Involvement of transporters in the hepatic uptake and biliary excretion of valsartan, a selective antagonist of the angiotensin II AT1-receptor, in humans
Involvement of transporters in the hepatic uptake and biliary excretion of valsartan, a selective antagonist of the angiotensin II AT1-receptor, in humans
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DOI：
10.1124/dmd.105.008938
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发表时间：
2006-07-01
影响因子：
3.9
通讯作者：
Sugiyama, Yuichi
中科院分区：
文献类型：
--
作者：
Yamashiro, Wakaba;Maeda, Kazuya;Sugiyama, Yuichi
缬沙坦是一种高选择性血管紧张素II at1受体拮抗剂，用于治疗高血压。缬沙坦主要以不变的形式排泄到胆汁中。由于缬沙坦具有阴离子羧基，我们假设一系列有机阴离子转运蛋白可能参与其肝脏清除。在本研究中，为了确定介导缬沙坦肝脏摄取和胆汁排泄的转运体，并估计每种转运体对肝脏摄取和排出的贡献，我们使用转运体表达系统、人类冷冻保存的肝细胞和mrp2缺陷的卫材高胆红素血症大鼠（EHBRs）来表征其转运。缬沙坦在有机阴离子转运多肽（OATP） 1B1 （OATP2/OATPC）和OATP1B3 （OATP8）表达的HEK293细胞中被显著摄取。我们还观察到人肝细胞的饱和摄取。根据我们的估计，OATP1B1对缬沙坦在人肝细胞吸收的相对贡献取决于批次，范围从20%到70%。在外排转运体方面，在OATP1B1/MRP2、OATP1B1/多药耐药1和OATP1B1/乳腺癌耐药蛋白表达MDCKII三种双转染细胞中，缬沙坦基底-根尖跨细胞转运与反方向转运的比例最高。我们观察到饱和atp依赖转运到表达人MRP2的膜囊中。我们还发现，与正常的Sprague-Dawley大鼠相比，EHBR从血浆中静脉给药缬沙坦的消除明显延迟，胆道排泄严重受损。这些结果表明，OATP1B1和OATP1B3作为摄取转运体和MRP2作为外排转运体参与缬沙坦的有效肝胆转运。
Valsartan is a highly selective angiotensin II AT1-receptor antagonist for the treatment of hypertension. Valsartan is mainly excreted into the bile in unchanged form. Because valsartan has an anionic carboxyl group, we hypothesized that a series of organic anion transporters could be involved in its hepatic clearance. In this study, to identify transporters that mediate the hepatic uptake and biliary excretion of valsartan and estimate the contribution of each transporter to the overall hepatic uptake and efflux, we characterized its transport using transporter-expressing systems, human cryopreserved hepatocytes, and Mrp2-deficient Eisai hyperbilirubinemic rats (EHBRs). Valsartan was significantly taken up into organic anion-transporting polypeptide (OATP) 1B1 (OATP2/OATPC)and OATP1B3 (OATP8)-expressing HEK293 cells. We also observed saturable uptake into human hepatocytes. Based on our estimation, the relative contribution of OATP1B1 to the uptake of valsartan in human hepatocytes depends on the batch, ranging from 20 to 70%. Regarding efflux transporters, the ratio of basal-to-apical transcellular transport of valsartan to that in the opposite direction in OATP1B1/MRP2 ( multidrug resistance-associated protein 2) double transfected cells was the highest among the three kinds of double transfectants, OATP1B1/MRP2, OATP1B1/multidrug resistance 1, and OATP1B1/breast cancer resistance protein-expressing MDCKII cells. We observed saturable ATP-dependent transport into membrane vesicles expressing human MRP2. We also found that the elimination of intravenously administered valsartan from plasma was markedly delayed, and the biliary excretion was severely impaired in EHBR compared with normal Sprague-Dawley rats. These results suggest that OATP1B1 and OATP1B3 as the uptake transporters and MRP2 as the efflux transporter are responsible for the efficient hepatobiliary transport of valsartan.