五个质子泵抑制剂对映体的分离及大鼠体内药动学研究
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摘要
手性药物的生物活性与其立体构型密切相关。目前新药研究的一个发展趋势是研制和生产光学纯的药物。手性药物的研究已成为国际新药研究的方向之一。手性药物分析在手性药物研究中作用越来越重要,已成为国际上分析科学中的热点和难点。本文以质子泵抑制剂泰妥拉唑、泮托拉唑、兰索拉唑、雷贝拉唑和奥美拉唑为研究对象,建立了对映体分离测定的毛细管电泳法和高效液相色谱法,制定了(-)-泰妥拉唑和(-)-泮托拉唑光学纯度的检测方法,初步研究了泰妥拉唑对映体在大鼠体内的立体选择性药物动力学过程,为此类手性药物的研究开发奠定了基础。
1.毛细管区带电泳法分离四个质子泵抑制剂对映体
采用以负电的磺丁基醚-β-环糊精(SBE-β-CD)为手性选择剂的毛细管区带电泳法对泰妥拉唑、雷贝拉唑、兰索拉唑和泮托拉唑对映体进行了手性分离研究。考察了环糊精种类和浓度、背景电解质的pH、有机改性剂种类和浓度等因素对分离的影响。在背景电解质为50 mmol／L硼砂—150 mmol／L磷酸二氢钠(含40mg/mL SBE-β-CD, pH6.5),分离电压为10 kV的条件下,四个质子泵抑制剂对映体实现了基线分离。测定了四个质子泵抑制剂对映体与SBE-β-CD的结合常数,证明了两对映体与SBE-β-CD结合常数的不同是实现手性分离的主要机制。对泰妥拉唑对映体的手性分离方法进行了方法学确证,两对映体浓度在0.65～100μg／mL范围内与峰面积呈良好的线性关系(r2≥0.9994),两个对映体的最低检测限和定量限分别为0.2和0.65μg／mL,方法的日内、日间精密度(RSD)均小于3.0%,回收率在91.6～100%之间。该方法应用于(-)-泰妥拉唑样品的对映体过量百分率测定。
2.手性流动相添加剂高效液相色谱法分离泮托拉唑对映体
采用以SBE-β-CD为手性流动相添加剂的高效液相色谱法对泮托拉唑对映体进行手性分离研究。考察了SBE-β-CD的浓度,缓冲溶液的种类、浓度和pH,有机改性剂的种类和浓度等因素对分离的影响。最后确定分离条件为：在Spherigel C18色谱柱(150mm×4.6mm,5μm)上,流动相为10 mmol／L磷酸二氢钾(含20 mg/mL SBE-β-CD, pH2.5)—乙腈(85：15,v／v),流速为0.9 mL／min,柱温为室温,检测波长为290 nm的条件下,泮托拉唑对映体在15min内分离度达到2.1。按照ICH指导原则对(-)-泮托拉唑中(+)-异构体杂质的定量测定进行方法学确证,(+)-泮托拉唑的浓度在0.5～6.0μg／mL范围内与峰面积呈良好的线性关系(r2=0.9991),(+)-泮托拉唑的检测限和定量限分别为0.2和0.5μg／mL,方法的日内、日间精密度(RSD)小于3.6%,回收率在92.1～101%之间。该方法应用于(-)-泮托拉唑原料药中(+)-泮托拉唑的定量测定。
3.手性配体交换高效液相色谱法分离五个质子泵抑制剂对映体.
