption Verapamil 030220 oncology & carcinogenesis biology.protein Topoisomerase I Inhibitors medicine.drug |
| Zdroj: | The Journal of pharmacy and pharmacology. 73(2) |
| ISSN: | 2042-7158 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|
Plný text