基于药物PK/PD关联探讨苯环壬酯对映体立体选择性作用机制

Phencynonate was the innovative drug for the treatment of motion sickness after the listing of the racemate with independent intellectual property rights of China. Phencynonate exhibited obvious anti-Parkinson effect in clinical application, its potency higher than that of commonly used drugs trihexyphenidyl. In an animal model of tremor, the R(-) configuration is more active than the S(+) configuration. In a mouse model of depression, the S(+) configuration showed obvious anti-depression effect, the R(-) configuration is invalid. In mice shock attack model of maximal electroshock, racemic was significantly better than the R(-) configuration and S(+) configuration, its potency higher than that of Phenytoin sodium and Phenobarbital. The above studies have shown that the phencynonate enantiomers exhibit different and even opposite pharmacodynamics, which may be related with the stereoselective metabolism and stereoselective distribution in brain nuclei of the enantiomers. To clarify the reason of phencynonate optical isomers produce different pharmacodynamics, this study intends to investigate the stereoselective metabolism and brain region distribution of optical isomers with chiral separation and stability isotope labeling technique. By using PK/PD link model association with targets and the Neurobiological Mechanisms of the optical isomer, this study was to clarify the molecular mechanism and pharmacodynamic material basis for phencynonate.

苯环壬酯为我国具有自主知识产权的一类创新药物，外消旋体上市后主要用于治疗晕动病。临床应用发现苯环壬酯具有明显的抗帕金森作用，效价高于常用药物苯海索，在震颤动物模型上，左旋体抗震颤效果明显优于右旋体；在小鼠抑郁模型上，右旋体抗抑郁效果明显，左旋体无效；在小鼠最大电休克发作模型上，消旋体抗癫痫作用明显优于左旋体和右旋体，效价高于苯妥英钠和苯巴比妥。以上研究表明苯环壬酯光学异构体具有不同甚至相反的药效作用，这可能与光学异构体的立体选择性代谢及在脑神经核团的立体选择性分布有关。为阐明苯环壬酯光学异构体产生不同药效作用的原因，本研究拟采用手性分离和稳定性同位素氚标记技术，探讨光学异构体立体选择性代谢及脑区分布，着重研究光学异构体作用靶标及神经生物学机制，通过药物动力学与药理学效应（PK/PD）关联研究，阐明苯环壬酯光学异构体不同药效作用的分子机制及药效学物质基础。

盐酸苯环壬酯左旋体为新型抗晕药物，本课题采用LC/MS/MS手性拆分方法揭示了该药在动物体内的动态变化规律，为临床用药提供了参考依据。主要结果如下： .大鼠单次口服不同剂量后Cmax分别为5.76±2.37、15.68±11.16和90.03±34.62 ng/ml；AUC0-t 分别为4.73±1.43、12.32±4.05 和44.73±3.35 ng/ml•h。Cmax和AUC分别与给药剂量呈良好的线性关系。. 比格犬口服苯环壬酯左旋体的绝对生物利用度为(17.82±2.13)％；单次口服不同剂量后Cmax分别为1.87±0.50、9.86±2.35和70.34±29.65 ng/ml；AUC0-12分别为9.80±0.98、42.73±8.73和250.12±94.55 ng/ml•h。Cmax和AUC分别与给药剂量呈良好的线性关系。. 左旋体和右旋体在比格犬体内不发生相互间转化，口服消旋体后右旋体的AUC(0-t)和Cmax明显高于左旋体。比格犬分别口服左旋体、右旋体和外消旋体后的Cmax分别为25.70±11.68、31.02 ±23.49和33.40 ±14.96 ng/ml；AUC0-24分别为64.17±15.52、52.57±32.11和67.17±23.62 ng/ml•h。主要动力学参数AUC(0-t)、AUC(0-∞)、MRT(0-t)、t1/2z、Tmax、Vz/F 、CLz/F和Cmax均无显著性差异，说明左旋体、右旋体和外消旋体三者在比格犬体内的动力学特性基本相同。. 小鼠口服苯环壬酯左旋体后，肝、脾、肺、心和血5min达到峰值，肝浓度最高，其它组织30min达峰，浓度从高至低为肌肉、睾丸、肾、脂肪和脑，给药后2h各组织中药物降至较低水平。. 苯环壬酯左旋体、右旋体和外消旋体与比格犬和人血浆蛋白的结合率均在85％以上。大鼠口服苯环壬酯左旋体后，经粪、尿、胆汁排泄分别为3.4‰、0.04‰、0.06‰。. 大鼠口服苯环壬酯左旋体后，尿中发现多种氧化型代谢产物，结构有待进一步确证。苯环壬酯左旋体在大鼠体内可能主要通过代谢转化途径消除；放射性同位素结果表明苯环壬酯外消旋体24小时排出88.61％，对映体在大鼠体内的代谢特性基本相同，可以认为苯环壬酯左旋体在大鼠体内无蓄积作用。