采用手性配体交换高效液相色谱法对泰妥拉唑、泮托拉唑、兰索拉唑、雷贝拉唑和奥美拉唑对映体进行手性分离研究。考察了配体的种类、配体与金属离子的比例和浓度、有机改性剂的种类和浓度、流动相pH等因素对手性分离的影响。在流动相为1 mmol／L L-组氨酸,0.5 mmol／L醋酸铜(pH7.0)—乙腈(75：25,v／v),流速1.0 mL／min条件下,奥美拉唑,泮托拉唑,雷贝拉唑和兰索拉唑实现基线分离。在上述条件下,将乙腈含量调整为18%,泰妥拉唑对映体实现基线分离。应用分子模拟构建了三元配合物的最低能量构型,通过量化计算证明了质子泵抑制剂对映体与Cu2+和L-组氨酸形成三元配合物的稳定性差异是实现对映体分离的主要分离机制。
4.手性固定相高效液相色谱法分离四个质子泵抑制剂对映体
应用多糖类手性色谱柱Chiralpak AS-H和大环糖肽抗生素类手性色谱柱Chirobiotic V为固定相对泰妥拉唑、泮托拉唑、兰索拉唑和奥美拉唑对映体进行了手性分离研究。采用Chiralpak AS-H手性固定相时,考察了流动相组成和柱温对手性分离的影响。在流动相为正己烷—乙醇—三乙胺(20：80：0.1%,v／v／v),流速为0.4 mL／min,柱温为40℃的条件下,四个质子泵抑制剂对映体在15 min内实现分离度大于3.3的基线分离。考察了此模式下四个质子泵抑制剂对映体的热力学参数的变化,证明了其与固定相之间的相互作用均是焓控过程。质子泵抑制剂与Chiralpak AS-H固定相之间的空间作用是实现对映体分离的最主要分离机制。采用Chirobiotic V手性固定相时,以泰妥拉唑为代表,考察了分离模式、流动相组成和柱温等因素对分离的影响。在流动相为20 mmol／L醋酸铵—四氢呋喃(93：7,v／v,pH6.0),流速为0.5 mL／min,温度为20℃的条件下,泰妥拉唑实现基线分离,其它三个质子泵抑制剂对映体得到部分分离。考察了此模式下泰妥拉唑热力学参数的变化,证明了其与固定相之间的相互作用是焓控过程。比较两种手性固定相的分离结果,Chiralpak AS-H更适合质子泵抑制剂手性药物对映体的分离。
5.大鼠血浆泰妥拉唑对映体的测定和立体选择性药物动力学初步研究
建立非手性—手性串联高效液相色谱法定量测定大鼠血浆中泰妥拉唑对映体。初步研究了大鼠单剂量灌胃给予泰妥拉唑消旋体后两对映体的药物动力学过程。结果表明血浆中(+)-泰妥拉唑的AUC0-∞。值高于(-)-泰妥拉唑(p<0.001),两对映体的t1／2和CL／F有显著性不同(p<0.01 and p<0.001),(+)-泰妥拉唑与(-)-泰妥拉唑的Cmax和AUC0-∞的比值分别为2.5和7.6。说明泰妥拉唑对映体在大鼠体内的药物动力学具有立体选择性。
Bioactivity of chiral drugs is closely related to the stereostructures. Nowadays development and production of optically pure drugs is the trend of new drugs research. The study on chiral drugs has become one of the important directions of new drugs research and development internationally. Analysis of chiral drugs, with increasing in importance in pharmaceutical research, is now a hot and difficult topic in analysis science. In this thesis, capillary electrophoresis (CE) and high performance liquid chromatography (HPLC) methods were developed for the chiral separation of proton pump inhibitors (PPIs) including tenatoprazole, pantoprazole, lansoprazole, rabeprazole and omeprazole. The optical determination method for (-)-pantoprazole and (-)-tenatoprazole and the seteroselective pharmacokinetics of tenatoprazole enantiomers in rats provided a reference for the development of optically pure PPIs.
1. Chiral separation of four PPIs with capillary zone electrophoresis
The chiral separation of tenatoprazole, pantoprazole, lansoprazole and rabeprazole was studied with capillary zone electrophoresis (CZE) using negatively charged sulfobutyl ether-β-CD (SBE-β-CD) as chiral selector. The influence of type and concentration of CDs, running buffer pH, the type and concentration of organic modifier on the chiral separation was investigated. The separation mechanism was discussed by comparing the chiral separation results and the determination of the complexation binding constant. The chiral recognition mechanism was proposed on the difference of the complexation binding constant between two enantiomers. Under the condition of 50 mmol/L borox-150 mmol/L phosphate buffer (pH6.5) containing 40 mg/mL SBE-P-CD, applied voltage of 10 kV, the enantiomers of all PPIs were baseline separated. The optimized method for determination of tenatoprazole enantiomers was validated. The limits of detection (LOD) and quantification (LOQ) were 0.2 and 0.65μg/mL for both the enatiomers, respectively. The linearity of the method was in the range of 0.65～100μg/mL with r2≥0.9994. The inter-and tra-day assay precision was less than 3.0%(RSD) and recoveries were in the range 91.6～100%. The method was applied to the enantiomeric excess (ee) determination of (-)-tenatoprazole bulk samples.
