Maeda Kazuya, Kambara Miyuki, Tian Ying, Hofmann Alan F, Sugiyama Yuichi
Graduate School of Pharmaceutical Sciences, University of Tokyo, Tokyo, Japan.
Mol Pharm. 2006 Jan-Feb;3(1):70-7. doi: 10.1021/mp050063u.
Ursodeoxycholate (UDCA) is widely used for the treatment of cholestatic liver disease. After oral administration, UDCA is absorbed, taken up efficiently by hepatocytes, and conjugated mainly with glycine to form glycoursodeoxycholate (GUDC) or partly with taurine to form tauroursodeoxycholate (TUDC), which undergo enterohepatic circulation. In this study, to check whether three basolateral transporters--Na(+)-taurocholate cotransporting polypeptide (NTCP, SLC10A1), organic anion transporting polypeptide (OATP) 1B1 (OATP-C), and OATP1B3 (OATP8)-mediate uptake of UDCA, GUDC, and TUDC by human hepatocytes, we investigated their transport properties using transporter-expressing HEK293 cells and human cryopreserved hepatocytes. TUDC and GUDC could be taken up via human NTCP, OATP1B1, and OATP1B3, whereas UDCA could be transported significantly by NTCP, but not OATP1B1 and OATP1B3 in our expression systems. We observed a time-dependent and saturable uptake of UDCA and its conjugates by human cryopreserved hepatocytes, and more than half of the overall uptake involved a saturable component. Kinetic analyses revealed that the contribution of Na(+)-dependent and -independent pathways to the uptake of UDCA or TUDC was very similar, while the Na(+)-independent uptake of GUDC was predominant. These results suggest that UDCA and its conjugates are taken up by both multiple saturable transport systems and nonsaturable transport in human liver with different contributions. These results provide an explanation for the efficient hepatic clearance of UDCA and its conjugates in patients receiving UDCA therapy.
熊去氧胆酸（UDCA）被广泛用于治疗胆汁淤积性肝病。口服后，UDCA被吸收，被肝细胞有效摄取，并主要与甘氨酸结合形成甘氨熊去氧胆酸（GUDC），或部分与牛磺酸结合形成牛磺熊去氧胆酸（TUDC），它们进行肠肝循环。在本研究中，为了检测三种基底外侧转运体——钠离子-牛磺胆酸盐共转运多肽（NTCP，SLC10A1）、有机阴离子转运多肽（OATP）1B1（OATP-C）和OATP1B3（OATP8）——是否介导人肝细胞对UDCA、GUDC和TUDC的摄取，我们使用表达转运体的HEK293细胞和人冷冻保存的肝细胞研究了它们的转运特性。在我们的表达系统中，TUDC和GUDC可通过人NTCP、OATP1B1和OATP1B3摄取，而UDCA可被NTCP显著转运，但不能被OATP1B1和OATP1B3转运。我们观察到人冷冻保存的肝细胞对UDCA及其结合物的摄取具有时间依赖性和饱和性，并且总摄取量的一半以上涉及一个饱和成分。动力学分析表明，钠离子依赖性和非依赖性途径对UDCA或TUDC摄取的贡献非常相似，而GUDC的非钠离子依赖性摄取占主导。这些结果表明，UDCA及其结合物在人肝脏中通过多种饱和转运系统和非饱和转运被摄取，且贡献不同。这些结果为接受UDCA治疗的患者中UDCA及其结合物的有效肝脏清除提供了解释。
