Comparison of "type I" and "type II" organic cation transport by organic cation transporters and organic anion-transporting polypeptides

Previous inhibition studies with taurocholate and cardiac glycosides sugges ted the presence of separate uptake systems for small "type I" (system1) an d for bulky "type II" (system2) organic cations in rat hepatocytes. To iden tify the transport systems involved in type I and type II organic cation up take, we compared the organic cation transport properties of the rat and hu man organic cation transporter 1 (rOCT1; hOCT1) and of the organic anion-tr ansporting polypeptides 2 and A (rat Oatp2; human OATP-A) in cRNA-injected Xenopus laevis oocytes. Based on characteristic cis-inhibition patterns of rOCT1-mediated tributylmethylammonium and Oatp2-mediated rocuronium uptake, rOCT1 and Oatp2 could be identified as the organic cation uptake systems1 and 2, respectively, in rat liver. While hOCT1 exhibited similar transport properties as rOCT1, OATP-A- but not Oatp2-mediated rocuronium uptake was i nhibited by the OATP-A substrate N-methyl-quinidine, The latter substrate w as also transported by rOCT1 and hOCT1, demonstrating distinct organic cati on transport activities for rOCT1 and Oatp2 and overlapping organic cation transport activities for hOCT1 and OATP-A. Finally, the data demonstrate th at unmethylated quinidine is transported by rOCT1, hOCT1, and OATP-A at pH 6.0, but not at pH 7.5, indicating that quinidine requires a positive charg e for carrier-mediated uptake into hepatocytes, In conclusion, the studies demonstrate that in rat liver the suggested organic cation uptake systems1 and 2 correspond to rOCT1 and Oatp2, respectively. However, the rat-based t ype I and II organic cation transporter classification cannot be extended w ithout modification from rat to human.