2. Chiral separation of pantoprazole enantiomers by HPLC using SBE-β-CD as chiral mobile phase additive
The chiral separation of pantoprazole enantiomers was studied by HPLC using SBE-β-CD as chiral mobile phase additive (CMPA). The factors affecting the resolution such as concentration of SBE-β-CD, buffer pH, type and concentration of buffer solution, type and concentration of organic modifier were investigated. A baseline resolution of 2.1 was achieved within 15 min on a Spherigel C18 column (150mm×4.6mm,5μm) using acetonitrile and 10 mmol/L phosphate buffer (pH2.5) containing 20 mg/mL SBE-P-CD (15:85, v/v) as mobile phase with a flow rate of 0.9 mL/min at room temprature. The detection wavelength was 290 nm. The optimized method was extensively validated in terms of accuracy, precision and linearity according to the ICH guidelines and proved to be robust. The LOD and LOQ for (+)-pantoprazole were 0.2 and 0.5μg/mL, respectively. The linearity of the method was in the range of 0.5～6.0μg/mL with r2=0.9991 for (+)-pantoprazole. The precision of the method was less than 3.6%(RSD) and recoveries were in the range 92.1～101% for (+)-pantoprazole. The method was applied to the enantiomeric impurity determination of (-)-pantoprazole bulk samples.
3. Chiral separation of five PPIs with chiral ligand-exchange chromatography
The chiral separation of tenatoprazole, pantoprazole, lansoprazole, rabeprazole and omeprazole was studied with chiral ligand-exchange chromatography (CLEC). The type of chiral ligand, type and concentration of organic modifier, the concentration ratio of chiral ligand to metal ion and pH were studied for the optimization of separation condition. Under the optimized conditions,1 mmol/L L-His,0.5 mmol/L copper acetate in water (pH7.0)-acetonitrile (75:25, v/v), at flow rate of 1.0 mL/min, the enantiomers of omeprazole, pantoprazole, rabeprazole and lansoprzole were baseline separated, and the enantiomers of tenatoprazole could be resovled with the content of acetonitrile decreased to 18%. The minimal energy configurations were obtained by simulated annealing, and based on that, quantum chemical calculation was performed to discuss the mechanism of chiral recognition. The chiral recognition mechanism was proposed to be on the difference of the stability of ternary complexes between two enantiomers.
4. Chiral separation of four PPIs by HPLC on chiral stationary phases
Direct enantioseparation of PPIs including tenatoprazole, pantoprazole, lansoprazole and omeprazole was studied using Amysole (Chiralpak AS-H) and Vancomycin (Chirobiotic V) as chiral stationary phases (CSPs). The effects of the concentration of mobile phase additive, composition of mobile phase and column temperature were investigated with Chiralpak AS-H as CSP. The enantiomers of all PPIs were resolved (Rs>3.3) within 15 min using n-hexane-ethanol-TEA (80:20:0.1%, v/v/v) as mobile phase with a flow rate of 0.4 mL/min at 40℃. The thermodynamic parameters of four PPIs in this mode were investigated, the enantioselectivety was proved to be enthalpocally controlled. The chiral recognition mechanism was discussed, inclusion interaction between the CSP and the analytes was confirmed to be the dramatic interaction responsible for the chiral discrimination. The separation mode, mobile phase and column temperature were also investigated when Chirobiotic V was adopted. Under the optimized conditions,20 mmol/mL ammonium acetate-tetrahydrofuran (93:7, v/v), at a flow rate of 0.5 mL/min and 20℃, the enantiomers of tenatoprazole got baseline separation, and the enantiomers of pantoprazole, lansoprazole and omeprazole got partial separation. The thermodynamic parameters of tenatoprazole in this mode was investigated, the enantioselectively was proved to be enthalpocally controlled. The results of enantiosparation on the two CSPs were compared with each other with Chiralpak AS-H CSP giving better results.
