Interaction of sirolimus and everolimus with hepatic and intestinal organic anion-transporting polypeptide transporters.

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Picard N, Levoir L, Lamoureux F, Yee SW, Giacomini KM, Marquet P

Interaction of sirolimus and everolimus with hepatic and intestinal organic anion-transporting polypeptide transporters.

Xenobiotica. 2011 Sep;41(9):752-7. doi: 10.3109/00498254.2011.573882. Epub 2011 Apr 27.

PubMed ID

21524191 [ View in PubMed

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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 [(3)H]-estrone sulphate by OATP1A2 and OATP1B1 and that of mycophenolic acid 7-O-glucuronide (MPAG) by OATP1B3. ImTOR apparent 50% inhibitory concentrations (IC(5)(0)) for OATPs were 11.9 microM (OATP1A2), 9.8 microM (OATP1B1) and 1.3 microM (OATP1B3) for sirolimus and 4.2 microM (OATP1A2), 4.1 microM (OATP1B1) and 4.3 microM (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.

DrugBank Data that Cites this Article

Drug Transporters

Drug	Transporter	Kind	Organism	Pharmacological Action	Actions
Everolimus	Solute carrier organic anion transporter family member 1A2	Protein	Humans	Unknown	Inhibitor	Details
Everolimus	Solute carrier organic anion transporter family member 1B1	Protein	Humans	Unknown	Inhibitor	Details
Everolimus	Solute carrier organic anion transporter family member 1B3	Protein	Humans	Unknown	Inhibitor	Details