Evaluation of the Endothelin Receptor Antagonists Ambrisentan, Bosentan, Macitentan, and Sitaxsentan as Hepatobiliary Transporter Inhibitors and Substrates in Sandwich-Cultured Human HepatocytesReportar como inadecuado




Evaluation of the Endothelin Receptor Antagonists Ambrisentan, Bosentan, Macitentan, and Sitaxsentan as Hepatobiliary Transporter Inhibitors and Substrates in Sandwich-Cultured Human Hepatocytes - Descarga este documento en PDF. Documentación en PDF para descargar gratis. Disponible también para leer online.

Background

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 µM for macitentan to 47 µM for ambrisentan. Macitentan and bosentan also inhibited NTCP with IC50 values of 10 and 36 µM, respectively. Similar to previously reported findings with sitaxsentan, BSEP inhibition was observed for bosentan and macitentan with IC50 values of 42 and 12 µM, 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 ∼100x followed by sitaxsentan ∼40x, bosentan ∼20x and ambrisentan ∼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.



Autor: Eve-Irene Lepist, Hunter Gillies, William Smith, Jia Hao, Cassandra Hubert, Robert L. St. Claire III, Kenneth R. Brouwer, Adrian

Fuente: http://plos.srce.hr/



DESCARGAR PDF




Documentos relacionados