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This Article Full Text Full Text (PDF) All Versions of this Article: jpet.104.081109v1 313/3/1172    most recent Submit a response Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Sharma, A. Articles by Hamelin, B. A. Search for Related Content PubMed PubMed Citation Articles by Sharma, A. Articles by Hamelin, B. A. Pubmed/NCBI databases Compound via MeSH Substance via MeSH Hazardous Substances DB DIPHENHYDRAMINE METOPROLOL

ABSORPTION, DISTRIBUTION, METABOLISM, AND EXCRETION

Modulation of Metoprolol Pharmacokinetics and Hemodynamics by Diphenhydramine Coadministration during Exercise Testing in Healthy Premenopausal Women

Quebec Heart and Lung Institute, Laval Hospital, Laval, Quebec, Canada (A.S., P.P., S.P., J.G.D., M.A., B.A.H.); Faculty of Pharmacy, Laval University, Laval, Quebec, Canada (A.S., P.M.B., B.A.H.); and College of Pharmacy, University of Tennessee, Knoxville, Tennessee (B.M.)

Premenopausal women may be most vulnerable to acute coronary syndromes at a point in their menstrual cycle when their plasma estrogen levels are the lowest during and immediately after menstruation. Metoprolol is a first-line drug in the management of patients with acute coronary syndrome; however, when metoprolol was marketed in 1982, women were largely excluded from clinical trials. Furthermore, the over-the-counter antihistamine diphenhydramine inhibited the metabolism of the CYP2D6 substrate metoprolol in healthy, young men with pharmacokinetic and pharmacodynamic consequences. The pharmacokinetics and pharmacodynamics of metoprolol and its interaction with diphenhydramine were investigated in a randomized, double-blind, crossover, placebo-controlled manner in healthy, premenopausal extensive (EM; n = 16) and poor metabolizer (PM; n = 4) women immediately after menstruation. During the placebo phase, EMs had between 5.2- and 8.4-fold higher total clearance (CL/F) of R- and S-metoprolol compared with PMs, whereas the latter had a 35% greater area under the effect curve (AUEC) and 60% greater EC₅₀ value for heart rate reduction than EMs (all P < 0.05). Diphenhydramine coadmininstration caused a 2.2- to 3.2-fold decrease in CL/F of metoprolol enantiomers with a resulting 21% increase in AUEC and 29% increase in EC₅₀ value for heart rate reduction in EMs (all P < 0.05). This is the first study to report an in-depth elucidation of metoprolol's pharmacokinetics and hemodynamics in premenopausal EM and PM women at a point in their menstrual cycle when vulnerability for acute coronary events may be greatest. Caution is warranted when the over-the-counter antihistamine diphenhydramine is part of a chronic therapeutic regimen.

Address correspondence to: Dr. Bettina A. Hamelin, Pfizer Canada Inc., 2408 rue Maritain, Sillery, Quebec G1T 1N7, Canada. E-mail: bettina.hamelin{at}pfizer.com