Sharma Ashish, Pibarot Philippe, Pilote Sylvie, Dumesnil Jean G, Arsenault Marie, Bélanger Pierre Maxime, Meibohm Bernd, Hamelin Bettina A
Quebec Heart and Lung Institute Institute, Laval Hospital, Canada.
J Pharmacol Exp Ther. 2005 Jun;313(3):1172-81. doi: 10.1124/jpet.104.081109. Epub 2005 Feb 17.
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.
绝经前女性在月经周期中血浆雌激素水平处于月经期间及刚结束后最低的阶段时，可能对急性冠脉综合征最为脆弱。美托洛尔是治疗急性冠脉综合征患者的一线药物；然而，1982年美托洛尔上市时，女性在很大程度上被排除在临床试验之外。此外，非处方抗组胺药苯海拉明在健康年轻男性中抑制了CYP2D6底物美托洛尔的代谢，产生了药代动力学和药效学后果。在月经刚结束后，以随机、双盲、交叉、安慰剂对照的方式，对健康的绝经前广泛代谢型（EM；n = 16）和慢代谢型（PM；n = 4）女性，研究了美托洛尔的药代动力学和药效学及其与苯海拉明的相互作用。在安慰剂阶段，与PM相比，EM的R-和S-美托洛尔的总清除率（CL/F）高5.2至8.4倍，而后者的效应曲线下面积（AUEC）比EM大35%，心率降低的EC(50)值比EM大60%（所有P < 0.05）。联合使用苯海拉明使美托洛尔对映体的CL/F降低了2.2至3.2倍，导致EM的AUEC增加21%，心率降低的EC(50)值增加29%（所有P < 0.05）。这是第一项深入阐明绝经前EM和PM女性在月经周期中急性冠脉事件易感性可能最大的阶段美托洛尔的药代动力学和血流动力学的研究。当非处方抗组胺药苯海拉明作为慢性治疗方案的一部分时，需谨慎使用。
