Prevention of Acetaminophen and Cocaine Hepatotoxicity in Mice by Cimetidine Treatment

Abstract

Hepatotoxicity occurs in animals after administration of large doses of acetaminophen and cocaine and is thought to result from production of reactive metabolites of these parent drugs by cytochrome P450. Because cimetidine binds to cytochrome P450 and inhibits hepatic drug metabolism in both humans and animals, we determined the effects of cimetidine coadministration on acetaminophen and cocaine hepatotoxicity in mice. Marked elevations of serum glutamic pyruvic transaminase and severe pericentral hepatocellular necrosis occurred in animals receiving intraperitoneal doses of 350 mg/kg acetaminophen or 35 mg/kg cocaine, while minimal serum glutamic pyruvic transaminase elevations and liver necrosis were seen in animals who also received 100 mg/kg cimetidine 1 h before and 1 h after administration of either acetaminophen or cocaine. Consistent with the hypothesis that these in vivo protective effects resulted from interaction with cytochrome P450, cimetidine inhibited in vitro hepatic microsomal metabolism of cocaine. However, despite its protective effect against acetaminophen-induced hepatic injury, concomitant administration of cimetidine did not significantly affect plasma pharmacokinetics of acetaminophen, prevent depletion of hepatic glutathione after acetaminophen administration, or alter in vivo covalent binding of [3H]acetaminophen to hepatic proteins. These studies suggest that current theories regarding production of acetaminophen-induced liver damage require reexamination. The possibility that cimetidine treatment might be useful in preventing hepatic damage due to acetaminophen and other hepatotoxins in humans is intriguing and also warrants consideration.