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 Be ´ langer, Bernd Meibohm, and Bettina A. Hamelin 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.) Received November 24, 2004; accepted February 7, 2005 ABSTRACT Premenopausal women may be most vulnerable to acute cor- onary 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 man- agement 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 phar- macokinetic and pharmacodynamic consequences. The phar- macokinetics and pharmacodynamics of metoprolol and its interaction with diphenhydramine were investigated in a ran- domized, double-blind, crossover, placebo-controlled manner in healthy, premenopausal extensive (EM; n = 16) and poor metabolizer (PM; n = 4) women immediately after menstrua- tion. 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 hemodynam- ics 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. Metoprolol is extensively metabolized in humans into three major metabolites: -hydroxymetoprolol (around 10% of the administered dose), O-desmethylmetoprolol, and deaminated metoprolol (Borg et al., 1975; Lennard, 1985). O-Desmethyl- metoprolol is further metabolized to form a carboxylic acid metabolite (metoprolol acid) with the latter accounting for approximately 65% of the administered dose. All these me- tabolites together account for around 85% of the adminis- tered dose (Godbillon and Duval, 1984). -Hydroxymeto- prolol and O-desmethylmetoprolol were found to have significant -blocking activity when tested in cats. However, their ED 50 values were around 9 to 10 times (heart rate), 5 to 8 times (contractile force), and 2 to 7 times (vasodilatation) higher than those of metoprolol (Borg et al., 1975). The -hy- droxylation pathway is controlled predominantly by the cy- tochrome P450 isoform CYP2D6. This cytochrome P450 iso- form is subject to a genetic polymorphism with around 6 to 10% of the white population, the so-called PMs, lacking this enzyme due to the inheritance of two mutant CYP2D6 null alleles. The other 90% of white persons have been classified as EMs, although more recently gene multiplications were This study was supported by grants from the Canadian Institutes of Health Research and the American College of Clinical Pharmacy (Wyeth-Ayerst Wom- en’s Health Care Research Award to B.A.H.). A.S. received a joint scholarship from the Canada’s Research Based Pharmaceutical Companies and Canadian Institutes of Health Research. P.P. is the recipient of the Canada Research Chair in Valvular Heart Diseases. The information contained in this article was part of the Ph.D. dissertation work of A.S. This work was presented in part at the American College of Clinical Pharmacy annual meeting in Los Angeles, CA, 5– 8 November 2000, and at the American Society of Clinical Pharmacol- ogy and Therapeutics annual meeting in Orlando, FL, 8 –10 March 2001. Article, publication date, and citation information can be found at http://jpet.aspetjournals.org. doi:10.1124/jpet.104.081109. ABBREVIATIONS: PM, poor metabolizer; EM, extensive metabolizer; LVOT, left ventricular outflow tract; HR, heart rate; BP, blood pressure; VTI, velocity time integral; SV, stroke volume; SVI, stroke volume index; CO, cardiac output; CI, cardiac index; RPP, rate-pressure product; BSA, body surface area; PK/PD, pharmacokinetics/pharmacodynamics; AUC 0– , area under the concentration-time curve; HPLC, high-performance liquid chromatography; AUEC, area under the effect curve. 0022-3565/05/3133-1172–1181$20.00 THE JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS Vol. 313, No. 3 Copyright © 2005 by The American Society for Pharmacology and Experimental Therapeutics 81109/1199542 JPET 313:1172–1181, 2005 Printed in U.S.A. 1172