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lüll Evaluation of the endothelin receptor antagonists ambrisentan, bosentan, macitentan, and sitaxsentan as hepatobiliary transporter inhibitors and substrates in sandwich-cultured human hepatocytes Lepist EI; Gillies H; Smith W; Hao J; Hubert C; St Claire RL 3rd; Brouwer KR; Ray ASPLoS One 2014[]; 9 (1): e87548BACKGROUND: Inhibition of the transporter-mediated hepatobiliary elimination of bile salts is a putative mechanism for liver toxicity observed with some endothelin receptor antagonists (ERAs). METHODS: Sandwich-cultured human hepatocytes were used to study the hepatobiliary distribution and accumulation of exogenous taurocholate, ERAs and endogenous bile acids. The molecular mechanisms for findings in hepatocytes or clinical observations were further explored using either vesicular assays (efflux transporters) or transfected cell-lines (uptake transporters). Inhibition constants (IC50) were measured for the human hepatobiliary transporters bile salt export pump (BSEP), sodium taurocholate cotransporting polypeptide (NTCP), multidrug resistance protein 2 (MRP2), P-glycoprotein (Pgp), breast cancer resistance protein (BCRP), organic anion-transporting polypeptide 1B1 (OATP1B1) and OATP1B3. RESULTS: The ERAs showed dose-dependent reductions in exogenous taurocholate cellular accumulation in human hepatocytes, with macitentan having the greatest effect. Consistent with their effects on bile acids, the ERAs inhibited bile transporters. IC50 values for OATP1B1 and OATP1B3 ranged from 2 microM for macitentan to 47 microM for ambrisentan. Macitentan and bosentan also inhibited NTCP with IC50 values of 10 and 36 microM, respectively. Similar to previously reported findings with sitaxsentan, BSEP inhibition was observed for bosentan and macitentan with IC50 values of 42 and 12 microM, respectively. In contrast, ambrisentan showed little or no inhibition of these transporters. Other transporters tested were weakly inhibited by the ERAs. Accumulation in hepatocytes was also a factor in the effects on bile transport. Macitentan demonstrated the greatest accumulation in human hepatocytes ( approximately 100x) followed by sitaxsentan ( approximately 40x), bosentan ( approximately 20x) and ambrisentan ( approximately 2x). CONCLUSIONS: Significant differences in the inhibition of hepatic transporters were observed between the evaluated ERAs in vitro. Macitentan had the highest level of cellular accumulation and caused the greatest effects on bile acid distribution in human hepatocytes followed by sitaxsentan and bosentan. Ambrisentan showed a low potential to affect bile acids.|*Endothelin Receptor Antagonists[MESH]|ATP Binding Cassette Transporter, Subfamily B, Member 1/metabolism[MESH]|ATP Binding Cassette Transporter, Subfamily G, Member 2[MESH]|ATP-Binding Cassette Transporters/metabolism[MESH]|Adult[MESH]|Bile Acids and Salts/metabolism[MESH]|Bile/*drug effects/metabolism[MESH]|Bosentan[MESH]|Female[MESH]|Hepatocytes/*drug effects/metabolism[MESH]|Humans[MESH]|Isoxazoles/*pharmacology[MESH]|Liver-Specific Organic Anion Transporter 1[MESH]|Liver/drug effects/metabolism[MESH]|Male[MESH]|Membrane Transport Proteins/metabolism[MESH]|Middle Aged[MESH]|Multidrug Resistance-Associated Proteins/metabolism[MESH]|Neoplasm Proteins/metabolism[MESH]|Organic Anion Transporters, Sodium-Dependent/metabolism[MESH]|Organic Anion Transporters, Sodium-Independent/metabolism[MESH]|Organic Anion Transporters/metabolism[MESH]|Phenylpropionates/*pharmacology[MESH]|Pyridazines/*pharmacology[MESH]|Pyrimidines/*pharmacology[MESH]|Receptors, Endothelin/metabolism[MESH]|Solute Carrier Organic Anion Transporter Family Member 1B3[MESH]|Sulfonamides/*pharmacology[MESH]|Symporters/metabolism[MESH]|Taurocholic Acid/pharmacology[MESH]|Thiophenes/*pharmacology[MESH] |