氯吡格雷及其非活性代谢物的比格犬体内药动学研究
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摘要
氯吡格雷是一种用于治疗急性冠脉综合征的抗血小板药物,与阿司匹林相比,有着更好的抑制血小板的效应,且能够显著的降低缺血事件的发生率,是减少心脑血管不良事件的重要药物。在文献查询过程中发现,国内外对于氯吡格雷及其代谢物的非临床研究数据很少,不利于相关制剂的进一步发展,因此展开此非临床药物动力学研究,以对其新剂型的开发研制提供更多的理论支持。
本文采用液相色谱-串联质谱法,对受试制剂氯吡格雷片和参比制剂波立维(?)进行比格犬体内药物动力学及生物利用度对照研究。受试制剂和参比制剂中氯吡格雷的达峰时间Tm积分别为1.7±0.7 h和1.9±0.6 h,最大血药浓度Cmax分别为1637.3±382.1 ng·mL-1和1663.0±472.2 ng·mL-1,血药浓度-时间曲线下面积AUC0-t分别为7622.8±2548.2 ng·h·mL-1和7876.6±2562.0 ng·h·mL-1,AUC0-∞分别为8128.5±2664.9 ng·h·mL-1和8563.4±2679.6 ng·h·mL-1。以AUC0-t计算,与参比制剂相比,受试制剂的相对生物利用度为99.3±25.5%。根据生物利用度和生物等效性试验的要求,受试制剂与参比制剂波立维(?)比较,AUC0-t、Cmax、Tmax符合生物等效性要求,但个体差异很大。
本文还建立了一种快速可靠的HPLC分析方法,对血浆内氯吡格雷羧酸代谢物(CRCA)的含量进行定量测定,并进行比格犬体内药物动力学研究。本方法以噻氯匹定为内标物质,以KH2PO4-乙腈(80：20,v／v,pH=4.0)为流动相,检测波长220 nm,流速1.2 mL·min-1,样品分析时间约9 min,线性范围在0.2-8μg·mL-1(r>0.99),以6只比格犬为研究对象,进行了氯吡格雷的药物动力学研究。受试制剂和参比制剂中氯吡格雷羧酸代谢物的达峰时间Tmax分别为1.7±0.7 h和1.8±1.2 h,最大血药浓度Cmax分别为4.1±1.5μg·mL-1和5.0±1.6μg·mL-1,血药浓度-时间曲线下面积AUC0-t分别为13.4±5.2μg·h·mL-1和12.9±5.4μg·h·mL-AUC0-∞分别为15.1±6.0μg·h·mL-1和14.6±5.9μg·h·mL-1。结果显示,本方法灵敏度高,在0.2-8μg·mL-1范围内线性良好且重现性好,分析时间短,满足日常分析的需求。
Clopidogrel is an antiplatelet prodrug for the therapy of acute coronary syndromes (ACS). Comparing to aspirin, clopidogrel has higher antiplatelet effect and could decrease the risk of ischemic events significantly. So it has being widely used in clinic to reduce adverse events of cardiovascular treatment. Few studies have been reported for its non-clinical pharmacokinetics and as a consequence being an obstacle of new dosage form development. As a result, we perform this study, to satisfy the research interest and support further studies of clopidogrel.
We perform study on pharmacokinetics of beagle dogs between testing drug clopidogrel bisulfate tablets and reference drug PLAVIX R using LC-MS/MS method. The time to peak (Tmax) of clopidogrel in testing and reference preparations are 1.7±0.7 h and 1.9±0.6 h; The maximum of concentration (Cmax) in plasma are 1637.3±382.1 ng·ml-1 and 1663.0±472.2 ng·mL-1. Calculated with trapezoidal rule, the area under concentration-time curve (AUC0-t) are 7622.8±2548.2 ng·h·ml-1 and 7876.6±2562.0 ng·h·mL-1; AUC0-∞are 8128.5±2664.9 ng·h·mL-1 and 8563.4±2679.6 ng-h-mL-1. Calculated with AUC0-t, the bioavailability of testing drug is 99.3±25.5% comparing to reference drug. According to the regulations of bioavailability and bioequivalence, we conclude that, comparing to reference drug PLAVIXR, the bioequivalence data (AUC0-t, Cmax and Tmax) of testing drug are acceptable, but have significant difference between individuals.
