Kyorin Pharmaceutical Co., LTD, Tokyo, Japan (J.T.); Graduate School of Pharmaceutical Sciences, The University of Tokyo, Tokyo, Japan (K.M., H.K.); and Sugiyama Laboratory, RIKEN Innovation Center, RIKEN Cluster for Industry Partnerships, RIKEN, Yokohama, Japan (Y.S.)
Kyorin Pharmaceutical Co., LTD, Tokyo, Japan (J.T.); Graduate School of Pharmaceutical Sciences, The University of Tokyo, Tokyo, Japan (K.M., H.K.); and Sugiyama Laboratory, RIKEN Innovation Center, RIKEN Cluster for Industry Partnerships, RIKEN, Yokohama, Japan (Y.S.).
Drug Metab Dispos. 2018 May;46(5):652-657. doi: 10.1124/dmd.117.079483. Epub 2018 Jan 18.
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 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 (K) 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 K 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 K, 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.
在啮齿动物肝脏中表达的有机阴离子转运多肽 (Oatp) 家族转运体中，如 Oatp1a1、Oatp1a4、Oatp1b2 和 Oatp2b1，Oatp1a4 具有独特的特征，除了有机阴离子外，还可以识别中性强心苷作为底物。Oatp1a4 对肝细胞摄取底物的相对贡献尚未阐明。在这项研究中，我们使用 小鼠研究了 Oatp1a4 在肝脏摄取其底物药物中的重要性。 小鼠肝脏 的 mRNA 表达显著降低，而野生型和 小鼠之间其他肝脏转运体没有差异。我们确定了 Oatp1a4 底物包括哇巴因、地高辛、BQ-123、非索非那定、瑞舒伐他汀、普伐他汀、萘夫西林和替米沙坦的血浆浓度和肝-血浆浓度比 (K)，这些底物在连续静脉输注后进行测定。 小鼠的哇巴因和瑞舒伐他汀的血浆浓度分别高出 2.1 倍和 1.7 倍，哇巴因和地高辛的 K 分别低 13.4 倍和 4.3 倍。此外， 小鼠的哇巴因和地高辛的胆汁清除率相对于血浆浓度分别低 21.9 倍和 4.1 倍，伴有 K 的显著降低，而哇巴因的全身清除率，但不是地高辛，在 小鼠中显著降低。这些结果表明 Oatp1a4 在小鼠心脏糖苷的肝脏积累中起主要作用。
