高效液相色谱法测定人血浆中奥美拉唑对映体的浓度
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摘要
目的:
质子泵抑制剂( proton pump inhibitors,PPIs )是目前显著抑制胃酸分泌、治疗消化性溃疡的一线药物。目前临床常用的PPIs有奥美拉唑( omeprazole )、兰索拉唑( 1ansoprazole )、泮托拉唑( pantoprazole )。PPIs都具有手性,存在两个光学异构体,临床上兰索拉唑、泮托拉唑都以消旋体的形式用药。奥美拉唑、兰索拉唑、泮托拉唑对映体药效都存在差异,故建立两个对映体含量测定的分析方法十分有必要。目前拆分PPIs的色谱法有毛细管电泳法、高速逆流色谱法、高效液相色谱法。其中高效液相色谱( HPLC )法应用广泛,用此法拆分PPIs具有快速、简单、可靠、分离效果好、准确度高的优点。
本文旨在考察奥美拉唑对映体、兰索拉唑对映体、泮托拉唑对映体在多糖类手性色谱柱(Chiralpak AD柱、Chiralpak AS柱、Chiralcel OD柱和Chiralcel OJ柱)上的分离行为以及流动相对对映体分离的影响,并建立测定人血浆中奥美拉唑对映体浓度的高效液相色谱分析方法。
方法:
色谱条件色谱柱:Chiralpak AD柱(250 mm×4.6 mm,10μm,Daicel Chemicals)、Chiralcel OJ柱(250 mm×4.6 mm,10μm, Daicel Chemicals)、Chiralpak AS柱(250 mm×4.6 mm, 10μm, Daicel Chemicals)、Chiralcel OD柱(250 mm×4.6 mm, 10μm, Daicel Chemicals),氰基保护柱(4 mm×4 mm ,10μm ,江苏汉邦)。基本流动相:正己烷-异丙醇、正己烷-乙醇、正己烷-异丙醇-甲醇、正己烷-异丙醇-乙醇。紫外检测波长:奥美拉唑302 nm,兰索拉唑285 nm,泮托拉唑289 nm;流速:0.5-1.0 mL/min;柱温:25℃;进样量:100μL。
血浆样品含量测定条件:Chiralpak AD柱(250 mm×4.6 mm ,10μm, Daicel Chemicals),氰基保护柱(4 mm×4 mm,10μm,江苏汉邦);流动相:正己烷-乙醇(30:70 , v/v);流速0.5 mL/min;检测波长:302 nm;柱温:25℃;进样量:100μL。
结果:
奥美拉唑对映体、兰索拉唑对映体、泮托拉唑对映体在使用Chiralpak AS柱拆分时效果最好。在使用Chiralpak AD柱拆分奥美拉唑对映体时,流动相分别为异丙醇和乙醇时的洗脱顺序不同。高效液相色谱法测定人血浆中奥美拉唑对映体浓度的方法的相对回收率为(-)-(S)-奥美拉唑96.7%～100.4%,(+)-(R)-奥美拉唑97.4%～100.2%;日内RSD小于4.7%,日间RSD小于3.3%;奥美拉唑对映体在5～1000 ng/mL浓度范围内线性关系良好, (-)-(S)-奥美拉唑(n =5, r=0.9998),(+)-(R)-奥美拉唑(n=5, r=0.9997),最低检测浓度(S/N=3)为2 ng/mL。
结论:
本文建立的奥美拉唑、兰索拉唑、泮托拉唑对映体的拆分方法可用于质子泵抑制剂单一对映体的光学纯度测定、质量控制及立体选择性药代动力学研究;建立的人血浆中奥美拉唑对映体浓度的测定方法简单、可靠、灵敏度高、准确度好,可用于人血浆中奥美拉唑对映体人体药代动力学研究。
OBJECTIVE:
Proton pump inhititors (PPIs) are a group of drugs whose main action is a pronounced and long-lasting reduction of gastric acid production.The PPIs most used clinicaily in the treatment of acid-related diseases are omeprazole (OME), lansoprazole (LAN), pantoprazole (PAN).
All these PPIs have a stereogenic center at the sulfur atom .OME and PAN are clinically administered as a racemic mixture. Since the omeprazole,lansoprazole,pantoprazole enantiomers may have different physiological effects in biological systems, it is significance that both enantiomers could be determined and analysed, not only the racemates. PPIs have been performed by capillary chromatography (CE), supercritical fluid chromatography (SFC), enantioselective HPLC methods. HPLC method is a simple, rapid, reliable, selective, accurate method for the determination of PPIs.