We have also developed a sensitive, simple and rapid method for determination of clopidogrel carboxylic acid metabolite, and this method is successfully used to study pharmacokinetics of beagle dogs between testing drug clopidogrel bisulfate tablets and reference drug PLAVIXR. In this Method, we use ticlopidine as internal standard substance, KH2PO4-acetonitrile (80:20, v/v, pH=4.0) as mobile phase, with UV detection at 220 run. The flow rate is 1.2 mL-min-1 and the total run time of analysis is about 9 min. The method is linear over the range of 0.2-8μg-mL"1 (r> 0.99). Double phase crossover experiment between two preparations is designed, and six beagle dogs are administered to determine those plasma concentrations in vivo. The time to peak (Tmax) of clopidogrel in testing and reference preparations are 1.7±0.7 h and 1.8±1.2 h; The maximum of concentration (Cmax) in plasma are 4.1±1.5μg-mL-1 and 5.0±1.6μg-mL-1. Calculated with trapezoidal rule, the area under concentration-time curve (AUC0-t) are 13.4±5.2μg-h-mL-1and 12.9 ±5.4μg·h·mL"1; AUC0-∞are 15.1±6.0μg·h·mL-1 and 14.6±5.9μg·h·mL-1. The method we provide has high sensitivity, good linearity and reproducibility, and that it can be used for the rapid and reliable determination of clopidogrel metabolite in plasma in pharmacokinetic studies.
本文采用液相色谱-串联质谱法,对受试制剂氯吡格雷片和参比制剂波立维(?)进行比格犬体内药物动力学及生物利用度对照研究。受试制剂和参比制剂中氯吡格雷的达峰时间Tm积分别为1.7±0.7 h和1.9±0.6 h,最大血药浓度Cmax分别为1637.3±382.1 ng·mL-1和1663.0±472.2 ng·mL-1,血药浓度-时间曲线下面积AUC0-t分别为7622.8±2548.2 ng·h·mL-1和7876.6±2562.0 ng·h·mL-1,AUC0-∞分别为8128.5±2664.9 ng·h·mL-1和8563.4±2679.6 ng·h·mL-1。以AUC0-t计算,与参比制剂相比,受试制剂的相对生物利用度为99.3±25.5%。根据生物利用度和生物等效性试验的要求,受试制剂与参比制剂波立维(?)比较,AUC0-t、Cmax、Tmax符合生物等效性要求,但个体差异很大。
本文还建立了一种快速可靠的HPLC分析方法,对血浆内氯吡格雷羧酸代谢物(CRCA)的含量进行定量测定,并进行比格犬体内药物动力学研究。本方法以噻氯匹定为内标物质,以KH2PO4-乙腈(80：20,v／v,pH=4.0)为流动相,检测波长220 nm,流速1.2 mL·min-1,样品分析时间约9 min,线性范围在0.2-8μg·mL-1(r>0.99),以6只比格犬为研究对象,进行了氯吡格雷的药物动力学研究。受试制剂和参比制剂中氯吡格雷羧酸代谢物的达峰时间Tmax分别为1.7±0.7 h和1.8±1.2 h,最大血药浓度Cmax分别为4.1±1.5μg·mL-1和5.0±1.6μg·mL-1,血药浓度-时间曲线下面积AUC0-t分别为13.4±5.2μg·h·mL-1和12.9±5.4μg·h·mL-AUC0-∞分别为15.1±6.0μg·h·mL-1和14.6±5.9μg·h·mL-1。结果显示,本方法灵敏度高,在0.2-8μg·mL-1范围内线性良好且重现性好,分析时间短,满足日常分析的需求。
Clopidogrel is an antiplatelet prodrug for the therapy of acute coronary syndromes (ACS). Comparing to aspirin, clopidogrel has higher antiplatelet effect and could decrease the risk of ischemic events significantly. So it has being widely used in clinic to reduce adverse events of cardiovascular treatment. Few studies have been reported for its non-clinical pharmacokinetics and as a consequence being an obstacle of new dosage form development. As a result, we perform this study, to satisfy the research interest and support further studies of clopidogrel.
