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

Hepatic uptake of albumin-bound amphipathic organic cations has been sugges ted to be mediated by multispecific bile salt and organic anion transport s ystems. 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 synth esized type II model compounds N- methyl-quinine and N-methyl-quinidine wer e transported only by the human organic anion transporting polypeptide. Thi s carrier-mediated uptake of N-methyl-quinine and N-methyl-quinidine was so dium-independent and saturable with apparent K-m values of similar to 5 and similar to 26 mu M, respectively. In contrast to bulky type II organic cat ions, more hydrophilic type I organic cations such as tributylmethylammoniu m and choline were not transported by any of the organic anion transporting polypeptides. These findings demonstrate that organic anion transporting p olypeptides can also mediate hepatocellular uptake of type II organic catio ns, whereas uptake of small and more water-soluble type I cations is mediat ed by different transport systems such as the organic cation transporters.