5. Determination of tenatoprazole enantiomers and their stereoselective pharmacokinetics in rats
An achiral-chiral sequential HPLC method was developed for the determination of tenatoprazole enantiomers in rat plasma. The method was used for the stereoselective pharmacokinetic study of tenatoprazole in rats after intra gastric administration of tenatoprazole racemate. The AUC0-∞value of (+)-tenatoprazole was significantly greater than that of (-)-tenatoprazole (p<0.001). There are also significant differences in t1/2 and CL/F (p<0.01 and p<0.001, respectively) values between enantiomers. The mean Cmax and AUC0-∞values for (+)-tenatoprazole were 2.5 and 7.6 times of those of (-)-tenatoprazole, which indicated that the pharmacokinetics of tenatoprazole in rats was stereoselective.
1.毛细管区带电泳法分离四个质子泵抑制剂对映体
采用以负电的磺丁基醚-β-环糊精(SBE-β-CD)为手性选择剂的毛细管区带电泳法对泰妥拉唑、雷贝拉唑、兰索拉唑和泮托拉唑对映体进行了手性分离研究。考察了环糊精种类和浓度、背景电解质的pH、有机改性剂种类和浓度等因素对分离的影响。在背景电解质为50 mmol／L硼砂—150 mmol／L磷酸二氢钠(含40mg/mL SBE-β-CD, pH6.5),分离电压为10 kV的条件下,四个质子泵抑制剂对映体实现了基线分离。测定了四个质子泵抑制剂对映体与SBE-β-CD的结合常数,证明了两对映体与SBE-β-CD结合常数的不同是实现手性分离的主要机制。对泰妥拉唑对映体的手性分离方法进行了方法学确证,两对映体浓度在0.65～100μg／mL范围内与峰面积呈良好的线性关系(r2≥0.9994),两个对映体的最低检测限和定量限分别为0.2和0.65μg／mL,方法的日内、日间精密度(RSD)均小于3.0%,回收率在91.6～100%之间。该方法应用于(-)-泰妥拉唑样品的对映体过量百分率测定。
2.手性流动相添加剂高效液相色谱法分离泮托拉唑对映体
采用以SBE-β-CD为手性流动相添加剂的高效液相色谱法对泮托拉唑对映体进行手性分离研究。考察了SBE-β-CD的浓度,缓冲溶液的种类、浓度和pH,有机改性剂的种类和浓度等因素对分离的影响。最后确定分离条件为：在Spherigel C18色谱柱(150mm×4.6mm,5μm)上,流动相为10 mmol／L磷酸二氢钾(含20 mg/mL SBE-β-CD, pH2.5)—乙腈(85：15,v／v),流速为0.9 mL／min,柱温为室温,检测波长为290 nm的条件下,泮托拉唑对映体在15min内分离度达到2.1。按照ICH指导原则对(-)-泮托拉唑中(+)-异构体杂质的定量测定进行方法学确证,(+)-泮托拉唑的浓度在0.5～6.0μg／mL范围内与峰面积呈良好的线性关系(r2=0.9991),(+)-泮托拉唑的检测限和定量限分别为0.2和0.5μg／mL,方法的日内、日间精密度(RSD)小于3.6%,回收率在92.1～101%之间。该方法应用于(-)-泮托拉唑原料药中(+)-泮托拉唑的定量测定。
3.手性配体交换高效液相色谱法分离五个质子泵抑制剂对映体.
