Polyspecific organic anion transporting polypeptides mediate hepatic uptake of amphipathic type II organic cations.

Hepatic uptake of albumin-bound amphipathic organic cations has been suggested to be mediated by multispecific bile salt and organic anion transport systems. Therefore, we investigated whether the recently cloned rat organic anion transporting polypeptides 1 and 2 as well as the human organic anion transporting polypeptide might be involved in the hepatocellular uptake of bulky type II organic cations. In cRNA-injected Xenopus laevis oocytes, all three carriers mediated uptake of the known type II model compounds N-(4, 4-azo-n-pentyl)-21-deoxy-ajmalinium and rocuronium, whereas the newly synthesized type II model compounds N-methyl-quinine and N-methyl-quinidine were transported only by the human organic anion transporting polypeptide. This carrier-mediated uptake of N-methyl-quinine and N-methyl-quinidine was sodium-independent and saturable with apparent K(m) values of approximately 5 and approximately 26 microM, respectively. In contrast to bulky type II organic cations, more hydrophilic type I organic cations such as tributylmethylammonium and choline were not transported by any of the organic anion transporting polypeptides. These findings demonstrate that organic anion transporting polypeptides can also mediate hepatocellular uptake of type II organic cations, whereas uptake of small and more water-soluble type I cations is mediated by different transport systems such as the organic cation transporters.