Mechanisms responsible for the altered pharmacokinetics of bosentan: Analysis utilizing rats with bile duct ligation-induced liver dysfunction

The purpose of this study was to evaluate the mechanisms responsible for the pharmacokinetic variability of bosentan utilizing rats with liver dysfunction induced by 7-day bile duct ligation (BDL). Bosentan was administered intravenously at a constant infusion rate (I) of 24, 40 or 60 μg/min/kg. The blood bosentan concentration (BBC) following infusion was measured by HPLC, and apparent clearance (CL) of the drug was estimated as I/BBC. The CL values in normal rats were 30.5 and 19.3 ml/min/kg at infusion rates of 24 and 60 μg/min/kg, respectively, suggesting non-linear pharmacokinetics of bosentan. The BBC in BDL rats was much higher than that in normal rats, and the CL values in BDL rats were 3.80 and 3.08 ml/min/kg at infusion rates of 24 and 60 μg/min/kg, respectively. The CL value of bosentan at an infusion rate of 40 μg/ min/kg in normal rats was decreased significantly by the coadministration of taurocholic acid or bilirubin. In addition, the hepatic mRNA expression of CYP2C6, CYP3A2, Oatp1a1, Oatp1a4 and Oatp1b2 in BDL rats decreased to 77.6%, 34.0%, 65.4%, 84.8% and 44.2% of that in normal rats, respectively. These results suggested that bile acids and/ or bilirubin accumulated in BDL rat plasma inhibited the hepatic uptake of bosentan, and that the decreased bosentan clearance in BDL rats was caused at least partly by the impaired expression of hepatic drug-metabolizing enzymes and uptake transporters. Moreover, because the pharmacokinetics of bosentan was non-linear at the tested doses, the increased BBC in BDL rats might further induce the saturation of hepatic uptake and/or metabolism of bosentan.