期刊
TOXICOLOGICAL SCIENCES
卷 149, 期 1, 页码 237-250出版社
OXFORD UNIV PRESS
DOI: 10.1093/toxsci/kfv231
关键词
drug-induced liver injury; bile acids; hepatic transporters
类别
资金
- Otsuka Pharmaceutical Development and Commercialization, Inc.
- National Institute of General Medical Sciences of the National Institutes of Health (NIH) [R01GM041935]
Tolvaptan is a vasopressin V-2-receptor antagonist that has shown promise in treating Autosomal Dominant Polycystic Kidney Disease (ADPKD). Tolvaptan was, however, associated with liver injury in some ADPKD patients. Inhibition of bile acid transporters may be contributing factors to drug-induced liver injury. In this study, the ability of tolvaptan and two metabolites, DM-4103 and DM-4107, to inhibit human hepatic transporters (NTCP, BSEP, MRP2, MRP3, and MRP4) and bile acid transport in sandwich-cultured human hepatocytes (SCHH) was explored. IC50 values were determined for tolvaptan, DM-4103 and DM-4107 inhibition of NTCP (similar to 41.5, 16.3, and 95.6 mu M, respectively), BSEP (31.6, 4.15, and 119 mu M, respectively), MRP2 (> 50, similar to 51.0, and > 200 mu M, respectively), MRP3 (> 50, similar to 44.6, and 61.2 mu M, respectively), and MRP4 (> 50, 4.26, and 37.9 mu M, respectively). At the therapeutic dose of tolvaptan (90 mg), DM-4103 exhibited a C-max/IC50 value > 0.1 for NTCP, BSEP, MRP2, MRP3, and MRP4. Tolvaptan accumulation in SCHH was extensive and not sodium-dependent; intracellular concentrations were similar to 500 mu M after a 10-min incubation duration with tolvaptan (15 mu M). The biliary clearance of taurocholic acid (TCA) decreased by 43% when SCHH were co-incubated with tolvaptan (15 mu M) and TCA (2.5 mu M). When tolvaptan (15 mu M) was co-incubated with 2.5 mu M of chenodeoxycholic acid, taurochenodeoxycholic acid, or glycochenodeoxycholic acid in separate studies, the cellular accumulation of these bile acids increased by 1.30-, 1.68-, and 2.16-fold, respectively. Based on these data, inhibition of hepatic bile acid transport may be one of the biological mechanisms underlying tolvaptan-associated liver injury in patients with ADPKD.
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