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首页> 外文期刊>Fundamental & clinical pharmacology. >Pharmacokinetic and pharmacodynamic interactions between metoprolol and dronedarone in extensive and poor CYP2D6 metabolizers healthy subjects.
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Pharmacokinetic and pharmacodynamic interactions between metoprolol and dronedarone in extensive and poor CYP2D6 metabolizers healthy subjects.

机译：美托洛尔与决奈达隆之间在广泛和较弱的CYP2D6代谢者中的药代动力学和药效相互作用是健康受试者。

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摘要

As dronedarone a new noniodinated antiarrhythmic agent structurally related to amiodarone could inhibit CYP2D6 and is planned to be associated with beta-blockers, interactions with CYP2D6 metabolized beta-blockers such as metoprolol, have to be studied. Forty-nine healthy male subjects genotyped for CYP2D6 were included in a randomized, double-blind, placebo-controlled study. Metoprolol was administrated during 13 days (200 mg/day). After the initial 5 days, subjects received placebo (n = 12), 800 mg (n = 6), 1200 mg (n = 9), or 1600 mg (n = 17) of dronedarone daily during eight additional days. Pharmacokinetic parameters of metoprolol were investigated at day 5 and at day 13 in 44 subjects, 39 extensive metabolizers and five poor metabolizers for CYP2D6. Cardiac contractility function was evaluated by the rate-corrected electromechanical systole duration (QS2i) and the mean velocity of endocardial circumferential fiber shortening (Vcfmean). Cmax and AUC0--24 h of metoprolol increased from days 5 to 13in proportion to dronedarone dose only in CYP2D6 extensive metabolizers genotyped subjects (P < 0.001). In all subjects, from days 5 to 13, Vcfmean decreased and QS2i significantly increased in dronedarone groups. The Vcfmean changes were however significant only with the 1600 mg dronedarone dose compared with placebo while QS2i changes induced by addition of dronedarone were significant compared with placebo at all dose levels. Between days 5 and 13, QS2i and Vcfmean changes were significantly correlated with both dronedarone concentrations at day 13 and with metoprolol concentration changes between days 5 and 13. Plasma metoprolol concentrations were highest in poor metabolizer subjects and dronedarone did not further increase their level but increased QS2i in the two subjects receiving the 1600 mg dose. Addition of dronedarone (800-1600 mg daily) to metoprolol (200 mg daily) increases bioavailability of metoprolol in CYP2D6 extensive metabolizers and induces an additive dronedarone dose-dependent negative inotropic effect. Nevertheless at 800 mg daily (anticipated therapeutic dose) these effects were modest.
机译：由于决奈达隆是一种新的与胺碘酮结构相关的非碘化抗心律不齐药物，可以抑制CYP2D6，并计划与β-受体阻滞剂有关，因此必须研究与CYP2D6代谢的β-受体阻滞剂如美托洛尔的相互作用。基因型为CYP2D6的49位健康男性受试者包括在一项随机，双盲，安慰剂对照研究中。美托洛尔在13天内（200毫克/天）给药。在最初的5天后，受试者在另外八天中每天接受安慰剂（n = 12），800 mg（n = 6），1200 mg（n = 9）或1600 mg（n = 17）决奈达隆。在第5天和第13天对44名受试者的CYP2D6的39种广泛代谢者和5种不良代谢者研究了美托洛尔的药代动力学参数。通过心率收缩率的机电收缩持续时间（QS2i）和心内膜周围纤维缩短的平均速度（Vcfmean）评估心脏收缩功能。美托洛尔的Cmax和AUC0--24 h从第5天起与决奈达隆剂量成比例增加，仅在CYP2D6基因型广泛代谢者中（P <0.001）。在所有受试者中，从第5天到第13天，决奈达隆组中Vcfmean降低且QS2i显着升高。然而，在所有剂量水平下，仅在1600 mg决奈达隆剂量下Vcfmean变化才显着，而在安慰剂中，由于添加决奈达隆而引起的QS2i变化与安慰剂相比才显着。在第5天和第13天之间，QS2i和Vcfmean的变化与第13天的决奈达隆浓度以及第5天和第13天的美托洛尔浓度均显着相关。血浆美托洛尔的浓度在代谢不良的受试者中最高，而决奈达隆并没有进一步增加其水平，反而增加了接受1600 mg剂量的两个受试者中的QS2i。在美托洛尔（每天200 mg）中添加决奈达隆（每天800-1600 mg）会增加CYP2D6广泛代谢者中美托洛尔的生物利用度并诱导加成性决奈达隆剂量依赖性负性肌力作用。然而，在每天800 mg（预期的治疗剂量）下，这些作用是中等的。

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