泮托拉唑的分析方法及大鼠体内的药物动力学研究
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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。
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.
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。
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.
引文
[1] 袁伯俊 主编．新药评价基础与实践．北京：人民军医出版社．1998．
[2] 魏尔清 主编．药理学前沿-信号、蛋白因子、基因与现代药理．北京：科学出版社．1999．
[3] 曾苏主编．手性药物与手性药理学．浙江：浙江大学出版社．2002．
[4] Borman S. Chirality emerges as key issus in pharmaceutical research. Chem. & Eng. News. 1990, 68(28): 9～14.
[5] 傅崇东，徐惠南．手性药物的立体选择性药物动力学．中国临床药学杂志．1998．7(6)：309～313．
[6] 尤启冬，林国强 主编．手性药物——研究与应用．北京：化学工业出版社．2004．
[7] Jacques J, Collet A, Wilen SH. Enantiomers racemates and resolutions. New York: John Wiley & sons. 1981.
[8] Morrison JD. ed. Asymmetric synthesis, vol 1～5. New York: Academic Press. 1983～1985.
[9] Crosby J. Tetrahedron, 1991, 47: 4789.
[10] Ojima I. ed. Catalytic asymmetric synthesis. New York: VCH, 1993.
[11] Ahuja S. ed. Chiral separation by liquid chromatography. ACS Symposium Series 471, Washington: ACS, 1991.
[12] Francotte E. Review Contribution of preparative chromatographic resolution to the investigation of chiral phenomena. J Chromatogr A, 1994, 666: 565～601.
[13] 苑可，戴立信．关注“手性药物”．科学术语研究，2002，4(2)：46～48．
[14] Stoechitzky K, Klein W, Stark G, et al. Different steroselective effects of(R)-and (S)-propafenone: Clinical pharmacologic and radioligand binding studies. Clin Pharmacol Ther. 1990, 47: 740～746.
[15] Burnett DM, Zahniser NR, et al. Propafenone interacts stereoselectivity with β1-and β2-adrenergic receptors. J cardiovasc Pharmacol, 1988, 12: 615～619.
[16] Guznna A, Yuste F, Toscano RA, et al. Absolute configuration of(-)-5-benzoyl-1, 2-dihydro3H-pyrrolo[1, 2α]pyrrole-1-carboxylic acid, the active enantiomer of ketorolac. J Med Chem., 1986, 29: 589～591.
[17] Mitscher LA, Sharma PN, Chu-Dannel TW, et al. Chiral DNA gyase inhibitors 2. Asymmetric synthesis and biological activity of the enantiomers of 9-fluoro-3-methyl-10(4-methyl-1-piperacinyl)-7-oxo-2, 3-dihydro-7H-pyrido[1, 2, 3-de]-1, 4-benzoxazine-6-carboxylic acid (oflo-xacin). J Med Chem, 1987, 30(12): 2283～2286.
[18] 姚伟，吉宏，李靖．手性药物对映体选择性药效学与临床合理用药．临沂医专学报，1999，21(1)：63～65．
[19] 许关煜，刘玲玲．手性药物．上海医药，1999，20(10)：9～11．
[20] Janiczek N, Smith DE, Chang T, et al. Pharmacokinetics and pharmacodynamics of pirmenol enantiomers in coronary artery ligated dogs. J Pharm Sci, 1997, 86(4): 443.
[21] Takahashi H, Ogata M, Shimizu M, et al. Relative bioavailability of two disopyramide capsules in humans based on total, unbound, and unbound enantiomer concentrations. Biopharm Drug Dispos, 1993, 14(5): 409.
[22] Boulton DW, Fawcett JP. Pharmacokinetics and pharmacodynamics of single oral doses of albuterol and its enantiomers in humans. Clin Pharmacol Ther, 1997, 62(2): 138.
[23] Karim A. Enantioselective assays in comparative bioavailability atudies of racemic drug formulations: nice to know or need to know? J Clin Pharmacol, 1996, 36(6): 490.
[24] Nerurkar SG, Dighe SV, Williams RL. Bioquivalence of racemic drugs. J Clin Pharmacol, 1992, 32(10): 935.
