Organic Anion Transporting Polypeptide (OATP)2B1 Contributes to Gastrointestinal Toxicity of Anticancer Drug SN 38, Active Metabolite of Irinotecan Hydrochloride
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 b 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.
Drug Metabolism and Disposition