Modulation of metoprolol pharmacokinetics and hemodynamics by diphenhydramine coadministration during exercise testing in healthy premenopausal women.
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 EC(50) 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 EC(50) 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.
Sharma
Ashish
A
Quebec Heart and Lung Institute Institute, Laval Hospital, Canada.
Pibarot
Philippe
P
Pilote
Sylvie
S
Dumesnil
Jean G
JG
Arsenault
Marie
M
Bélanger
Pierre Maxime
PM
Meibohm
Bernd
B
Hamelin
Bettina A
BA
D000293:Adolescent; D000328:Adult; D019540:Area Under Curve; D001794:Blood Pressure / Q000187:drug effects; D018592:Cross-Over Studies; D019389:Cytochrome P-450 CYP2D6 / Q000502:physiology; D004155:Diphenhydramine / Q000494:pharmacology*; D004311:Double-Blind Method; D004347:Drug Interactions; D005080:Exercise Test; D005260:Female; D006339:Heart Rate / Q000187:drug effects; D006801:Humans; D008790:Metoprolol / Q000493:pharmacokinetics* / Q000494:pharmacology; D010641:Phenotype; D017697:Premenopause / Q000502:physiology*; D013237:Stereoisomerism; D013318:Stroke Volume / Q000187:drug effects
D004155:Diphenhydramine; D019389:Cytochrome P-450 CYP2D6; D008790:Metoprolol