Pharmacologic Toxicity of Cimetidine on Hepatic and Renal Drug Metabolism

Abstract

We studied the effect of cimetidine on liver and kidney heme metabolism and on the activity of the cytochrome P-450 drug metabolizing enzyme system. Results show that the induction of a heme biosynthetic enzyme and the activities of two drug metabolizing enzymes are impaired when cimetidine is given in combination with phenobarbital (PB). When rats were given four 33 mg doses of cimetidine IP per day for 2 days and sacrificed, we found no significant effect on kidney or liver delta-aminolevulinic acid (ALA) synthase activity. Heme oxygenase and cytochrome P-450 levels were also unchanged in these tissues. In contrast, when we measured activities of certain liver drug metabolizing enzymes, it was found that cimetidine significantly inhibited aniline hydroxylase and aminopyrine-N-demethylase by 43% and 65%, respectively. The observed changes in the activities of these drug metabolizing enzymes led us to study cimetidine in combination with other drugs. When the porphyric inducing agent allylisoprophyacetamide (AIA) was administered alone, we found a 326% increase in hepatic ALA synthase activity at 16 hours. Cimetidine given together with AIA increases hepatic ALA synthase 291 and 300% at 16 and 20 hour intervals respectively. Cytochrome P-450 levels in AIA treated rats with or without cimetidine were decreased to 52-65% of control values without a significant change in heme oxygenase levels. When PB was given alone, we found an increase in hepatic ALA synthase activity by 223 and 400% at 16 and 20 hour intervals, respectively. Cimetidine in combination with PB at the same time intervals showed a slightly diminished increase of hepatic ALA synthase activity by 146 and 238%, respectively. When PB was given alone, hepatic cytochrome P-450 was increased 96% at 16 hours, whereas when combined with cimetidine a similar increase of hepatic cytochrome P-450 was observed. In conclusion cimetidine does not significantly alter the action of the porphyric agents PB and ALA on cytochrome P-450; however, combined administration of PB plus cimetidine does impair the induction of ALA synthase. Additionally, cimetidine markedly decreased the drug metabolizing enzymes aniline hydroxylase and aminopyrine-N-demethylase in vivo, and subsequently may interfere with the endogenous metabolism of other drugs.