We perform study on pharmacokinetics of beagle dogs between testing drug clopidogrel bisulfate tablets and reference drug PLAVIX R using LC-MS/MS method. The time to peak (Tmax) of clopidogrel in testing and reference preparations are 1.7±0.7 h and 1.9±0.6 h; The maximum of concentration (Cmax) in plasma are 1637.3±382.1 ng·ml-1 and 1663.0±472.2 ng·mL-1. Calculated with trapezoidal rule, the area under concentration-time curve (AUC0-t) are 7622.8±2548.2 ng·h·ml-1 and 7876.6±2562.0 ng·h·mL-1; AUC0-∞are 8128.5±2664.9 ng·h·mL-1 and 8563.4±2679.6 ng-h-mL-1. Calculated with AUC0-t, the bioavailability of testing drug is 99.3±25.5% comparing to reference drug. According to the regulations of bioavailability and bioequivalence, we conclude that, comparing to reference drug PLAVIXR, the bioequivalence data (AUC0-t, Cmax and Tmax) of testing drug are acceptable, but have significant difference between individuals.
We have also developed a sensitive, simple and rapid method for determination of clopidogrel carboxylic acid metabolite, and this method is successfully used to study pharmacokinetics of beagle dogs between testing drug clopidogrel bisulfate tablets and reference drug PLAVIXR. In this Method, we use ticlopidine as internal standard substance, KH2PO4-acetonitrile (80:20, v/v, pH=4.0) as mobile phase, with UV detection at 220 run. The flow rate is 1.2 mL-min-1 and the total run time of analysis is about 9 min. The method is linear over the range of 0.2-8μg-mL"1 (r> 0.99). Double phase crossover experiment between two preparations is designed, and six beagle dogs are administered to determine those plasma concentrations in vivo. The time to peak (Tmax) of clopidogrel in testing and reference preparations are 1.7±0.7 h and 1.8±1.2 h; The maximum of concentration (Cmax) in plasma are 4.1±1.5μg-mL-1 and 5.0±1.6μg-mL-1. Calculated with trapezoidal rule, the area under concentration-time curve (AUC0-t) are 13.4±5.2μg-h-mL-1and 12.9 ±5.4μg·h·mL"1; AUC0-∞are 15.1±6.0μg·h·mL-1 and 14.6±5.9μg·h·mL-1. The method we provide has high sensitivity, good linearity and reproducibility, and that it can be used for the rapid and reliable determination of clopidogrel metabolite in plasma in pharmacokinetic studies.
引文
[1]Fuster V, Badimon L, Badimon J, et al. The pathogenesis of coronary artery disease and the acute coronary syndromes (first of two parts) [J]. The New England Journal of Medicine,1992,326:242-250.
[2]Ibid (second of two parts) [J]. The New England Journal of Medicine,1992,326:310-318.
[3]柯元南.急性冠脉综合征诊断和治疗进展[J].中华老年心脑血管病杂志,2006,8：2-4.
[4]孙忠实,朱珠,肖燕萍.抗血小板药物的合理应用(一)[J].中国药物警戒,2007,4：240-244.
[5]US Preventive Services Task Force. Aspirin for the primary prevention of cardiovascular event: Recommendation and rationales [J]. Annals of Internal Medicine,2002,136:157-160.
[6]Caprie Steering Committee. A randomized, blinded, trial of clopidogrel versus aspirin in patients at risk for ischemic event (CAPRIE) [J]. The Lancet,1996,348:1329-1339.
[7]王应志,吕吉元,王睿.氯吡格雷抵抗与临床应用[J].中西医结合心脑血管病杂志,2006,4：327-329.
[8]Clarke TA, Waskell LA. Themetabolism of clopidogrel is catalyzed by human cytochrome P450 3A and is inhibited by atorvastatin [J]. Drug Metabolism and Disposition,2003,31:53-59.
[9]Cha JK, Jeong MH, Lee KM, et al. Changes in platelet P-selection and in plasma C-reactive protein in acute atherosclerotic ischemic stroke treated with a loading dose of clopidogrel [J]. Journal of Thrombosis and Thrombolysis,2002,14:145-150.
[10]Yusuf S, Zhao F, Mehta SR, et al. Effects of clopidogrel in addition to aspirin in patients with acute coronary syndromes without ST-segment elevation [J]. The New England Journal of Medicine,2001,345: 494-502.
