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 wer e studied in rabbits. Method. A single dose of chlorpheniramine 10 mg (Group A) or diphenhydramine 10 mg (Group B) was given intravenously o n three different study days as follows: 2 weeks before cimetidine adm inistration, 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 measure d by HPLC. Histamine H-1-blockade was assessed by measuring suppressio n of the histamine-induced wheals in the skin. Results. The chlorpheni ramine and diphenhydramine terminal elimination half-life values and a rea under the curve values were significantly increased, and the syste mic clearance rates were significantly decreased, during concomitant a dministration of cimetidine. For each H-1-receptor antagonist, pharmac okinetic parameters were similar before cimetidine was co-administered and two weeks after cimetidine was discontinued. Wheal suppression pr oduced by chlorpheniramine or diphenhydramine was increased and prolon ged when cimetidine was administered concomitantly. Conclusion. Any en hanced peripheral H-1-blockade observed could be attributed, at least in part, to a pharmacokinetic interaction.