Hexobarbital sleeping time and drug metabolism in rats with ligated bile ducts—A lack of correlation

Hexobarbital sleeping time is commonly used as an index of the activity of hepatic microsomal drug-metabolizing enzymes in animals. This report describes anomalies between hexobarbital sleeping time and the rate of metabolism in vitro by microsomal enzymes in rats after bile duct ligation (BDL). The duration of hexobarbital sleeping time, 2–24 hr after BDL, was approximately twice that of sham-operated controls. No significant decrease in the activity of microsomal aminopyrine demethylase, aniline hydroxylase, hexobarbital oxidase or the amount of cytochrome P-450 was detected during this period. A further prolongation of hexobarbital sleeping time was observed 48–72 hr after BDL, and this was accompanied by a significant impairment of drug metabolism in vitro. The effect of BDL on hexobarbital sleeping time was independent of the route of administration. Thiopental sleeping time was prolonged at 12 and 72 hr after BDL. Zoxazolamine paralysis time was prolonged at 72 hr after BDL, but not at 12 hr. Plasma protein binding of hexobarbital and thiopental was not altered by hyperbilirubinemia. These data suggest that changes in drug metabolism are not responsible for the prolongation of hexobarbital sleeping time during the early phase of cholestasis caused by BDL.