[25] 刘会臣，于洋，王娜等．反式曲马多和反式氧去甲基曲马多在大鼠胆汁中排泄的立体选择性．药学学报，2003，38：412～415．
[26] Mehvar R, Jamali F. Bioequivalence of chiral drugs, stereospecific versus non-stereospecific methods. Clin Pharmacokinet, 1997, 33(2): 122.
[27] 蒋兆健，吴笑春．手性药物的对映体选择性与临床应用．中国药房，2001，12(3)：162～164．
[28] Stinson SC. Chiral drugs. C & EN. 2000, 78(43): 55～78.
[29] Rouhi AM. Chiral drugs. C & EN. 2001, 80(23): 43～50.
[30] 王炜，廖愚生．浅谈手性药物的研究与发展．淮南职业技术学院学报，2002．2(3)：122～124．
[31] Schmidt N, Brune K, Geisslinger G. Stereoselective determination of the enantiomers of methadone in plasma using high-performance liquid chromatography. J Chromatogr Biomed Appl, 1992, 583(2): 195～200.
[32] 曾苏，章立，刘志强．RP-HPLC手性流动相添加剂法分析尿中氧氟沙星对映体．药学学报．1994，29(3)：223～227．
[33] 李玉梅，邹晓平，李兆申．胃壁细胞及质子泵的细胞与分子生物学研究进展．国外医学．消化系疾病分册，2002，22(3)：140～141．
[34] 李阳．胃H~+／K~+-ATP酶与胃酸分泌及酶抑制剂．国外医药合成药、生化药、制剂分册，1992，13 (1)：15～20．
[35] Cass QB, Cegani ALG, Cassiano NM, et al. Enantiomeric determination of pantoprazole in human plasma by multidimensional high-performance liquid chromatography. J Chromatogr B, 2002, 766: 153～160.
[36] 许长青，卢爱君，杨东风等．泮托拉唑的药理作用于临床应用．武警医学，2002，13(05)：304～305．
[37] 李静．质子泵抑制剂——泮托拉唑．中国药学杂志，2001，36(10)：710～711．
[38] Pue MA, Latoche J, Meineke I, et al. Pharmacokinetics of pantoprazole following single intravenous and oral administration to healthy male subjects. Eur J Clin Pharmacol, 1993, 44: 575～578.
[39] 姚光．质子泵抑制剂潘他拉唑．中华消化杂志，1998，18(3)：164～165．
[40] Bliesath H, Huber R, Hartmann M, et al. Dose linearity of the pharmacokinetics of the new H~+/K~+-ATPase inhibitor pantoprazole after single intraveous administration. Int J Clin Pharmacol Ther, 1994, 32: 44.
[41] Eberle D, Hummel R, Kuhn R. Chiral resolution of pantoprazole sodium and related solfoxides by complex formation with bovine serum albumin in capillary electrophoresis. J Chromatogr A, 1997, 759: 185～192.
[42] Balmer K, Persson BA, Lagerstrom PO. Stereoselective effects in the separation of enantiomers of omeprazole and other substituted benzimidazoles on different chiral stationary phases. J Chromatogr A, 1994, 660: 269～273.
[43] Erlandsson P, lsaksson R, Lorentzon P, et al. Resolution of the enantiomers of omeprazole and some of its analogues by liquid chromatography on a trisphenylcarbamoylcellulose based stationary phases. J Chromatogr, 1990, 532: 305～309.
[44] Marle I, Erlandsson P, Hansson L, et al. Separation of enantiomers using cellulose(CBH I) silica as a chiral stationary phase. J Chromatogr, 1991, 586: 233～237.
[45] Tanaka M, Yamazaki H. Direct determination of pantoprazole enantiomers in human serum by reversed-phase high-performance liquid chromatography using a cellulose-based chiral stationary phase and column-switching system as a sample cleanup procedure. Anal Chem, 1996, 68: 1513～1516.
