Quebec Heart and Lung Institute, Ste-Foy, Quebec, Canada.
J Clin Pharmacol. 2010 Feb;50(2):214-25. doi: 10.1177/0091270009340417. Epub 2009 Nov 30.
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 had 62% and 59% higher S-metoprolol AUC(0-infinity) and 26% and 71% lower CL/F, 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.
本研究旨在确定性别是否影响 CYP2D6 底物美托洛尔的药代动力学和血液动力学，以及其与 CYP2D6 抑制剂（苯海拉明）在具有高（广泛代谢者 [EM]）或低（弱代谢者 [PM]） CYP2D6 活性的健康年轻参与者中的相互作用。对 2 项临床试验数据进行了预设的比较分析，这 2 项临床试验共纳入 16 名 EM 女性和 4 名 PM 女性，以及 10 名 EM 男性和 6 名 PM 男性。这 2 项试验中的参与者均接受了单次口服 100mg 美托洛尔，同时给予稳态苯海拉明或安慰剂。在美托洛尔给药后 48 小时内采集连续的血浆和尿液样本，并在 12 小时内采集血液动力学数据。在安慰剂组中，EM 和 PM 女性的 S-美托洛尔 AUC（0-无穷大）分别比男性高 62%和 59%，CL/F 分别低 26%和 71%（所有 P 值<.05，女性与男性比较）。这些差异在体重（WT）校正后消失。与男性相比，女性（尤其是 PM 女性）经历了更大的美托洛尔负性变时作用（P <.0001，女性与男性比较）。苯海拉明合用使 EM 女性的 S-美托洛尔 AUC 增加了 84%，EM 男性的 AUC 增加了 45%（P <.009，女性与男性比较）。在苯海拉明组中，药代动力学的性别差异即使在 WT 校正后仍然存在，导致女性的负性变时作用更大（所有 P 值<.05，女性与男性比较）。美托洛尔剂量应根据体重进行调整，尤其是在女性中。对于两性患者，以相似剂量合用 CYP2D6 抑制剂（如苯海拉明），可能会导致 CYP2D6 底物清除的更大抑制，从而导致女性比男性发生明显的药物和不良作用的风险更高。
