【作者】 唐淑含；

【导师】 赵怀清；

【作者基本信息】 沈阳药科大学 ， 药物分析学， 2005， 硕士

【摘要】 泮托拉唑是一种选择性长效质子泵抑制剂，可治疗胃及十二指肠溃疡，中度及重度的反流性食管炎，也用于Zullinger-Ellison综合症等的治疗。其分子结构中含有一个手性硫原子，目前临床以外消旋体给药。本文研究了使用纤维素衍生物类手性固定相拆分泮托拉唑对映体的方法；并用CSP-HPLC紫外检测法对大鼠给药后，泮托拉唑对映体立体选择性药物动力学进行了研究，为进一步研究立体选择性产生的机理以及开发单一对映体提供依据。1．泮托拉唑的手性分离本文使用纤维素类手性固定相纤维素-三-（4-甲基苯甲酸酯）（Chiralcel OJ-RH）研究了泮托拉唑的对映异构体拆分。考察了不同因素对泮托拉哗对映体拆分的影响，优化了拆分条件，并初步探讨了对映体在纤维素手性固定相上的拆分机理。发现其保留行为及手性识别受流动相中有机改性剂比例、pH值的影响较大。最终确定对映体的最佳拆分条件是：50mmol·L^-1磷酸盐缓冲液（pH 5.5）-乙腈（76∶24），流速0.7mL·min^-1，柱温35℃。为进一步的立体选择性药物动力学研究奠定了良好的基础。2．泮托拉唑在大鼠体内的立体选择性药物动力学研究本文采用上述的CSP-HPLC法，对泮托拉唑对映体的立体选择性药物动力学进行了初步研究。静注给药后泮托拉唑对映体之间的构型转化研究大鼠经静注给予左旋或右旋泮托拉唑后，在大鼠体内不发生构型转化。泮托拉唑对映体的吸收动力学研究泮托拉唑对映体在大鼠体内的药物动力学具有立体选择性。分别以三个剂量对大鼠灌胃给予左旋泮托拉唑及外消旋体，用CSP-HPLC法测定不同时刻各对映体的血药浓度。用非室模型方法计算药物动力学参数，两对映体各自的C_max、AUC_0-t和AUC_0-∞与给药剂量均呈线性相关（r＞0.631，P＜0.05）。以一个剂量对大鼠静脉给药。血药浓度数据经3P87拟合，各对映体在大鼠体内的动力学过程均符合二室模型。比较灌胃和静脉给药后的AUC_0-t值，大鼠灌胃给予左旋泮托拉唑后的平均绝对生物利用度为25.9％；大鼠灌胃给予外消旋体后左旋体及右旋体的平均绝对生物利用度分别为39.2％和33.7％。泮托拉唑各对映体在大鼠体内的药物动力学性质，未表现出明显的性别差异。静注或灌胃给予泮托拉唑后，在雄性大鼠体内的消除较雌性大鼠慢，但不具有统计学意义（P＞0.05）。比较左旋泮托拉唑单独给药和作为消旋体组分在大鼠体内的药物动力学性质，在低、中剂量时，t_1／2、K_e和AUC_0-∞存在显著差异，但高剂量组未观察到明显差异。泮托拉唑对映体的组织分布研究大鼠灌胃给予外消旋泮托拉唑后，在各组织广泛分布，而且消除较快。受试化合物在脑中含量较低，说明该药不容易通过血脑屏障。试验中还发现，给药后受试化合物在大鼠各组织中的含量未表现出性别差异，表明泮托拉唑在大鼠体内的吸收和分布过程不存在性别差异。3个采样点的测定结果均表明，在靶向器官胃壁中左旋体的浓度始终高于右旋体，证明左旋体的靶点选择性较右旋体好，有利于其作为质子泵抑制剂的药理作用发挥。更多还原