[46] 谢智勇，钟大放，杨炳华等．α1-酸糖蛋白手性住拆分泮托拉唑对映体．药物分析杂志，2004，24(1)：1～4．
[47] 杜丰．新型质子泵抑制剂——埃索美拉唑．首都医药，2004，6：34～35．
[48] Fitton A, Wiseman L. Pantoprazole: A review of its pharmacological properties and therapeutic in acid-related disorders. Drugs, 1996, 51: 460～482.
[49] HumpHries TJ, Mernitt GJ. Review article: drug interactions with agents used to treat acidrelated diseases. Aliment pharmacol Ther, 1999, 13(supple3): 18.
[50] 贾健辉，王敏伟，卢方正等．左旋泮托拉唑镁对动物实验性胃溃疡的影响．沈阳药科大学学报，2004，21(3)：218～221．
[51] 贾健辉，王敏伟，曹红等．左旋泮托拉唑镁对动物实验性十二指肠溃疡的影响．沈阳药科大学学报，2004，21(4)：294～296．
[52] 邹公伟，郑琦，胡冠九等．高效液相色谱中的纤维素衍生物手性同定相．分析化学，1995，23(4)：466～473．
[53] Jingli Liu, James T. Stewart. Quantitation of promethazine enantiomers in human serum using a chiralcel OJ-R column and mixed-mode disc solid-phase extraction. J Pharm Biomed Anal, 1997, 16: 303～309.
[54] Hassan Y. Aboul-Enein, Martin G. Schmid, Claudia Tuscher, et al. Chiral separation of several thiobarbiturates on a cellulose tris(4-methylbenzoate) phase under reversed-phase conditions. J Liq Chrom & Rel Technol, 2001, 24(1): 69～77.
[55] Kauffman R, Lieh-Lai M, Uy H, et al. Enantiomer-selective pharmacokinetics and metabolism of ketorolac in children. Clin Pharmacol Ther, 1998, 65: 382～388.
[56] 徐修容．高效液相色谱分离光学异构体．色谱，1991，9(6)：363～368．
[57] Okamoto Y, Aburatani R, Hatada K. Chromatographic chiral resolution ⅪⅤ cellulose tribenzoate derivatives as chiral stationary phases for high-performance liquid chromatography. J Chromatogr, 1987, 389: 95～102.
[58] Wainer IW, Alembik MC. Resolution of enantiomeric amides on a cellulose-based chiral stationary phase. J Chromatogr, 1986, 358: 85～93.
[59] Wainer IW, Alembik MC, Smith E. Resolution of enantiomeric amides on a cellulose tribenzoate chiral stationary phase. Mobile phase modifier effects on retention and stereoselectivity. J Chromatogr, 1987, 388: 65～74.
[60] Wainer IW, Stiffin RM, Shibata T. Resolution of enantiomeric aromatic alcohols on a celloluse tribenzoate high-performance liquid chromatography chiral stationary phase. A proposed chiral recognition mechanism. J Chromatogr, 1987, 411: 139～151.
[61] Ishikawa A, Shibata T. Cellulosic chiral stationary phase under reversed-phase condition. J Liq Chromatogr, 1993, 16(4): 859～878.
[62] Marle I, Jonsson S, Isaksson R, et al. Chiral stationary phases based on intact and fragmented cellobiohydrolase Ⅰ immobilized on silica. J Chromatogr, 1993, 648: 333～347.
[63] 崔欣，付芳敏，朱槿等．奥美拉唑、兰索拉唑对映体及相关物质在不同手性柱的分离比较．分析化学，2002，30(12)：1494～1496．
[64] Karlsson A, Aspegren A. The use of mobile phase pH and column temperature to reverse the retention order of enantiomers on Chiral-AGP. Chromatographia, 1998, 47: 189～196.
[65] Iredale J, Aubry A-F, Wainer I. The effects of pH and alcoholic organic modifiers on the direct separation of some acidic, basic and neutral compounds on a commercially available ovomucoid column. Chromatographia, 1991, 31: 329～334.
[66] Kummer M and Werner G. Chiral resolution of enantiomeric steroids by high-performance liquid chromatography on amylose tris (3, 5-dimethylphenylcarbamate) under reversed-phase conditions. J Chromatogr, 1988, 825: 107～114.