The direct HPLC method for the separation of omeprazole, lansoprazole, pantoprazole enantiomers was carried on derivatized cellulose and amylose chiral stationary phase (Chiralpak AD column, Chiralpak AS column, Chiralcel OD column, Chiralcel OJ column) was studied. In this assay, a high sensitivity and selectivity HPLC method for the analysis and quantification of omeprazole enantiomers in human plasma was also established.
METHODS:
Chromatography conditions: column: Chiralpak AD column (250 mm×4.6 mm, 10μm, Daicel Chemical), Chiralcel OJ column (250 mm×4.6 mm,10μm, Daicel Chemicals), Chiralpak AS column (250 mm×4.6 mm , 10μm, Daicel Chemicals), Chiralcel OD column (250 mm×4.6 mm, 10μm, Daicel Chemicals). Mobile phase: hexane-isopropanol, hexane-ethanol,hexane-isopropanol-ethanol, hexane-isopropanol-methanol. The flow rate was 0.5-1mL/min. The absorbance wavelength of omeprazole, lansoprazole and pantoprazole was 302 nm, 285 nm, and 289 nm, respectively. The column temperature was 25℃and the injection volume was 100μL.
Plasma smples Chromatography conditions: Agilent BOND ODS-C18 Solid Phase Extraction (SPE) cartidges were used to extract the enantiomers from plasma samples and the chiral separation was carried on a Chiralpak AD column (250 mm×4.6 mm, 10μm, Daicel Chemical), with hexane-ethanol (30:70, v/v) as the mobile phase with the flow rate of 0.5 mL/min. The detection was carried out at 302 nm. The column temperature was 25℃and the injection volume was 100μL.
RESULTS:
The recoveris of (-)-(S)-omeprazole were between 96.7%～100.4%, and (+)-(R)-omeprazole were between 97.4%～100.2% in the determination of plasma samples. Intra- and inter-day precision values were lower than 3.3% and 4.7%, respectively. The linear ranges for (-)-(S)-omeprazole and (+)-(R)-omeprazole were 5~1000 ng/mL, (-)-(S)-omeprazole (n = 5, r = 0.9998), (+)-(R)-omeprazole (n = 5, r = 0.9997) with a detection limit of 2 ng/mL at a signal/noise ratio of 3.
CONCLUSION:
The established high-performance liquid chromatography separation of omeprazole, lansoprazole, pantoprazole enantiomers could be applied to the determination of optical purity, quality control and stereoselective pharmacokinetics research. This method presented in this assay is rapid, reliable, simple and high sensitivity with a satisfactory result in the study the pharmacokinetics of omeprazole enantiomers.
质子泵抑制剂( proton pump inhibitors,PPIs )是目前显著抑制胃酸分泌、治疗消化性溃疡的一线药物。目前临床常用的PPIs有奥美拉唑( omeprazole )、兰索拉唑( 1ansoprazole )、泮托拉唑( pantoprazole )。PPIs都具有手性,存在两个光学异构体,临床上兰索拉唑、泮托拉唑都以消旋体的形式用药。奥美拉唑、兰索拉唑、泮托拉唑对映体药效都存在差异,故建立两个对映体含量测定的分析方法十分有必要。目前拆分PPIs的色谱法有毛细管电泳法、高速逆流色谱法、高效液相色谱法。其中高效液相色谱( HPLC )法应用广泛,用此法拆分PPIs具有快速、简单、可靠、分离效果好、准确度高的优点。
本文旨在考察奥美拉唑对映体、兰索拉唑对映体、泮托拉唑对映体在多糖类手性色谱柱(Chiralpak AD柱、Chiralpak AS柱、Chiralcel OD柱和Chiralcel OJ柱)上的分离行为以及流动相对对映体分离的影响,并建立测定人血浆中奥美拉唑对映体浓度的高效液相色谱分析方法。
方法:
色谱条件色谱柱:Chiralpak AD柱(250 mm×4.6 mm,10μm,Daicel Chemicals)、Chiralcel OJ柱(250 mm×4.6 mm,10μm, Daicel Chemicals)、Chiralpak AS柱(250 mm×4.6 mm, 10μm, Daicel Chemicals)、Chiralcel OD柱(250 mm×4.6 mm, 10μm, Daicel Chemicals),氰基保护柱(4 mm×4 mm ,10μm ,江苏汉邦)。基本流动相:正己烷-异丙醇、正己烷-乙醇、正己烷-异丙醇-甲醇、正己烷-异丙醇-乙醇。紫外检测波长:奥美拉唑302 nm,兰索拉唑285 nm,泮托拉唑289 nm;流速:0.5-1.0 mL/min;柱温:25℃;进样量:100μL。
