title: Active transepithelial transport of irinotecan (CPT-11) and its metabolites by human intestinal Caco-2 cells.
abstract: Irinotecan (CPT-11) is a camptothecin analog with low (about 10--20%) and variable oral bioavailability in animal models. Here, Caco-2 cells were used to evaluate the transepithelial transport of CPT-11 and its metabolites. Caco-2 cells demonstrated significant expression of P-glycoprotein (P-gp), multidrug resistance-associated protein and canalicular multispecific organic anion transporter. Both the lactone and carboxylate forms of CPT-11 and SN-38 were actively transported across the cell monolayers, mainly by the apical-localized P-gp pump. Cellular permeability of CPT-11 at a concentration of 17 microM converted from active to passive-diffusional transport between the 2 and 6 h exposure time points. Antiproliferative effects of CPT-11 were related to permeability of the lactone form, whereas for SN-38 efficacy was dependent on lactone accumulation. Exposure of CPT-11 with cyclosporin A significantly enhanced its efficacy, whereas this was not observed with verapamil and R101933. In contrast, SN-38 efficacy decreased in the presence of P-gp inhibitors due to active transport toward the basolateral side, thereby reducing drug accumulation. Hence, multiple-active transport systems could be demonstrated to be responsible for not only accumulation profiles but also cytotoxic efficacy of CPT-11 and SN-38 in the intestinal Caco-2 cells. It is suggested that CPT-11 might act in a time-dependent manner and that SN-38-mediated cytotoxicity relates to (dose-dependent) lactone kinetics. The results detailed in this report could contribute toward the development of a clinically useful oral formulation of CPT-11 with improved absorption characteristics and suggest that cyclosporin A is a suitable agent for further research of this concept.
authors.affiliation: Department of Medical Oncology, Rotterdam Cancer Institute, Daniel den Hoed Kliniek, and University Hospital Rotterdam, 3008 AE Rotterdam, The Netherlands.
authors.forename: W
authors.initials: W
authors.lastname: Yamamoto
authors.forename: J
authors.initials: J
authors.lastname: Verweij
authors.forename: P
authors.initials: P
authors.lastname: de Bruijn
authors.forename: M J
authors.initials: MJ
authors.lastname: de Jonge
authors.forename: H
authors.initials: H
authors.lastname: Takano
authors.forename: M
authors.initials: M
authors.lastname: Nishiyama
authors.forename: M
authors.initials: M
authors.lastname: Kurihara
authors.forename: A
authors.initials: A
authors.lastname: Sparreboom
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000037:antagonists & inhibitors / Q000378:metabolism; D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000493:pharmacokinetics*; D001552:Benzazepines / Q000494:pharmacology; D001692:Biological Transport; D001711:Biotransformation; D018938:Caco-2 Cells / Q000378:metabolism*; D002166:Camptothecin / Q000031:analogs & derivatives / Q000493:pharmacokinetics*; D002470:Cell Survival / Q000187:drug effects; D002851:Chromatography, High Pressure Liquid; D016572:Cyclosporine / Q000494:pharmacology; D006801:Humans; D007413:Intestinal Mucosa / Q000378:metabolism*; D000077146:Irinotecan; D011804:Quinolines / Q000494:pharmacology; D012333:RNA, Messenger / Q000378:metabolism; D014700:Verapamil / Q000494:pharmacology
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000972:Antineoplastic Agents, Phytogenic; D001552:Benzazepines; D011804:Quinolines; D012333:RNA, Messenger; D000077146:Irinotecan; D016572:Cyclosporine; D014700:Verapamil; C411474:laniquidar; D002166:Camptothecin