Toward Optimal Treatment in Women: The Effect of Sex on Metoprolol-Diphenhydramine Interaction
Toward Optimal Treatment in Women: The Effect of Sex on Metoprolol-Diphenhydramine Interaction
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DOI：
10.1177/0091270009340417
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发表时间：
2010-02-01
影响因子：
2.9
通讯作者：
Hamelin, Bettina A.
中科院分区：
文献类型：
--
作者：
Sharma, Ashish;Pibarot, Philippe;Hamelin, Bettina A.
本研究的目的是确定性别是否影响CYP 2D 6底物美托洛尔的药代动力学和血流动力学及其与苯海拉明（CYP 2D 6抑制剂）在高（快代谢型[EM]）或低（慢代谢型[PM]）CYP 2D 6活性的健康年轻受试者中的相互作用。对来自2项连续临床试验的数据进行了预先规定的比较分析，其中包括16名EM和4名PM女性以及10名EM和6名PM男性。2项试验的受试者在苯海拉明或安慰剂处于稳态的情况下单次口服100 mg美托洛尔。在美托洛尔给药后48小时连续采集血浆和尿液样本，并在12小时内采集血液动力学数据。在安慰剂组中，EM和PM女性与具有相同表型的男性相比，S-美托洛尔AUC（0-无穷大）分别高62%和59%，CLIF分别低26%和71%（所有P <0.05女性与男性相比）。这些差异在体重（WT）校正后消失。女性（尤其是PM）比男性经历了更大的美托洛尔负性变时作用（P <0.0001女性与男性相比）。同时给予苯海拉明使EM女性患者的S-美托洛尔AUC增加84%，EM男性患者增加45%（女性与男性相比P <0.009）。在苯海拉明组中，即使在WT校正后，药代动力学的性别差异仍然存在，导致女性的负性变时作用更大（女性与男性相比，所有P <0.05）。美托洛尔剂量应根据体重调整，尤其是女性。两种性别患者以相似剂量同时给予CYP 2D 6抑制剂（如苯海拉明）可能导致对CYP 2D 6底物清除的抑制更大，导致女性患者发生明显药理学和不良反应的风险高于男性患者。
The objective of this study was to determine if sex influences the pharmacokinetics and hemodynamics of the CYP2D6 substrate metoprolol and its interaction with diphenhydramine (CYP2D6 inhibitor) in healthy young participants with high (extensive metabolizer [EM]) or low (poor metabolizer [PM]) CYP2D6 activities. A prespecified comparative analysis of data from 2 sequential clinical trials that included 16 EM and 4 PM women and 10 EM and 6 PM men was performed. The participants in the 2 trials were administered a single oral dose of 100 mg metoprolol in the presence of steady-state diphenhydramine or placebo. Serial plasma and urine samples were obtained for 48 hours, and hemodynamic data was obtained for 12 hours after metoprolol. In the placebo arm, EM and PM women hod 62% and 59% higher S-metoprolol AUC(0-infinity) and 26% and 71% lower CLIF respectively, compared to men with the same phenotype (all Ps < .05 women compared to men). These differences dissipated on body weight (WT) correction. Women (especially PMs) experienced greater negative chronotropic effects of metoprolol than men (P < .0001 women compared to men). Diphenhydramine coadministration increased S-metoprolol AUC by 84% in EM women and 45% in EM men (P < .009 women compared to men). In the diphenhydramine arm, sex differences in pharmacokinetics persisted even after WT correction, resulting in greater negative chronotropic effects in women (all Ps < .05 women compared to men). Metoprolol dose should be adjusted for body weight, particularly in women. Coadministration of a CYP2D6 inhibitor such as diphenhydramine, by a patient at similar doses in the 2 sexes, could result in a greater inhibition of clearance of CYP2D6 substrates with a resulting higher risk of pronounced pharmacological and adverse effects in women compared to men.