title: Interaction of sirolimus and everolimus with hepatic and intestinal organic anion-transporting polypeptide transporters.
abstract: The goal of this study was to assess the interaction of the mTOR inhibitors (ImTORs) sirolimus and everolimus with the human organic anion-transporting polypeptides (OATPs) expressed in hepatocytes and enterocytes by conducting uptake experiments using (i) transfected HEK293T cells, (ii) the hepatocyte-like HepaRG cell line and (iii) the enterocyte-like Caco-2 cell line. Sirolimus and everolimus inhibited in a dose-dependent manner the uptake of [³H]-estrone sulphate by OATP1A2 and OATP1B1 and that of mycophenolic acid 7-O-glucuronide (MPAG) by OATP1B3. ImTOR apparent 50% inhibitory concentrations (IC₅₀) for OATPs were 11.9 µM (OATP1A2), 9.8 µM (OATP1B1) and 1.3 µM (OATP1B3) for sirolimus and 4.2 µM (OATP1A2), 4.1 µM (OATP1B1) and 4.3 µM (OATP1B3) for everolimus. No transport of sirolimus or everolimus by OATP1A2, OATP1B1 or OATP1B3 was observed in HEK-transfected cells and the OAT/OATP/MRP chemical inhibitor probenecid did not significantly decrease the uptake of sirolimus and everolimus in HepaRG and Caco-2 cells, but tended to increase their intracellular accumulation presumably through efflux inhibition. In conclusion, our data suggest that the major OATP transporters expressed in the liver and the intestine do not contribute to the pharmacokinetics of sirolimus and everolimus. However, ImTORs are inhibitors of these transporters.
authors.affiliation: INSERM, UMR-S850, Limoges, France. nicolas.picard@unilim.fr
authors.forename: Nicolas
authors.initials: N
authors.lastname: Picard
authors.forename: Laure
authors.initials: L
authors.lastname: Levoir
authors.forename: Fabien
authors.initials: F
authors.lastname: Lamoureux
authors.forename: Sook Wah
authors.initials: SW
authors.lastname: Yee
authors.forename: Kathleen M
authors.initials: KM
authors.lastname: Giacomini
authors.forename: Pierre
authors.initials: P
authors.lastname: Marquet
mesh_terms: D018938:Caco-2 Cells; D016572:Cyclosporine / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D000068338:Everolimus; D057809:HEK293 Cells; D006801:Humans; D007166:Immunosuppressive Agents / Q000378:metabolism / Q000494:pharmacology; D020128:Inhibitory Concentration 50; D007413:Intestinal Mucosa / Q000378:metabolism*; D007422:Intestines / Q000187:drug effects; D008099:Liver / Q000187:drug effects / Q000378:metabolism*; D027361:Organic Anion Transporters / Q000378:metabolism*; D011339:Probenecid / Q000494:pharmacology; D020123:Sirolimus / Q000031:analogs & derivatives* / Q000378:metabolism* / Q000494:pharmacology; D014162:Transfection
chemical_list: D007166:Immunosuppressive Agents; D027361:Organic Anion Transporters; D016572:Cyclosporine; D000068338:Everolimus; D011339:Probenecid; D020123:Sirolimus