血浆样品含量测定条件:Chiralpak AD柱(250 mm×4.6 mm ,10μm, Daicel Chemicals),氰基保护柱(4 mm×4 mm,10μm,江苏汉邦);流动相:正己烷-乙醇(30:70 , v/v);流速0.5 mL/min;检测波长:302 nm;柱温:25℃;进样量:100μL。
结果:
奥美拉唑对映体、兰索拉唑对映体、泮托拉唑对映体在使用Chiralpak AS柱拆分时效果最好。在使用Chiralpak AD柱拆分奥美拉唑对映体时,流动相分别为异丙醇和乙醇时的洗脱顺序不同。高效液相色谱法测定人血浆中奥美拉唑对映体浓度的方法的相对回收率为(-)-(S)-奥美拉唑96.7%～100.4%,(+)-(R)-奥美拉唑97.4%～100.2%;日内RSD小于4.7%,日间RSD小于3.3%;奥美拉唑对映体在5～1000 ng/mL浓度范围内线性关系良好, (-)-(S)-奥美拉唑(n =5, r=0.9998),(+)-(R)-奥美拉唑(n=5, r=0.9997),最低检测浓度(S/N=3)为2 ng/mL。
结论:
本文建立的奥美拉唑、兰索拉唑、泮托拉唑对映体的拆分方法可用于质子泵抑制剂单一对映体的光学纯度测定、质量控制及立体选择性药代动力学研究;建立的人血浆中奥美拉唑对映体浓度的测定方法简单、可靠、灵敏度高、准确度好,可用于人血浆中奥美拉唑对映体人体药代动力学研究。
OBJECTIVE:
Proton pump inhititors (PPIs) are a group of drugs whose main action is a pronounced and long-lasting reduction of gastric acid production.The PPIs most used clinicaily in the treatment of acid-related diseases are omeprazole (OME), lansoprazole (LAN), pantoprazole (PAN).
All these PPIs have a stereogenic center at the sulfur atom .OME and PAN are clinically administered as a racemic mixture. Since the omeprazole,lansoprazole,pantoprazole enantiomers may have different physiological effects in biological systems, it is significance that both enantiomers could be determined and analysed, not only the racemates. PPIs have been performed by capillary chromatography (CE), supercritical fluid chromatography (SFC), enantioselective HPLC methods. HPLC method is a simple, rapid, reliable, selective, accurate method for the determination of PPIs.
The direct HPLC method for the separation of omeprazole, lansoprazole, pantoprazole enantiomers was carried on derivatized cellulose and amylose chiral stationary phase (Chiralpak AD column, Chiralpak AS column, Chiralcel OD column, Chiralcel OJ column) was studied. In this assay, a high sensitivity and selectivity HPLC method for the analysis and quantification of omeprazole enantiomers in human plasma was also established.
METHODS:
Chromatography conditions: column: Chiralpak AD column (250 mm×4.6 mm, 10μm, Daicel Chemical), Chiralcel OJ column (250 mm×4.6 mm,10μm, Daicel Chemicals), Chiralpak AS column (250 mm×4.6 mm , 10μm, Daicel Chemicals), Chiralcel OD column (250 mm×4.6 mm, 10μm, Daicel Chemicals). Mobile phase: hexane-isopropanol, hexane-ethanol,hexane-isopropanol-ethanol, hexane-isopropanol-methanol. The flow rate was 0.5-1mL/min. The absorbance wavelength of omeprazole, lansoprazole and pantoprazole was 302 nm, 285 nm, and 289 nm, respectively. The column temperature was 25℃and the injection volume was 100μL.
Plasma smples Chromatography conditions: Agilent BOND ODS-C18 Solid Phase Extraction (SPE) cartidges were used to extract the enantiomers from plasma samples and the chiral separation was carried on a Chiralpak AD column (250 mm×4.6 mm, 10μm, Daicel Chemical), with hexane-ethanol (30:70, v/v) as the mobile phase with the flow rate of 0.5 mL/min. The detection was carried out at 302 nm. The column temperature was 25℃and the injection volume was 100μL.