[67] 国家药品监督管理局药品审评中心．化学药物非临床药代动力学研究技术指导原则(第二稿)．2004．
[68] 钟大放．以加权最小二乘法建立生物分析标准曲线的若干问题．药物分析杂志，1996，16(5)：343～346．
[69] Kames HT, March C. Precision, accuracy and data acceptance criteria in biopharmaceutical analysis. Pharm Res, 1993, 10: 1420～1422.
[70] Shah VP, Midha KK, Dighe S, et al. Analytical methods validation: bioavailability, bioequivalence and pharmacokinetic studies. J Pharm Sci, 1992, 81: 309～312.
[71] 萧参，陈坚行．生物药剂分析方法的认证．中国药学杂志，1993，24：425～426．
[72] 梁文权 主编．生物药剂学与药物动力学，第2版．人民卫生出版社，2003．
[73] 郭祖超 主编．医用数理统计方法，第三版．人民卫生出版社，1988．
[74] 焦效兰，段京莉，司凯英等．高效液相色谱法测定血浆中泮托拉唑浓度．中国药学杂志，1999，34(7)：483～485．
[75] Masubuchi N, Todaka T, Odomi M, et al. Stereoselective chiral inversion of pantoprazole enantiomers after separateon doses to rats. Chirality, 1998, 10: 747～753.
[76] Mano N, Oda Y, Takakuwa S, et al. Plasma direct injection high-performance liquid chromatographic method for simultaneously determining E3810 enantiomers and their metabolites by using flavoprotein-conjugated column. J Pham Sci, 1996, 85: 903～907.
[77] Stenhoff H, Blomqvist A, Lagerstrom PO. Determination of the enantiomers of omeprazole in blood plasma by normal-phase liquid chromatography and detection by atmospheric pressure ionization tandem mass spectrometry. J Chromatogr B, 1999, 734: 191～201.
[78] 谢志勇，杨炳华，张逸凡等．右旋泮托拉唑在人体内构型转化的研究．药学学报，2004，39(5)：370～373．
[79] Kashiyama E, Yokoi T, Todaka T, et al. Chiral inversion of drug: role of intestinal bacteria in the stereoselective sulphoxide reduction of flosequinan. Biochem Pharmacol, 1994, 48: 237～243.
[2] 魏尔清 主编．药理学前沿-信号、蛋白因子、基因与现代药理．北京：科学出版社．1999．
[3] 曾苏主编．手性药物与手性药理学．浙江：浙江大学出版社．2002．
[4] Borman S. Chirality emerges as key issus in pharmaceutical research. Chem. & Eng. News. 1990, 68(28): 9～14.
[5] 傅崇东，徐惠南．手性药物的立体选择性药物动力学．中国临床药学杂志．1998．7(6)：309～313．
[6] 尤启冬，林国强 主编．手性药物——研究与应用．北京：化学工业出版社．2004．
[7] Jacques J, Collet A, Wilen SH. Enantiomers racemates and resolutions. New York: John Wiley & sons. 1981.
[8] Morrison JD. ed. Asymmetric synthesis, vol 1～5. New York: Academic Press. 1983～1985.
[9] Crosby J. Tetrahedron, 1991, 47: 4789.
[10] Ojima I. ed. Catalytic asymmetric synthesis. New York: VCH, 1993.
[11] Ahuja S. ed. Chiral separation by liquid chromatography. ACS Symposium Series 471, Washington: ACS, 1991.
[12] Francotte E. Review Contribution of preparative chromatographic resolution to the investigation of chiral phenomena. J Chromatogr A, 1994, 666: 565～601.
[13] 苑可，戴立信．关注“手性药物”．科学术语研究，2002，4(2)：46～48．
[14] Stoechitzky K, Klein W, Stark G, et al. Different steroselective effects of(R)-and (S)-propafenone: Clinical pharmacologic and radioligand binding studies. Clin Pharmacol Ther. 1990, 47: 740～746.
[15] Burnett DM, Zahniser NR, et al. Propafenone interacts stereoselectivity with β1-and β2-adrenergic receptors. J cardiovasc Pharmacol, 1988, 12: 615～619.