采用手性配体交换高效液相色谱法对泰妥拉唑、泮托拉唑、兰索拉唑、雷贝拉唑和奥美拉唑对映体进行手性分离研究。考察了配体的种类、配体与金属离子的比例和浓度、有机改性剂的种类和浓度、流动相pH等因素对手性分离的影响。在流动相为1 mmol／L L-组氨酸,0.5 mmol／L醋酸铜(pH7.0)—乙腈(75：25,v／v),流速1.0 mL／min条件下,奥美拉唑,泮托拉唑,雷贝拉唑和兰索拉唑实现基线分离。在上述条件下,将乙腈含量调整为18%,泰妥拉唑对映体实现基线分离。应用分子模拟构建了三元配合物的最低能量构型,通过量化计算证明了质子泵抑制剂对映体与Cu2+和L-组氨酸形成三元配合物的稳定性差异是实现对映体分离的主要分离机制。
4.手性固定相高效液相色谱法分离四个质子泵抑制剂对映体
应用多糖类手性色谱柱Chiralpak AS-H和大环糖肽抗生素类手性色谱柱Chirobiotic V为固定相对泰妥拉唑、泮托拉唑、兰索拉唑和奥美拉唑对映体进行了手性分离研究。采用Chiralpak AS-H手性固定相时,考察了流动相组成和柱温对手性分离的影响。在流动相为正己烷—乙醇—三乙胺(20：80：0.1%,v／v／v),流速为0.4 mL／min,柱温为40℃的条件下,四个质子泵抑制剂对映体在15 min内实现分离度大于3.3的基线分离。考察了此模式下四个质子泵抑制剂对映体的热力学参数的变化,证明了其与固定相之间的相互作用均是焓控过程。质子泵抑制剂与Chiralpak AS-H固定相之间的空间作用是实现对映体分离的最主要分离机制。采用Chirobiotic V手性固定相时,以泰妥拉唑为代表,考察了分离模式、流动相组成和柱温等因素对分离的影响。在流动相为20 mmol／L醋酸铵—四氢呋喃(93：7,v／v,pH6.0),流速为0.5 mL／min,温度为20℃的条件下,泰妥拉唑实现基线分离,其它三个质子泵抑制剂对映体得到部分分离。考察了此模式下泰妥拉唑热力学参数的变化,证明了其与固定相之间的相互作用是焓控过程。比较两种手性固定相的分离结果,Chiralpak AS-H更适合质子泵抑制剂手性药物对映体的分离。
5.大鼠血浆泰妥拉唑对映体的测定和立体选择性药物动力学初步研究
建立非手性—手性串联高效液相色谱法定量测定大鼠血浆中泰妥拉唑对映体。初步研究了大鼠单剂量灌胃给予泰妥拉唑消旋体后两对映体的药物动力学过程。结果表明血浆中(+)-泰妥拉唑的AUC0-∞。值高于(-)-泰妥拉唑(p<0.001),两对映体的t1／2和CL／F有显著性不同(p<0.01 and p<0.001),(+)-泰妥拉唑与(-)-泰妥拉唑的Cmax和AUC0-∞的比值分别为2.5和7.6。说明泰妥拉唑对映体在大鼠体内的药物动力学具有立体选择性。
Bioactivity of chiral drugs is closely related to the stereostructures. Nowadays development and production of optically pure drugs is the trend of new drugs research. The study on chiral drugs has become one of the important directions of new drugs research and development internationally. Analysis of chiral drugs, with increasing in importance in pharmaceutical research, is now a hot and difficult topic in analysis science. In this thesis, capillary electrophoresis (CE) and high performance liquid chromatography (HPLC) methods were developed for the chiral separation of proton pump inhibitors (PPIs) including tenatoprazole, pantoprazole, lansoprazole, rabeprazole and omeprazole. The optical determination method for (-)-pantoprazole and (-)-tenatoprazole and the seteroselective pharmacokinetics of tenatoprazole enantiomers in rats provided a reference for the development of optically pure PPIs.
1. Chiral separation of four PPIs with capillary zone electrophoresis
The chiral separation of tenatoprazole, pantoprazole, lansoprazole and rabeprazole was studied with capillary zone electrophoresis (CZE) using negatively charged sulfobutyl ether-β-CD (SBE-β-CD) as chiral selector. The influence of type and concentration of CDs, running buffer pH, the type and concentration of organic modifier on the chiral separation was investigated. The separation mechanism was discussed by comparing the chiral separation results and the determination of the complexation binding constant. The chiral recognition mechanism was proposed on the difference of the complexation binding constant between two enantiomers. Under the condition of 50 mmol/L borox-150 mmol/L phosphate buffer (pH6.5) containing 40 mg/mL SBE-P-CD, applied voltage of 10 kV, the enantiomers of all PPIs were baseline separated. The optimized method for determination of tenatoprazole enantiomers was validated. The limits of detection (LOD) and quantification (LOQ) were 0.2 and 0.65μg/mL for both the enatiomers, respectively. The linearity of the method was in the range of 0.65～100μg/mL with r2≥0.9994. The inter-and tra-day assay precision was less than 3.0%(RSD) and recoveries were in the range 91.6～100%. The method was applied to the enantiomeric excess (ee) determination of (-)-tenatoprazole bulk samples.
