Department of Clinical Pharmacology and Therapeutics, Clinical Trials Center, Seoul National University Bundang Hospital, 82, Gumi-ro 173beon-gil, Bundang-gu, Seongnam, 13620, Republic of Korea.
Department of Clinical Pharmacology and Therapeutics, Seoul National University College of Medicine and Hospital, Seoul, Republic of Korea.
Sci Rep. 2021 Sep 27;11(1):19150. doi: 10.1038/s41598-021-98689-z.
To investigate pharmacokinetic and pharmacodynamic differences of zolpidem between males and females and their causes, including CYP3A4 activity. A single oral dose of zolpidem (10 mg) was administered to 15 male and 15 female healthy subjects. Blood samples were collected up to 12 h post-dose to determine plasma zolpidem concentrations. Pharmacokinetic parameters were obtained using non-compartmental analysis. Digit symbol substitution test, choice reaction time, and visual analog scale of sleepiness were used to evaluate pharmacodynamics. We measured CYP3A4 activity using 4β-hydroxycholesterol, an endogenous metabolite. Mean maximum plasma concentration and area under the plasma concentration-time curve were higher for females than for males (9.9% and 32.5%, respectively); other pharmacokinetic parameters showed no significant differences. Pharmacodynamic scores for females showed delayed recovery compared with that for males. CYP3A4 activity was higher in females than in males (p = 0.030). There was no serious adverse event, and adverse event incidence was not different between the sexes. Zolpidem exposure was about 30% higher in females than in males. Delayed pharmacodynamic score recovery in females could be related to higher zolpidem concentrations. Although apparent clearance was lower in females, systemic clearance might not be the cause of the different exposures to zolpidem.
为了研究男性和女性之间唑吡坦的药代动力学和药效学差异及其原因，包括 CYP3A4 活性。给 15 名男性和 15 名女性健康受试者单次口服唑吡坦（10 毫克）。在给药后 12 小时内采集血样，以确定血浆唑吡坦浓度。使用非房室分析获得药代动力学参数。数字符号替换测试、选择反应时间和睡眠困倦的视觉模拟量表用于评估药效学。我们使用内源性代谢产物 4β-羟基胆固醇来测量 CYP3A4 活性。女性的最大血浆浓度和血浆浓度-时间曲线下面积均高于男性（分别为 9.9%和 32.5%）；其他药代动力学参数无显著差异。女性的药效学评分显示恢复延迟，而男性则没有。女性的 CYP3A4 活性高于男性（p=0.030）。无严重不良事件，且两性不良反应发生率无差异。女性唑吡坦暴露量比男性高约 30%。女性药效学评分恢复延迟可能与唑吡坦浓度较高有关。尽管女性的表观清除率较低，但全身清除率可能不是导致唑吡坦暴露差异的原因。
