Modulation of metoprolol pharmacokinetics and hemodynamics by diphenhydramine coadministration during exercise testing in healthy premenopausal women
| Autor: | Marie Arsenault, Bernd Meibohm, Sylvie Pilote, Bettina A. Hamelin, Ashish Sharma, Pierre M. Bélanger, Philippe Pibarot, Jean G. Dumesnil |
|---|---|
| Rok vydání: | 2005 |
| Předmět: |
Adult
medicine.medical_specialty Adolescent medicine.medical_treatment media_common.quotation_subject Blood Pressure Placebo Pharmacokinetics Double-Blind Method Heart Rate Internal medicine Heart rate medicine Humans Drug Interactions Menstrual cycle Metoprolol media_common Pharmacology Cross-Over Studies business.industry Diphenhydramine Stereoisomerism Stroke Volume Phenotype Cytochrome P-450 CYP2D6 Premenopause Anesthesia Pharmacodynamics Area Under Curve Cardiology Exercise Test Molecular Medicine Antihistamine Female business medicine.drug |
| Zdroj: | The Journal of pharmacology and experimental therapeutics. 313(3) |
| ISSN: | 0022-3565 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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