Indexed on: 10 Aug '16Published on: 10 Aug '16Published in: Drug metabolism and disposition: the biological fate of chemicals
Important antimalarial drugs including quinolines act against blood schizonts by interfering with hemoglobin metabolism. To reach their site of action, these compounds have to cross the plasma membrane of red blood cells (RBCs). Organic cation transporters (OCTs) and organic anion transporting polypeptides (OATPs) are important uptake transporters and interesting candidates for local drug transport. We therefore studied their interaction with antimalarial compounds (quinine, chloroquine, mefloquine, pyrimethamine, artemisinin and artesunate) and characterized the expression of OATP1A2 and OATP2B1 in RBCs. Competition assays using transporter-overexpressing MDCKII cells and the model substrate estrone-3-sulfate identified quinine and chloroquine as potent inhibitors of OATP1A2 function (IC50: quinine: 0.7 ± 1.2 μmol/l; chloroquine: 1.0 ± 1.5 μmol/l), while no or only moderate effects were observed for OATP2B1. Subsequently, quinine was identified as a substrate of OATP1A2 (Km: 23.4 μmol/l). The OATP1A2-mediated uptake was sensitive to the OATP1A2-specific inhibitor naringin. Both OATPs were expressed in human RBCs and ex vivo transport studies demonstrated naringin-sensitive accumulation of quinine in these cells (60 pmol vs. 38 pmol/5 × 105 RBCs). Additional transport studies using OCT1-3 and OCTN1 indicated only significant quinine uptake by OCT1, which was not detected in RBCs. In conclusion, our data demonstrate expression of OATP2B1 and OATP1A2 in RBCs, as well as OATP1A2-mediated uptake of quinine. Therefore, modulation of OATP1A2 function may affect quinine uptake into erythrocytes.