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Organic Anion Transporting Polypeptide 1a4 is Responsible for the Hepatic Uptake of Cardiac Glycosides in Mice.

Drug Metab. Dispos.2018 May;46(5):652-657. Epub 2018 Jan 18
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摘要


Among organic anion transporting polypeptide (Oatp) family transporters expressed in the rodent liver, such as Oatp1a1, Oatp1a4, Oatp1b2, and Oatp2b1, Oatp1a4 has a unique character to recognize neutral cardiac glycosides as a substrate in addition to organic anions. The relative contribution of Oatp1a4 to the substrate uptake into hepatocytes has not been clarified. In this study, we investigated the importance of Oatp1a4 in the hepatic uptake of its substrate drugs using mice. The hepatic mRNA expression of Slco1a4 was decreased significantly in mice, whereas no differences were seen in other hepatic transporters between wild-type and mice. We determined the plasma concentrations and liver-to-plasma concentration ratios (Kp,liver) of Oatp1a4 substrates, including ouabain, digoxin, BQ-123, fexofenadine, rosuvastatin, pravastatin, nafcillin, and telmisartan, after continuous intravenous infusion. The plasma concentrations of ouabain and rosuvastatin were 2.1-fold and 1.7-fold higher in mice, and Kp,liver of ouabain and digoxin were 13.4-fold and 4.3-fold lower in mice, respectively. Furthermore, the biliary clearance of ouabain and digoxin with regard to plasma concentration were 21.9-fold and 4.1-fold lower in mice, respectively, accompanied with a marked reduction in their Kp,liver, whereas the systemic clearance of ouabain, but not digoxin, was reduced significantly in mice. These results suggest that Oatp1a4 plays a major role in the hepatic accumulation of cardiac glycosides in mice.

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