RESULTS:
The recoveris of (-)-(S)-omeprazole were between 96.7%～100.4%, and (+)-(R)-omeprazole were between 97.4%～100.2% in the determination of plasma samples. Intra- and inter-day precision values were lower than 3.3% and 4.7%, respectively. The linear ranges for (-)-(S)-omeprazole and (+)-(R)-omeprazole were 5~1000 ng/mL, (-)-(S)-omeprazole (n = 5, r = 0.9998), (+)-(R)-omeprazole (n = 5, r = 0.9997) with a detection limit of 2 ng/mL at a signal/noise ratio of 3.
CONCLUSION:
The established high-performance liquid chromatography separation of omeprazole, lansoprazole, pantoprazole enantiomers could be applied to the determination of optical purity, quality control and stereoselective pharmacokinetics research. This method presented in this assay is rapid, reliable, simple and high sensitivity with a satisfactory result in the study the pharmacokinetics of omeprazole enantiomers.
引文
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[48]催欣,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[J].分析化学杂志,2002, 30(12):1494～1496
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[1]陈立仁,蒋生祥,刘霞.高效液相色谱基础与实践[M].北京:科学出版社, 2001
[2]B.Martine,M.Philippe,R.Jean-Paul,et al.HPLC quantitation of the four stereois-omers of benzoxathiepin derivatives with cellulose phenyl type chiral stationary phase and circular dichroism detection[J].Journal of pharmacy biomedical analysis,2006,41(2):544～548
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[4]AM Thayer.Harnessing microreactions[J].Chemical and Engineering News, 2005,83(22):43～52
[5]A.M.Rouhi. Chiral chemistry[J].Chemical & engineering news ,2004,82(24):47～62
[6]Chiyo Yamamoto,Yoshio Okamoto.Optically Active Polymers for Chiral Separation[J].Bulletin of the Chemical Society of Japan, 2004, 77(2):227～257
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[18] Y. Okamoto, R. Aburatani, T. Fukumoto et al .Useful Chiral Stationary Phases for HPLC Amylose Tris(3,5-dimethylphenylcarbamate) and Tris(3,5-dichlorophenylcarbamate) Supported on Silica Gel[J].Chemistry Letters, 1987, 16(9):1857～1860
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[22] Michael Frohn, Xiaoming Zhou, Jian-Rong Zhang.Kinetic Resolution of Racemic Cyclic Olefins via Chiral Dioxirane[J].Journal of chemical society.1999,121 (33):7718～7719
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[1]陈立仁,蒋生祥,刘霞.高效液相色谱基础与实践[M].北京:科学出版社, 2001
[2]B.Martine,M.Philippe,R.Jean-Paul,et al.HPLC quantitation of the four stereois-omers of benzoxathiepin derivatives with cellulose phenyl type chiral stationary phase and circular dichroism detection[J].Journal of pharmacy biomedical analysis,2006,41(2):544～548
[3]Hava Caner, Efrat Groner, Liron Levy. Trends in the development of chiral drugs[J].drug discovery today, 2004, 9, (3):105～110
[4]AM Thayer.Harnessing microreactions[J].Chemical and Engineering News, 2005,83(22):43～52
[5]A.M.Rouhi. Chiral chemistry[J].Chemical & engineering news ,2004,82(24):47～62
[6]Chiyo Yamamoto,Yoshio Okamoto.Optically Active Polymers for Chiral Separation[J].Bulletin of the Chemical Society of Japan, 2004, 77(2):227～257
[7]Y Okamoto, E Yashima. Polysaccharide Derivatives for Chromatographic Separation of Enantiomers[J].Angewandte Chemie International Edition, 1998,37(8):1020～1043
[8]H.Y.Aboul-Enein,I.W.Wainer.The Impact of Stereochemistry on drug development and use, john Wiley,New York,1997
[9]G. Hesse, R. Hagel. Complete separation of a racemic mixture by elution chromatography on cellulose triacetate [J]. Chromatographia,1973, 6(6):277
[10] G. Blaschke.Chromatographic resolution of chiral drugs on polyamides and cellulose triacetate[J].Journal of liquid chromatography, 1986,9:341～368
[11] Gottfried Blaschke.Chromatographic Resolution of Chiral Drugs on Polyamides and Cellulose Triacetate[J].Journal of Liquid Chromatography & RelatedTechnologies, 1986,9(2):341～368
