Figure 1.
Depiction of hepatocyte basolateral and canalicular transport proteins.
Figure 2.
d8-Taurocholate (d8-TCA) total (A) and cellular (B) accumulation in sandwich-cultured human hepatocytes exposed to ambrisentan, bosentan and macitentan.
Bosentan and macitentan treatment resulted in a dose-dependent reduction in total accumulation of d8-TCA. Ambrisentan, bosentan and macitentan treatment each resulted in a dose-dependent reduction in cellular accumulation of d8-TCA. Data presented as mean (±SD) expressed as percent of control treated; n = 3 donors; *P<0.05 bosentan vs. control; # P<0.05 macitentan vs. control.
Figure 3.
d8-Taurocholate (d8-TCA) biliary efflux (A) and clearance (B) in sandwich-cultured human hepatocytes exposed to ambrisentan, bosentan, and macitentan.
The biliary excretion index (BEI) of d8-TCA was largely unaffected by the test ERAs. Bosentan and macitentan treatment resulted in dose-dependent reductions in biliary clearance (Clb) of d8-TCA. Data presented as mean (±SD) expressed as percent of control treated; n = 3 donors; *P<0.05 bosentan vs. control; #P<0.05 macitentan vs. control.
Table 1.
Effect of Ambrisentan, Bosentan, Sitaxsentan, and Macitentan on Hepatic Uptake and Efflux Transporters.
Figure 4.
Dose-dependent intracellular accumulation of test ERAs in sandwich-cultured human hepatocytes.
Ambrisentan displayed the lowest intracellular accumulation followed by bosentan, sitaxsentan, and macitentan. Data are presented as mean (±SD) micromolar (µM) concentration; n = 3 donors; *P<0.05 vs. corresponding intracellular accumulation value for ambrisentan at the same test concentration.
Figure 5.
Uptake of bosentan and macitentan into human hepatocytes.
ERAs were evaluated either in the absence or presence of the transporter inhibitors rifampicin (40 µM) and cyclosporin A (5 µM). Data presented as mean (±SD) pmol/million cells; n = 4 donors; *P<0.05 for comparisons indicated.