title: Organic Anion Transporting Polypeptide (OATP)2B1 Contributes to Gastrointestinal Toxicity of Anticancer Drug SN-38, Active Metabolite of Irinotecan Hydrochloride.
abstract: Gastrointestinal toxicity, such as late-onset diarrhea, is a significant concern in irinotecan hydrochloride (CPT-11)-containing regimens. Prophylaxis of late-onset diarrhea has been reported with use of Japanese traditional (Kampo) medicine containing baicalin and with the antibiotic cefixime, and this has been explained in terms of inhibition of bacterial deconjugation of SN-38-glucuronide since unconjugated SN-38 (active metabolite of CPT-11) is responsible for the gastrointestinal toxicity. It is also prerequisite for SN-38 to be accumulated in intestinal tissues to exert toxicity. Based on the fact that liver-specific organic anion transporting polypeptide (OATP)1B1, a member of the same family as OATP2B1, is known to be involved in hepatic transport of SN-38, we hypothesized that intestinal transporter OATP2B1 contributes to the accumulation of SN-38 in gastrointestinal tissues, and its inhibition would help prevent associated toxicity. We found that uptake of SN-38 by OATP2B1-expressing Xenopus oocytes was significantly higher than that by control oocytes. OATP2B1-mediated uptake of SN-38 was saturable, pH dependent, and decreased in the presence of baicalin, cefixime, or fruit juices such as apple juice. In vivo gastrointestinal toxicity of SN-38 in mice caused by oral administration for consecutive 5 days was prevented by coingestion of apple juice. Thus, OATP2B1 contributes to the uptake of SN-38 by intestinal tissues, triggering gastrointestinal toxicity. So, in addition to the reported inhibition of bacterial β-glucuronidase by cefixime or baicalin, inhibition of OATP2B1 may also contribute to prevention of gastrointestinal toxicity. Apple juice may be helpful for prophylaxis of late-onset diarrhea observed in CPT-11 therapy without disturbance of the intestinal microflora.
authors.affiliation: Faculty of Pharmaceutical Sciences, Institute of Medical, Pharmaceutical and Health Sciences, Kanazawa University, Kanazawa, Japan (D.F., Y.S., T.N., I.T.), and Department of Pharmacy, National Cancer Center Hospital, Tokyo, Japan (Y.S.).
authors.forename: Daichi
authors.initials: D
authors.lastname: Fujita
authors.affiliation: Faculty of Pharmaceutical Sciences, Institute of Medical, Pharmaceutical and Health Sciences, Kanazawa University, Kanazawa, Japan (D.F., Y.S., T.N., I.T.), and Department of Pharmacy, National Cancer Center Hospital, Tokyo, Japan (Y.S.).
authors.forename: Yoshimasa
authors.initials: Y
authors.lastname: Saito
authors.affiliation: Faculty of Pharmaceutical Sciences, Institute of Medical, Pharmaceutical and Health Sciences, Kanazawa University, Kanazawa, Japan (D.F., Y.S., T.N., I.T.), and Department of Pharmacy, National Cancer Center Hospital, Tokyo, Japan (Y.S.).
authors.forename: Takeo
authors.initials: T
authors.lastname: Nakanishi
authors.affiliation: Faculty of Pharmaceutical Sciences, Institute of Medical, Pharmaceutical and Health Sciences, Kanazawa University, Kanazawa, Japan (D.F., Y.S., T.N., I.T.), and Department of Pharmacy, National Cancer Center Hospital, Tokyo, Japan (Y.S.) tamai@p.kanazawa-u.ac.jp.
authors.forename: Ikumi
authors.initials: I
authors.lastname: Tamai
mesh_terms: D000284:Administration, Oral; D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000378:metabolism / Q000633:toxicity*; D001419:Bacteria / Q000187:drug effects / Q000201:enzymology; D001426:Bacterial Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D002166:Camptothecin / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000378:metabolism / Q000633:toxicity; D020682:Cefixime / Q000494:pharmacology; D003967:Diarrhea / Q000139:chemically induced* / Q000378:metabolism / Q000382:microbiology / Q000517:prevention & control; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D005419:Flavonoids / Q000494:pharmacology; D018565:Food-Drug Interactions; D000067030:Fruit and Vegetable Juices; D000069196:Gastrointestinal Microbiome; D018014:Gene Transfer Techniques; D005966:Glucuronidase / Q000037:antagonists & inhibitors / Q000378:metabolism; D006863:Hydrogen-Ion Concentration; D007408:Intestinal Absorption; D007413:Intestinal Mucosa / Q000378:metabolism; D007422:Intestines / Q000187:drug effects* / Q000382:microbiology; D000077146:Irinotecan; D007700:Kinetics; D027845:Malus; D008810:Mice, Inbred C57BL; D009865:Oocytes; D027361:Organic Anion Transporters / Q000235:genetics / Q000378:metabolism*; D014982:Xenopus laevis
chemical_list: D000970:Antineoplastic Agents; D001426:Bacterial Proteins; D004791:Enzyme Inhibitors; D005419:Flavonoids; D027361:Organic Anion Transporters; C450859:SLCO2B1 protein, human; C000610580:Slco2b1 protein, mouse; C038044:baicalin; D000077146:Irinotecan; D020682:Cefixime; D005966:Glucuronidase; D002166:Camptothecin