[12] T.Shibata, I.Okamoto,K.Ishii.Chromatographic Optical Resolution on Polysacc-harides and Their Derivatives[J].Journal of Liquid Chromatography & RelatedTechnologies, 1986, 9(2):313～340
[13] Y. Okamoto, M. Kawashima, K. Yamamoto,et al.Useful chiral packing materials for high-performance liquid chromatographic resolution cellulose triaceand tribenzoate coated on maroporous silica gel[J].Chemistry Letters 1984, 13(5):739～742
[14] Yoshio Okamoto, Mitsunobu Kawashima,Koichi Hatada. Chromatographic re-solution:XI Controlled chiral recognition of cellulose triphenylcarbamate deri-vatives supported on silica gel [J]. Journal of Chromatography A, 1986, 363(2):173～186
[15] Yoshio Okamoto, Ryo Aburatani, Koichi Hatada, Chromatographic chiral Resolution:XIV.Cellulose tribenzoate derivatives as chiral stationary phases for high-performance liquid chromatography [J].Journal of Chromatography A,1987, 389:95～102
[16] Y. Okamoto, M. Kawashima, K. Hatada. Chromatographic resolution 7 Useful chiral packing materials for high-performance liquid chromatographic resolution of enantiomers: phenylcarbamates of polysaccharides coated on silica gel[J]Journal of America Chemical Society,1984,106(18):5357～5359
[17] Y. Okamoto, M. Kawashima, K. Hatada.Chromatographic resolution:XI. Con-trolled chiral recognition of cellulose triphenylcarbamate derivatives supported on silica gel[J].Journal of Chromatography A, 1986,363(2):173～186
[18] Y. Okamoto, R. Aburatani, T. Fukumoto et al .Useful Chiral Stationary Phases for HPLC Amylose Tris(3,5-dimethylphenylcarbamate) and Tris(3,5-dichlorophenylcarbamate) Supported on Silica Gel[J].Chemistry Letters, 1987, 16(9):1857～1860
[19] I.W. Wainer, M.C. Alembik, Resolution of enantiomeric amides on a cellulose based chiral stationary phase:Steric and electronic effects[J].Journal of Chromatography A. 1986,358:85～93.
[20] I.W. Wainer, R.M. Stiffin, T. Shibata.Resolution of enantiomeric aromatic alcohols on a cellulose tribenzoate high-performance liquid chromatography chiral stationary phase:A proposed chiral recognition mechanism[J].Journal ofChromatography A. 1987, (411):139～151
[21] David Haigh, Helen C. Birrell, Barrie C. C. Non-thiazolidinedione antihyper-glycaemic agents Part 5:Asymmetric aldol synthesis of (S)-(-)-2-oxy-3-arylpropanoic acids[J].Tetrahedron: Asymmetry,1999, 10(7):1353～1367
[22] Michael Frohn, Xiaoming Zhou, Jian-Rong Zhang.Kinetic Resolution of Racemic Cyclic Olefins via Chiral Dioxirane[J].Journal of chemical society.1999,121 (33):7718～7719
[23] Y. Okamoto, Y. Kaida, H. Hayashida et al.[J]. Chemistry Letters,1990 ,902
[24] Y. Kaida and Y. Okamoto.Optical resolution by high-performance liquid chromatography on benzylcarbamates of cellulose and amylose[J].Journal of Chromatography A, 1993,641 (2):267～278
[25] Y.Okamoto,Yuriko kaida, Resolution by high-performance liquid chromatogr-aphy using polysaccharide carbamates and benzoates as chiral stationary ph-ases[J].Journal of Chromatography A,1994,666:404～419
[26] Y.Okamato,Y.Kaida,H.hayashida et al,Tris(1-phenylethylcarbamate)s of Cellu-lose and Amylose as Useful Chiral Stationary Phases for Chromatographic Optical Resolution[J].Chemistry Letters,1990,19:909
[27] Y.Okamoto,E.Yashima,Angew.Chem.Separation of enantiomers by HPLC[J].International Education English,1998, 37:1020～1043
[28] E.Yashima,C.Yamamoto,Y.Okamoto.Polysaccharide-Based Chiral LC Columns[J].Synlett, 1998(4):344～360
[29] Y.Okamoto,Y.Kaida.Resolution by high-performance liquid chromatography using polysaccharide carbamates and benzoates as chiral stationary phases[J].Journal of Chromatography A,1994,666(1-2):403～419
[30] U.Vogt, P.Zugenmaier.Structural Models for Some Liquid Crystalline Cellul-ose Derivatives[J].Berichte der Bunsengesellschaft für Physikalische Chemie,1985, 89(11):1217～1224