[16] Guznna A, Yuste F, Toscano RA, et al. Absolute configuration of(-)-5-benzoyl-1, 2-dihydro3H-pyrrolo[1, 2α]pyrrole-1-carboxylic acid, the active enantiomer of ketorolac. J Med Chem., 1986, 29: 589～591.
[17] Mitscher LA, Sharma PN, Chu-Dannel TW, et al. Chiral DNA gyase inhibitors 2. Asymmetric synthesis and biological activity of the enantiomers of 9-fluoro-3-methyl-10(4-methyl-1-piperacinyl)-7-oxo-2, 3-dihydro-7H-pyrido[1, 2, 3-de]-1, 4-benzoxazine-6-carboxylic acid (oflo-xacin). J Med Chem, 1987, 30(12): 2283～2286.
[18] 姚伟，吉宏，李靖．手性药物对映体选择性药效学与临床合理用药．临沂医专学报，1999，21(1)：63～65．
[19] 许关煜，刘玲玲．手性药物．上海医药，1999，20(10)：9～11．
[20] Janiczek N, Smith DE, Chang T, et al. Pharmacokinetics and pharmacodynamics of pirmenol enantiomers in coronary artery ligated dogs. J Pharm Sci, 1997, 86(4): 443.
[21] Takahashi H, Ogata M, Shimizu M, et al. Relative bioavailability of two disopyramide capsules in humans based on total, unbound, and unbound enantiomer concentrations. Biopharm Drug Dispos, 1993, 14(5): 409.
[22] Boulton DW, Fawcett JP. Pharmacokinetics and pharmacodynamics of single oral doses of albuterol and its enantiomers in humans. Clin Pharmacol Ther, 1997, 62(2): 138.
[23] Karim A. Enantioselective assays in comparative bioavailability atudies of racemic drug formulations: nice to know or need to know? J Clin Pharmacol, 1996, 36(6): 490.
[24] Nerurkar SG, Dighe SV, Williams RL. Bioquivalence of racemic drugs. J Clin Pharmacol, 1992, 32(10): 935.
[25] 刘会臣，于洋，王娜等．反式曲马多和反式氧去甲基曲马多在大鼠胆汁中排泄的立体选择性．药学学报，2003，38：412～415．
[26] Mehvar R, Jamali F. Bioequivalence of chiral drugs, stereospecific versus non-stereospecific methods. Clin Pharmacokinet, 1997, 33(2): 122.
[27] 蒋兆健，吴笑春．手性药物的对映体选择性与临床应用．中国药房，2001，12(3)：162～164．
[28] Stinson SC. Chiral drugs. C & EN. 2000, 78(43): 55～78.
[29] Rouhi AM. Chiral drugs. C & EN. 2001, 80(23): 43～50.
[30] 王炜，廖愚生．浅谈手性药物的研究与发展．淮南职业技术学院学报，2002．2(3)：122～124．
[31] Schmidt N, Brune K, Geisslinger G. Stereoselective determination of the enantiomers of methadone in plasma using high-performance liquid chromatography. J Chromatogr Biomed Appl, 1992, 583(2): 195～200.
[32] 曾苏，章立，刘志强．RP-HPLC手性流动相添加剂法分析尿中氧氟沙星对映体．药学学报．1994，29(3)：223～227．
[33] 李玉梅，邹晓平，李兆申．胃壁细胞及质子泵的细胞与分子生物学研究进展．国外医学．消化系疾病分册，2002，22(3)：140～141．
[34] 李阳．胃H~+／K~+-ATP酶与胃酸分泌及酶抑制剂．国外医药合成药、生化药、制剂分册，1992，13 (1)：15～20．
[35] Cass QB, Cegani ALG, Cassiano NM, et al. Enantiomeric determination of pantoprazole in human plasma by multidimensional high-performance liquid chromatography. J Chromatogr B, 2002, 766: 153～160.
[36] 许长青，卢爱君，杨东风等．泮托拉唑的药理作用于临床应用．武警医学，2002，13(05)：304～305．
[37] 李静．质子泵抑制剂——泮托拉唑．中国药学杂志，2001，36(10)：710～711．
[38] Pue MA, Latoche J, Meineke I, et al. Pharmacokinetics of pantoprazole following single intravenous and oral administration to healthy male subjects. Eur J Clin Pharmacol, 1993, 44: 575～578.
