IMPAIRED DRUG-METABOLISM IN EXPERIMENTAL CIRRHOSIS IN RAT

Cirrhosis was produced in the rat by chronic administration of phenobarbital and carbon tetrachloride for 10 weeks. The metabolism of three substrates, aminopyrine. hexobarbital and propranolol, has been investigated in a 9000 g supernatant fraction of liver homogenate and in intact hepatocytes in cirrhotic livers and compared to appropriate phenobarbital-treated controls. In the 9000 g supernatant preparation, the maximal velocity of metabolism for each substrate and the cytochrome P450 concentration were reduced significantly in cirrhotic livers, while total protein and DNA concentration remained unchanged. In intact hepatocytes, the Vmaxfor each substrate was reduced, while the apparent Km remained unchanged. In both in vitro systems, the metabolism of propranolol and of hexobarbital was influenced by cirrhosis to a greater extent than that of aminopyrine. It is concluded that the carbon tetrachloride-phenobarbital model of cirrhosis in the rat is a suitable model in which to study the effects of chronic liver disease on drug disposition. © 1968.