Potential use of cimetidine for treatment of acetaminophen overdose.
Acetaminophen, a drug frequently taken in intentional and accidental overdose, causes liver toxicity when concentration of the cytochrome P-450-derived metabolite exceeds the metabolic capacity of available glutathione. Present treatment of acetaminophen overdose involves oral N-acetylcysteine (NAC), which enhances liver glutathione synthesis. An alternative or additive approach to therapy would be to inhibit the formation of the toxic metabolite by inhibiting the cytochrome P-450 system. The H2-receptor antagonist cimetidine inhibits the cytochrome P-450 system, does not interfere with the administration or function of NAC, and therefore affords additive protection. Also, it has little effect on the nontoxic routes of elimination of acetaminophen and is itself quite nontoxic. That cimetidine protects against acetaminophen toxicity in animal models has been demonstrated on the basis of improved survival, as well as decreases in several critical elements used to monitor acetaminophen toxicity: classic histologic changes, aminotransferase activity, metabolite covalent binding, and liver glutathione depletion. Administration of cimetidine well after the overdose is also protective. In contrast, animal models of acetaminophen toxicity demonstrate that ranitidine does not afford protection from acetaminophen hepatotoxicity. Clinical data in well-done trials in humans will be needed to support the experimental animal data.
Speeg
K V
KV
Department of Medicine, University of Texas Health Science Center, San Antonio 78284-7842.
D000082:Acetaminophen / Q000506:poisoning*; D000818:Animals; D002927:Cimetidine / Q000627:therapeutic use*; D006801:Humans
D000082:Acetaminophen; D002927:Cimetidine