2. Chiral separation of pantoprazole enantiomers by HPLC using SBE-β-CD as chiral mobile phase additive
The chiral separation of pantoprazole enantiomers was studied by HPLC using SBE-β-CD as chiral mobile phase additive (CMPA). The factors affecting the resolution such as concentration of SBE-β-CD, buffer pH, type and concentration of buffer solution, type and concentration of organic modifier were investigated. A baseline resolution of 2.1 was achieved within 15 min on a Spherigel C18 column (150mm×4.6mm,5μm) using acetonitrile and 10 mmol/L phosphate buffer (pH2.5) containing 20 mg/mL SBE-P-CD (15:85, v/v) as mobile phase with a flow rate of 0.9 mL/min at room temprature. The detection wavelength was 290 nm. The optimized method was extensively validated in terms of accuracy, precision and linearity according to the ICH guidelines and proved to be robust. The LOD and LOQ for (+)-pantoprazole were 0.2 and 0.5μg/mL, respectively. The linearity of the method was in the range of 0.5～6.0μg/mL with r2=0.9991 for (+)-pantoprazole. The precision of the method was less than 3.6%(RSD) and recoveries were in the range 92.1～101% for (+)-pantoprazole. The method was applied to the enantiomeric impurity determination of (-)-pantoprazole bulk samples.
3. Chiral separation of five PPIs with chiral ligand-exchange chromatography
The chiral separation of tenatoprazole, pantoprazole, lansoprazole, rabeprazole and omeprazole was studied with chiral ligand-exchange chromatography (CLEC). The type of chiral ligand, type and concentration of organic modifier, the concentration ratio of chiral ligand to metal ion and pH were studied for the optimization of separation condition. Under the optimized conditions,1 mmol/L L-His,0.5 mmol/L copper acetate in water (pH7.0)-acetonitrile (75:25, v/v), at flow rate of 1.0 mL/min, the enantiomers of omeprazole, pantoprazole, rabeprazole and lansoprzole were baseline separated, and the enantiomers of tenatoprazole could be resovled with the content of acetonitrile decreased to 18%. The minimal energy configurations were obtained by simulated annealing, and based on that, quantum chemical calculation was performed to discuss the mechanism of chiral recognition. The chiral recognition mechanism was proposed to be on the difference of the stability of ternary complexes between two enantiomers.
4. Chiral separation of four PPIs by HPLC on chiral stationary phases
Direct enantioseparation of PPIs including tenatoprazole, pantoprazole, lansoprazole and omeprazole was studied using Amysole (Chiralpak AS-H) and Vancomycin (Chirobiotic V) as chiral stationary phases (CSPs). The effects of the concentration of mobile phase additive, composition of mobile phase and column temperature were investigated with Chiralpak AS-H as CSP. The enantiomers of all PPIs were resolved (Rs>3.3) within 15 min using n-hexane-ethanol-TEA (80:20:0.1%, v/v/v) as mobile phase with a flow rate of 0.4 mL/min at 40℃. The thermodynamic parameters of four PPIs in this mode were investigated, the enantioselectivety was proved to be enthalpocally controlled. The chiral recognition mechanism was discussed, inclusion interaction between the CSP and the analytes was confirmed to be the dramatic interaction responsible for the chiral discrimination. The separation mode, mobile phase and column temperature were also investigated when Chirobiotic V was adopted. Under the optimized conditions,20 mmol/mL ammonium acetate-tetrahydrofuran (93:7, v/v), at a flow rate of 0.5 mL/min and 20℃, the enantiomers of tenatoprazole got baseline separation, and the enantiomers of pantoprazole, lansoprazole and omeprazole got partial separation. The thermodynamic parameters of tenatoprazole in this mode was investigated, the enantioselectively was proved to be enthalpocally controlled. The results of enantiosparation on the two CSPs were compared with each other with Chiralpak AS-H CSP giving better results.
5. Determination of tenatoprazole enantiomers and their stereoselective pharmacokinetics in rats
An achiral-chiral sequential HPLC method was developed for the determination of tenatoprazole enantiomers in rat plasma. The method was used for the stereoselective pharmacokinetic study of tenatoprazole in rats after intra gastric administration of tenatoprazole racemate. The AUC0-∞value of (+)-tenatoprazole was significantly greater than that of (-)-tenatoprazole (p<0.001). There are also significant differences in t1/2 and CL/F (p<0.01 and p<0.001, respectively) values between enantiomers. The mean Cmax and AUC0-∞values for (+)-tenatoprazole were 2.5 and 7.6 times of those of (-)-tenatoprazole, which indicated that the pharmacokinetics of tenatoprazole in rats was stereoselective.
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