Abstract
Abstract
Models for producing toxic liver injury and cirrhosis have been developed in rats and applied to the study of drug pharmacokinetics, but lack of a well-characterized model of hepatic congestion has prevented previous investigation of the effects of elevated hepatic venous pressure on drug metabolism in the rat. Chronic hepatic congestion was produced in rats by partial ligation of the inferior vena cava immediately below the diaphragm and above the entrance of the hepatic veins. Significant elevation of hepatic venous pressure, prolongation of prothrombin time, and pericentral fibrosis, and sinusoidal dilitation on histological examination were seen 6 weeks after initial surgery. Liver weight in the hepatic congestion group was significantly increased when compared to sham-operated controls, while no significant difference was seen between the two groups with regard to body weight gain, bile flow, bile acid output, serum bilirubin, and alanine aminotransferase. Pentobarbital pharmacokinetic parameters were determined after intravenous administration of [14C]pentobarbital to animals with hepatic congestion and sham-operated control animals. Plasma disappearance of pentobarbital was prolonged in rats with hepatic congestion and systemic plasma clearance was reduced. Additional studies of drug metabolism in this rat model of hepatic congestion may suggest important questions for future clinical investigation in man.
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