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.