Alterations in pentobarbital and meperidine pharmacokinetics induced by bile duct ligation in the rat

Although impaired microsomal drug metabolism has been demonstrated in response to bile duct ligation, there has been little previous assessment of the effects of extrahepatic biliary obstruction on drug pharmacokinetics in vivo. In this study, the effects of bile duct ligation on overall disposition on pentobarbital and meperidine in the rat have been assessed in vivo and in isolated perfused rat livers. A significant reduction in clearance of both compounds was seen in response to bile duct ligation. No change in protein binding of either drug was demonstrated, but alterations in initial volume of distribution of both drugs occurred in response to extrahepatic biliary tract obstruction. A significant reduction in the rate of perfusate flow was also seen in perfused liver experiments using livers from animals with previous bile duct ligation. Reduction in clearance of both a high extraction drug (meperidine) and a lower extraction drug (pentobrbital) in response to bile duct ligation suggests that both hepatic blood flow and drug metabolizing enzyme activity may be altered by extrahepatic biliary tract obstruction.