[39] 姚光．质子泵抑制剂潘他拉唑．中华消化杂志，1998，18(3)：164～165．
[40] Bliesath H, Huber R, Hartmann M, et al. Dose linearity of the pharmacokinetics of the new H~+/K~+-ATPase inhibitor pantoprazole after single intraveous administration. Int J Clin Pharmacol Ther, 1994, 32: 44.
[41] Eberle D, Hummel R, Kuhn R. Chiral resolution of pantoprazole sodium and related solfoxides by complex formation with bovine serum albumin in capillary electrophoresis. J Chromatogr A, 1997, 759: 185～192.
[42] Balmer K, Persson BA, Lagerstrom PO. Stereoselective effects in the separation of enantiomers of omeprazole and other substituted benzimidazoles on different chiral stationary phases. J Chromatogr A, 1994, 660: 269～273.
[43] Erlandsson P, lsaksson R, Lorentzon P, et al. Resolution of the enantiomers of omeprazole and some of its analogues by liquid chromatography on a trisphenylcarbamoylcellulose based stationary phases. J Chromatogr, 1990, 532: 305～309.
[44] Marle I, Erlandsson P, Hansson L, et al. Separation of enantiomers using cellulose(CBH I) silica as a chiral stationary phase. J Chromatogr, 1991, 586: 233～237.
[45] Tanaka M, Yamazaki H. Direct determination of pantoprazole enantiomers in human serum by reversed-phase high-performance liquid chromatography using a cellulose-based chiral stationary phase and column-switching system as a sample cleanup procedure. Anal Chem, 1996, 68: 1513～1516.
[46] 谢智勇，钟大放，杨炳华等．α1-酸糖蛋白手性住拆分泮托拉唑对映体．药物分析杂志，2004，24(1)：1～4．
[47] 杜丰．新型质子泵抑制剂——埃索美拉唑．首都医药，2004，6：34～35．
[48] Fitton A, Wiseman L. Pantoprazole: A review of its pharmacological properties and therapeutic in acid-related disorders. Drugs, 1996, 51: 460～482.
[49] HumpHries TJ, Mernitt GJ. Review article: drug interactions with agents used to treat acidrelated diseases. Aliment pharmacol Ther, 1999, 13(supple3): 18.
[50] 贾健辉，王敏伟，卢方正等．左旋泮托拉唑镁对动物实验性胃溃疡的影响．沈阳药科大学学报，2004，21(3)：218～221．
[51] 贾健辉，王敏伟，曹红等．左旋泮托拉唑镁对动物实验性十二指肠溃疡的影响．沈阳药科大学学报，2004，21(4)：294～296．
[52] 邹公伟，郑琦，胡冠九等．高效液相色谱中的纤维素衍生物手性同定相．分析化学，1995，23(4)：466～473．
[53] Jingli Liu, James T. Stewart. Quantitation of promethazine enantiomers in human serum using a chiralcel OJ-R column and mixed-mode disc solid-phase extraction. J Pharm Biomed Anal, 1997, 16: 303～309.
[54] Hassan Y. Aboul-Enein, Martin G. Schmid, Claudia Tuscher, et al. Chiral separation of several thiobarbiturates on a cellulose tris(4-methylbenzoate) phase under reversed-phase conditions. J Liq Chrom & Rel Technol, 2001, 24(1): 69～77.
[55] Kauffman R, Lieh-Lai M, Uy H, et al. Enantiomer-selective pharmacokinetics and metabolism of ketorolac in children. Clin Pharmacol Ther, 1998, 65: 382～388.
[56] 徐修容．高效液相色谱分离光学异构体．色谱，1991，9(6)：363～368．
[57] Okamoto Y, Aburatani R, Hatada K. Chromatographic chiral resolution ⅪⅤ cellulose tribenzoate derivatives as chiral stationary phases for high-performance liquid chromatography. J Chromatogr, 1987, 389: 95～102.
[58] Wainer IW, Alembik MC. Resolution of enantiomeric amides on a cellulose-based chiral stationary phase. J Chromatogr, 1986, 358: 85～93.
