Effect of cimetidine on the pharmacokinetics and pharmacodynamics of chlorpheniramine and diphenhydramine in rabbits

Purpose. The effects of concomitant administration of the H-2-receptor antagonist cimetidine on the pharmacokinetics and pharmacodynamics of the H-1-receptor antagonists chlorpheniramine and diphenhydramine were studied in rabbits. Method. A single dose of chlorpheniramine 10 mg (Group A) or diphenhydramine 10 mg (Group B) was given intravenously on three different study days as follows: 2 weeks before cimetidine administration, after giving cimetidine 100 mg/kg intravenously every 12 hours for one week, and two weeks after discontinuing the cimetidine. Serum chlorpheniramine and diphenhydramine concentrations were measured by HPLC. Histamine H-1-blockade was assessed by measuring suppression of the histamine-induced wheals in the skin. Results. The chlorpheniramine and diphenhydramine terminal elimination half-life values and area under the curve values were significantly increased, and the systemic clearance rates were significantly decreased, during concomitant administration of cimetidine. For each H-1-receptor antagonist, pharmacokinetic parameters were similar before cimetidine was co-administered and two weeks after cimetidine was discontinued. Wheal suppression produced by chlorpheniramine or diphenhydramine was increased and prolonged when cimetidine was administered concomitantly. Conclusion. Any enhanced peripheral H-1-blockade observed could be attributed, at least in part, to a pharmacokinetic interaction.