Ranitidine–Acetaminophen Interaction: Effects on Acetaminophen–Induced Hepatotoxicity in Fischer 344 Rats

Abstract

Cimetidine has been shown to protect against acetaminophen–mediated hepatotoxicity in both rats and mice. In contrast to cimetidine, ranitidine recently has been determined to potentiate the hepatotoxic action of acetaminophen in Fischer 344 rats. The present studies were designed to characterize this ranitidine–acetaminophen interaction. Acetaminophen administration (750 mg per kg, p.o.) to F344 rats produced maximal hepatic necrosis, 24 hr after treatment, as assessed by SGPT activity and histopathology. Ranitidine pretreatment 30 min prior to acetaminophen treatment increased the toxicity but did not alter its course. Ranitidine administration (50 mg per kg) enhanced acetaminophen hepatotoxicity throughout the toxic dose range of acetaminophen (600 to 1,000 mg per kg) and potentiation of acetaminophen hepatotoxicity by ranitidine was dose–dependent. Maximal increases were observed at 50 mg per kg ranitidine whereas, doses of ranitidine greater than 100 mg per kg inhibited acetaminophen toxicity. SGPT data were corroborated by histopathologic evaluation. Ranitidine was not intrinsically hepatotoxic when administered alone (500 mg per kg), or following glutathione depletion, or after induction of hepatic mixed–function oxidase activity. The results obtained in these studies support the suggestion that, at high doses (>100 mg per kg), ranitidine reduces acetaminophen hepatotoxicity by reducing metabolic activation, while at lower doses ranitidine potentiates acetaminophen hepatotoxicity. Inhibition by ranitidine of acetaminophen conjugation is proposed as a possible mechanism of this potentiation.