[59] Wainer IW, Alembik MC, Smith E. Resolution of enantiomeric amides on a cellulose tribenzoate chiral stationary phase. Mobile phase modifier effects on retention and stereoselectivity. J Chromatogr, 1987, 388: 65～74.
[60] Wainer IW, Stiffin RM, Shibata T. Resolution of enantiomeric aromatic alcohols on a celloluse tribenzoate high-performance liquid chromatography chiral stationary phase. A proposed chiral recognition mechanism. J Chromatogr, 1987, 411: 139～151.
[61] Ishikawa A, Shibata T. Cellulosic chiral stationary phase under reversed-phase condition. J Liq Chromatogr, 1993, 16(4): 859～878.
[62] Marle I, Jonsson S, Isaksson R, et al. Chiral stationary phases based on intact and fragmented cellobiohydrolase Ⅰ immobilized on silica. J Chromatogr, 1993, 648: 333～347.
[63] 崔欣，付芳敏，朱槿等．奥美拉唑、兰索拉唑对映体及相关物质在不同手性柱的分离比较．分析化学，2002，30(12)：1494～1496．
[64] Karlsson A, Aspegren A. The use of mobile phase pH and column temperature to reverse the retention order of enantiomers on Chiral-AGP. Chromatographia, 1998, 47: 189～196.
[65] Iredale J, Aubry A-F, Wainer I. The effects of pH and alcoholic organic modifiers on the direct separation of some acidic, basic and neutral compounds on a commercially available ovomucoid column. Chromatographia, 1991, 31: 329～334.
[66] Kummer M and Werner G. Chiral resolution of enantiomeric steroids by high-performance liquid chromatography on amylose tris (3, 5-dimethylphenylcarbamate) under reversed-phase conditions. J Chromatogr, 1988, 825: 107～114.
[67] 国家药品监督管理局药品审评中心．化学药物非临床药代动力学研究技术指导原则(第二稿)．2004．
[68] 钟大放．以加权最小二乘法建立生物分析标准曲线的若干问题．药物分析杂志，1996，16(5)：343～346．
[69] Kames HT, March C. Precision, accuracy and data acceptance criteria in biopharmaceutical analysis. Pharm Res, 1993, 10: 1420～1422.
[70] Shah VP, Midha KK, Dighe S, et al. Analytical methods validation: bioavailability, bioequivalence and pharmacokinetic studies. J Pharm Sci, 1992, 81: 309～312.
[71] 萧参，陈坚行．生物药剂分析方法的认证．中国药学杂志，1993，24：425～426．
[72] 梁文权 主编．生物药剂学与药物动力学，第2版．人民卫生出版社，2003．
[73] 郭祖超 主编．医用数理统计方法，第三版．人民卫生出版社，1988．
[74] 焦效兰，段京莉，司凯英等．高效液相色谱法测定血浆中泮托拉唑浓度．中国药学杂志，1999，34(7)：483～485．
[75] Masubuchi N, Todaka T, Odomi M, et al. Stereoselective chiral inversion of pantoprazole enantiomers after separateon doses to rats. Chirality, 1998, 10: 747～753.
[76] Mano N, Oda Y, Takakuwa S, et al. Plasma direct injection high-performance liquid chromatographic method for simultaneously determining E3810 enantiomers and their metabolites by using flavoprotein-conjugated column. J Pham Sci, 1996, 85: 903～907.
[77] Stenhoff H, Blomqvist A, Lagerstrom PO. Determination of the enantiomers of omeprazole in blood plasma by normal-phase liquid chromatography and detection by atmospheric pressure ionization tandem mass spectrometry. J Chromatogr B, 1999, 734: 191～201.
[78] 谢志勇，杨炳华，张逸凡等．右旋泮托拉唑在人体内构型转化的研究．药学学报，2004，39(5)：370～373．
[79] Kashiyama E, Yokoi T, Todaka T, et al. Chiral inversion of drug: role of intestinal bacteria in the stereoselective sulphoxide reduction of flosequinan. Biochem Pharmacol, 1994, 48: 237～243.
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