【Abstract】 Pantoprazole, an asymmetrical substituted benzimidazole sulfoxide, is a selective and long-acting proton pump inhibitor which is used clinically as racemate mixture in the treatment for gastric and duodenal ulcer, reflux esophagitis, Zullinger-Ellison syndrome and other acid-related gastrointestinal disorders. In this study, a chiral separation method for pantoprazole enantiomers was developed using cellulose tris- （4-methylbenzoate） chiral stationary phase, which was successfully used to determine plasma concentration of pantoprazole enantiomers after administration to rats and to study of stereoselective pharmacokinetics of pantoprazole enantiomers. It would offer some references and inspirations for developing pantoprazole enantiomer and further studying on the mechanism of stereoselective pharmacokinetics of pantoprazole.1. Enantiomeric separation of pantoprazoleInfluences of different factors on the enantiomeric separation of pantoprazole using cellulose tris- （4-methylbenzoate） chiral stationary phase were investigated. The mechanism of enantiomeric separation on the chiral stationary phase was initially approached by optimizing separation condition. The results indicated that the pH value of the mobile phase and the organic modifer concentration were very important for retention behavior and chiral recogition. Pantoprazole enantiomers were well separated with a mobile phase consisted of 50 mmol·L^-1 sodium phosphate buffer （pH 5.5） - acetonitrile （76:24） at a flow rate of 0.7 mL·min^-1. The column temperature was 35℃. It would offer good basis for further studies of stereoselective pharmacokinetics of pantoprazole.2. Investigation of stereoselective pharmacokinetics of pantoprazole in ratsThe stereoselective pharmacokinetics of pantoprazole enantiomers were studied by the validated CSP-HPLC method. Investigation of the chiral inversion of pantoprazole enantiomers after single intravenous administration to rats The results indicated that the chiral inversion of pantoprazole enantiomers would not occur after single i.v. administration of each enantiomer to Wistar rats.Investigation of disorption of pantoprazole enantiomers The pharmacokinetics of pantoprazole has an stereoselective character in rats. Following an i.g. administration of l-pantoprazole and pantoprazole racemate to rats in three doses, respectively, the plasma concentrations of each enantiomer were determined by the validated CSP-HPLC method. The pharmacokinetic parameters were calculated by non-compartmental method. C_max, A UC_0-t and AUC_0-∞ were all dose proportional （r＞0.631, P＜0.05） in rats. The pharmacokinetic behaviors of each enantiomer in rats were all fitted to two-compartmental models by 3P87 software. Comparison between AUC_0-t after an i.g. administration and an i.v. administration of l-pantoprazole indicated that the average absolute bioavailability of l-pantoprazole in rats was 25.9%. Comparison between A UUC_0-t after an i.g. administration and an i.v. administration of pantoprazole racemate indicated that the average absolute bioavailabilities of l-pantoprazole and d-pantoprazole in rats were 39.2% and 33.7%, respectively.There were no gender differences in pharmacokinetics of pantoprazole enantiomers in rats. After an i.v. or an i.g. administration of pantoprazole, lower elimination rate in male rats than that in female ones was found, but the difference was of no statistical significance （P＞0.05）.By comparison of the pharmacokinetic charater of l-pantoprazole to that of l-pantoprazole as a component of pantoprazole racemate, t_1/2, K_e and AUC_0-∞ showed significant deviation at low and middle dose, but there was no difference at high dose.Investigation of the distribution of pantoprazole enantiomers After an i.g. administration of l-pantoprazole and pantoprazole racemate to rats, the distributions of each enantiomer in tissues were extensive and the elimination rates in all tissues were relatively fast. The lower concentration existed in brain showed a poor penetration into central nervous system. After i.g. administration, the concentrations in the tissues showed no gender difference, that is to say, the procedure of absorption and distribution in rats showed no evidence of gender difference. The enantiomeric concentrations in stomach wall——target organ at three times indicated that the concentration of l-pantoprazole was higher than that of d-pantoprazole and the selectivity of l-pantoprazole was better than that of d-pantoprazole. To sum up, l-pantoprazole is more advantageous of the pharmacodynamics as PPI.更多还原