Bertera Facundo, Di Verniero Carla Andrea, Mayer Marcos Alejandro, Chiappetta Diego, Buontempo Fabián, Polizio Ariel Héctor, Taira Carlos Alberto, Höcht Christian
Department of Pharmacology, School of Pharmacy and Biochemistry, University of Buenos Aires, Argentina.
Xenobiotica. 2012 Feb;42(2):206-19. doi: 10.3109/00498254.2011.604746. Epub 2011 Sep 5.
Cardiovascular effects and pharmacokinetics of carvedilol were assessed in fructose-fed rats using pharmacokinetic-pharmacodynamic (PK-PD) modeling. Male Sprague-Dowley rats were randomly assigned to receive tap water (C rats) or fructose solution (10% w/v) (F rats) during 6 weeks. Effects of carvedilol (1-3 mg/kg i.v.) on blood pressure, heart rate and blood pressure variability were recorded. Carvedilol plasma pharmacokinetics was studied by traditional blood sampling. Relationship between carvedilol concentrations and their hypotensive and bradycardic effects was established by PK-PD modeling. Vascular sympatholytic activity of carvedilol was assessed by estimation of drug effects on low frequency blood pressure variability using spectral analysis. A greater volume of distribution and clearance of S-carvedilol compared to R-enantiomer was found in both experimental groups. Although PK-PD properties of S-carvedilol chronotropic effect were not altered in F rats, hypertensive rats showed greater efficacy to the carvedilol hypotensive response after administration of the higher dose. A similar potency of carvedilol to inhibit sympathetic vascular activity was found in F rats. Carvedilol showed enantioselective pharmacokinetic properties with increased distribution in F rats compared with normotensive animals. An enhanced hypotensive activity of carvedilol was found in F rats compared with C rats, which is not related to enhance sympatholytic activity.
使用药代动力学 - 药效学（PK - PD）模型，在喂食果糖的大鼠中评估了卡维地洛的心血管效应和药代动力学。雄性Sprague - Dowley大鼠在6周内随机分为两组，分别饮用自来水（C组大鼠）或果糖溶液（10% w/v）（F组大鼠）。记录卡维地洛（1 - 3mg/kg静脉注射）对血压、心率和血压变异性的影响。通过传统的采血方法研究卡维地洛的血浆药代动力学。通过PK - PD模型建立卡维地洛浓度与其降压和减慢心率作用之间的关系。使用频谱分析估计药物对低频血压变异性的影响，评估卡维地洛的血管交感神经溶解活性。在两个实验组中，均发现S - 卡维地洛的分布容积和清除率比R - 对映体更大。虽然F组大鼠中S - 卡维地洛变时作用的PK - PD特性未改变，但高血压大鼠在给予较高剂量后对卡维地洛的降压反应显示出更大的疗效。在F组大鼠中发现卡维地洛抑制交感神经血管活性的效力相似。与正常血压动物相比，卡维地洛在F组大鼠中表现出对映选择性药代动力学特性，分布增加。与C组大鼠相比，F组大鼠中卡维地洛的降压活性增强，这与交感神经溶解活性增强无关。
