Effect of cimetidine on the pharmacokinetics and pharmacodynamics of chlorpheniramine and diphenhydramine in rabbits.
OBJECTIVE
The effects of concomitant administration of the H2-receptor antagonist cimetidine on the pharmacokinetics and pharmacodynamics of the H1-receptor antagonists chlorpheniramine and diphenhydramine were studied in rabbits.


METHODS
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 H1-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 H1-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.


CONCLUSIONS
Any enhanced peripheral H1-blockade observed could be attributed, at least in part, to a pharmacokinetic interaction.
Simons
K J
KJ
Health Sciences Clinical Research Centre, Faculties of Pharmacy, Science, and Medicine, University of Manitoba, Winnipeg, Canada.
Chen
X
X
Fraser
T G
TG
Simons
F E
FE
D000410:Alanine Transaminase / Q000097:blood; D000469:Alkaline Phosphatase / Q000097:blood; D000818:Animals; D001219:Aspartate Aminotransferases / Q000097:blood; D002744:Chlorpheniramine / Q000493:pharmacokinetics* / Q000494:pharmacology*; D002927:Cimetidine / Q000494:pharmacology*; D004155:Diphenhydramine / Q000493:pharmacokinetics* / Q000494:pharmacology*; D004347:Drug Interactions; D006634:Histamine H1 Antagonists / Q000493:pharmacokinetics* / Q000494:pharmacology*; D006635:Histamine H2 Antagonists / Q000494:pharmacology*; D007770:L-Lactate Dehydrogenase / Q000097:blood; D008099:Liver / Q000187:drug effects / Q000502:physiology; D011817:Rabbits
D006634:Histamine H1 Antagonists; D006635:Histamine H2 Antagonists; D002744:Chlorpheniramine; D002927:Cimetidine; D004155:Diphenhydramine; D007770:L-Lactate Dehydrogenase; D001219:Aspartate Aminotransferases; D000410:Alanine Transaminase; D000469:Alkaline Phosphatase