Modulation of metoprolol pharmacokinetics and hemodynamics by diphenhydramine coadministration during exercise testing in healthy premenopausal women

Ashish Sharma, Philippe Pibarot, Sylvie Pilote, Jean G. Dumesnil, Marie Arsenault, Pierre Maxime Bélanger, Bernd Meibohm, Bettina A. Hamelin

Research output: Contribution to journalArticle

22 Citations (Scopus)

Abstract

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.

Original languageEnglish (US)
Pages (from-to)1172-1181
Number of pages10
JournalJournal of Pharmacology and Experimental Therapeutics
Volume313
Issue number3
DOIs
StatePublished - Jun 1 2005

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Diphenhydramine
Metoprolol
Pharmacokinetics
Hemodynamics
Exercise
Menstruation
Histamine Antagonists
Acute Coronary Syndrome
Menstrual Cycle
Area Under Curve
Heart Rate
Placebos
Cytochrome P-450 CYP2D6
Estrogens
Clinical Trials
Pharmaceutical Preparations

All Science Journal Classification (ASJC) codes

  • Molecular Medicine
  • Pharmacology

Cite this

Modulation of metoprolol pharmacokinetics and hemodynamics by diphenhydramine coadministration during exercise testing in healthy premenopausal women. / Sharma, Ashish; Pibarot, Philippe; Pilote, Sylvie; Dumesnil, Jean G.; Arsenault, Marie; Bélanger, Pierre Maxime; Meibohm, Bernd; Hamelin, Bettina A.

In: Journal of Pharmacology and Experimental Therapeutics, Vol. 313, No. 3, 01.06.2005, p. 1172-1181.

Research output: Contribution to journalArticle

Sharma, Ashish ; Pibarot, Philippe ; Pilote, Sylvie ; Dumesnil, Jean G. ; Arsenault, Marie ; Bélanger, Pierre Maxime ; Meibohm, Bernd ; Hamelin, Bettina A. / Modulation of metoprolol pharmacokinetics and hemodynamics by diphenhydramine coadministration during exercise testing in healthy premenopausal women. In: Journal of Pharmacology and Experimental Therapeutics. 2005 ; Vol. 313, No. 3. pp. 1172-1181.
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