[11]Mehta SR, Yusuf S, Peters RJG, et al. Effects of pretreatment with clopidogrel and aspirin followed by long-term therapy in patients undergoing percutaneous coronary intervention:the PCI-CURE study [J]. The Lancet,2001,358:527-533.
[12]Steinhubl SR, Berger PB, Mann JT III, et al. Early and sustained dual oral antiplatelet therapy following percutaneous coronary intervention [J]. Journal of the American Medical Association,2002,288:2411-20.
[13]鲁胜.氯吡格雷在抗血小板治疗中的临床应用[J].医学综述,2008,16：2505-2508.
[14]陈玉国,孙伟,张远,等.氯吡格雷对非ST抬高急性冠脉综合症病人炎症因子及其预后影响[J].中国新药与临床杂志,2006,25：413-416.
[15]韩万隆,许勇.氯吡格雷在抗血小板治疗中的临床应用[J].安徽医药,2008,7：662.
[16]Chew DP, Bhatt DL, Robbins MA, et al. Effect of clopidogrel added to aspirin before percutaneous coronary intervention on the risk associated with C-reactive protein [J]. American Journal of Cardiology, 2001,88:672-674.
[17]Steinbubl SR, Berger PB, Mann JT, et al. Early and sustain dual oral antiplatelet therapy following percutaneous coronary intervention:a randomized controlled trial [J]. Journal of the American Medical Association,2002,288:2411-2420.
[18]罗心平,施海明,倪唤春,等.负荷剂量的氯吡格雷在38例急性心肌梗死直接支架术中的应用[J].中国新药与临床杂志,2004,23：667-670.
[19]Fraker TD Jr, Fihn SD,2002 Chronic Stable Angina Writing Committee, et al.2007 chronic angina focused update of the ACC/AHA 2002 guidelines for the management of patients with chronic stable angina:a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines Writing Group to develop the focused update of the 2002 guidelines for the management of patients with chronic stable angina [J]. Journal of the American College of Cardiology,2007,50: 2264-2274.
[20]Patti G, Colonna G, Pasceri V, et al. Randomized trial of high loading dose of clopidogrel for reduction of periprocedural myocardial infarction in patients undergoing coronary intervention. Results from the ARMYDA-2 (Antiplatelet therapy for Reduction of Myocardial Damage during Angioplasty) study. Circulation,2005 Mar 6.
[21]王应志,吕吉元,王睿.氯吡格雷抵抗与临床应用[J].中西医结合心脑血管病杂志,2006.
[22]P Lagorce, Y Perez, J Ortiz, et al. Assay method for the carboxylic acid metabolite of clopidogrel in human plasma by gas chromatography-mass spectrometry [J]. Journal of Chromatography B,1998,720:107-117.
[23]D Taubert, A Kastrati, S Harlfinger, et al. Pharmacokinetics of clopidogrel after administration of hish loading dose [J]. Thrombosis and Haemostasis,2004,92:311.
[24]A Lainesse, Y Ozalp, H Wong, et al. Bioequivalence Study of Clopidogrel Bisulfate Film-coated Tablets [J], Arzneimittel-Forschung/Drug Research,2004,54:600.
[25]Ramakrishna VS Nirogi, Vishwottam N Kandikere, Manoj Shukla, et al. Quantification of clopidogrel in human plasma by sensitive liquid chromatography/tandem mass spectrometry [J]. Rapid Communications in Mass Spectrometry,2006,20:1695-1700.
[26]Ksycinska H, Rudzki P, Bukowska-Kiliszek M, et al. Determination of clopidogrel metabolite (SR26334) in human by LC-MS [J]. Journal of Pharmaceutical and Biomedical Analysis,2006,41(2):533.
[27]A Robinson, J Hillis, C Neal, et al. The validation of a bioanalytical method for the determination of clopidogrel in human plasma [J]. Journal of Chromatography B,2007,848:344-354.
[28]Reist M, Roy-De Vos M, Montseny JP. Very slow chiral inversion of clopidogrel in rats:a pharmacokinetics and mechanistic investigation [J]. Drug Metabolism and Disposition 2000,28(12):1405.
[29]D Agbaba, D Antic, S Filipic. A simple and sensitive TLC method for determination of clopidogrel and its impurity SR 26334 in pharmaceutical products [J]. Acta Chromatographica,2007,18:199-206.
