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 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.

Gene-by-Environment Interaction of Bcrp−/− and Methionine- and Choline-Deficient Diet–Induced Nonalcoholic Steatohepatitis Alters SN-38 Disposition

“…Uptake transporters may also have an effect on the disposition of SN-38. SN-38 is known to be transported by human OATP1B1, OATP1B3, and OATP2B1 (Kalliokoski and Niemi, 2009;Fujita et al, 2016), and rodent transporters OATP1B2, OATP2B1, and OATP1A4 (Wang et al, 2016), although other transporters of organic anions may also be involved. The MCD diet has been shown to alter the mRNA and protein expression of various hepatic uptake transporters, including rat OATP1A1, OATP1A3, OATP1B2, and OATP2B1.…”

Organic Anion Transporting Polypeptides: Emerging Roles in Cancer Pharmacology

“…OATP1B1 does not transport SN-38 glucuronide (Nozawa et al, 2005a). OATP2B1 transports SN-38 in Xenopus oocytes (Fujita et al, 2016), but not in HEK293 cells (Fujita et al, 2014). Oatp1a/1b null mice have markedly increased plasma exposure of irinotecan and SN-38 and significantly decreased liverto-plasma ratios of these compounds compared with wild type.…”

“…It is spontaneously converted to an active metabolite, 7-ethyl-10-hydroxycamptothecin (SN-38), by hepatic carboxylesterase and butyrylcholinesterase (de Man et al, 2018). SN-38 is believed to play a role in both the efficacy and toxicity associated with irinotecan-containing regimens, especially diarrhea (Kehrer et al, 2001;Fujita et al, 2016). SN-38 is further metabolized to an inactive form, SN-38glucuronide, by uridine diphosphate glucuronosyltransferases, most prominently by the 1A1 isoform (UGT1A1); this glucuronide form is transported to the intestinal lumen via bile (Lokiec et al, 1995;de Man et al, 2018).…”

“…Additionally, several drugs are known to inhibit the function of one or more OATP, notably inhibition of OATP1B1 and OATP1B3 by macrolide antibiotics and rifampicin, inhibition of OATP1B1 by cyclosporine (Clarke and Cherrington, 2012;König et al, 2013), and inhibition of all OATPs by rifamycin (Hagenbuch and Meier, 2004). Intestinal OATP2B1 is inhibited by baicalin, cefixime, and fruit juices (most notably apple juice; also orange and grapefruit juices) (Dresser et al, 2002;Clarke and Cherrington, 2012;Shirasaka et al, 2013;Fujita et al, 2016), while OATP1A2 is inhibited by grapefruit juice (specifically its component naringin) (Glaeser et al, 2007;Clarke and Cherrington, 2012;Rebello et al, 2012). Testosterone and progesterone (and steroid hormones closely related to them) inhibit OATP2B1-mediated transport but are not substrates for OATP2B1 (Grube et al, 2006a).…”

Impact of Breast Cancer Resistance Protein Expression on the In Vitro Efficacy of Anticancer Drugs in Pancreatic Cancer Cell Lines

“…SN-38 and topotecan are pharmacologically active in the lactone form, but most drugs are in the inactive carboxylate form at physiologic pH (Oguma, 2001). With reference to the transport of lactone and carboxylate forms of SN-38, we have recently shown that they are similarly transported by another type of transporter, organic anion-transporting polypeptide 2B1 (Fujita et al, 2016). However, the same result may not be directly applicable to BCRP-mediated transport, and evaluation of the efflux ratio of the lactone forms of these drugs separately from their carboxylate forms will be required.…”