[30]Singh SS, Sharma K, Barot D, et al. Estimation of carboxylic acid metabolite of clopidogrel in Wister rat plasma by HPLC and its application to a pharmacokinetic study [J]. Journal of Chromatography B,2005, 821:173.
[31]Effat Souri, Hassan Jalalizadeh, Abbas Kebriaee-Zadeh, et al. Validated HPLC method for determination of carboxylic acid metabolite of clopidogrel in human plasma and its application to a pharmacokinetic study [J]. Biomedical Chromatography,2006,20:1309-1314.
[32]Gholamreza Bahrami, Bahareh Mohammadia, Sajjad Sisakhtnezhad. High-performance liquid chromatographic determination of inactive carboxylic acid metabolite of clopidogrel in human serum: Application to a bioequivalence study [J]. Journal of Chromatography B,2008,864:168-172.
[33]国家食品药品监督管理局.化学药物制剂人体生物利用度和生物等效性研究技术指导原则.2005年3月.
[34]国家食品药品监督管理局.化学药物和生物制品临床试验的生物统计学技术指导原则.2005年3月.
[35]A Mitakos, I Panderi. A validated LC method for the determination of clopidogrel in pharmaceutical preparations [J]. Journal of Pharmaceutical and Biomedical Analysis.2002,28:43-438.
[36]L Dal Bo, F Verga, A MaTzo. Determination of ticlopidine in human plasma by high performance liquid chromatography and ultraviolet absorbance detection [J]. Journal of Chromatography B,1995,665: 404-409.
[37]PLAVIXR-clopidogrel bisulfate tablets. http://products.sanofi-aventis.us/plavix/plavix.html.
[2]Ibid (second of two parts) [J]. The New England Journal of Medicine,1992,326:310-318.
[3]柯元南.急性冠脉综合征诊断和治疗进展[J].中华老年心脑血管病杂志,2006,8：2-4.
[4]孙忠实,朱珠,肖燕萍.抗血小板药物的合理应用(一)[J].中国药物警戒,2007,4：240-244.
[5]US Preventive Services Task Force. Aspirin for the primary prevention of cardiovascular event: Recommendation and rationales [J]. Annals of Internal Medicine,2002,136:157-160.
[6]Caprie Steering Committee. A randomized, blinded, trial of clopidogrel versus aspirin in patients at risk for ischemic event (CAPRIE) [J]. The Lancet,1996,348:1329-1339.
[7]王应志,吕吉元,王睿.氯吡格雷抵抗与临床应用[J].中西医结合心脑血管病杂志,2006,4：327-329.
[8]Clarke TA, Waskell LA. Themetabolism of clopidogrel is catalyzed by human cytochrome P450 3A and is inhibited by atorvastatin [J]. Drug Metabolism and Disposition,2003,31:53-59.
[9]Cha JK, Jeong MH, Lee KM, et al. Changes in platelet P-selection and in plasma C-reactive protein in acute atherosclerotic ischemic stroke treated with a loading dose of clopidogrel [J]. Journal of Thrombosis and Thrombolysis,2002,14:145-150.
[10]Yusuf S, Zhao F, Mehta SR, et al. Effects of clopidogrel in addition to aspirin in patients with acute coronary syndromes without ST-segment elevation [J]. The New England Journal of Medicine,2001,345: 494-502.
[11]Mehta SR, Yusuf S, Peters RJG, et al. Effects of pretreatment with clopidogrel and aspirin followed by long-term therapy in patients undergoing percutaneous coronary intervention:the PCI-CURE study [J]. The Lancet,2001,358:527-533.
[12]Steinhubl SR, Berger PB, Mann JT III, et al. Early and sustained dual oral antiplatelet therapy following percutaneous coronary intervention [J]. Journal of the American Medical Association,2002,288:2411-20.
[13]鲁胜.氯吡格雷在抗血小板治疗中的临床应用[J].医学综述,2008,16：2505-2508.
[14]陈玉国,孙伟,张远,等.氯吡格雷对非ST抬高急性冠脉综合症病人炎症因子及其预后影响[J].中国新药与临床杂志,2006,25：413-416.
[15]韩万隆,许勇.氯吡格雷在抗血小板治疗中的临床应用[J].安徽医药,2008,7：662.
[16]Chew DP, Bhatt DL, Robbins MA, et al. Effect of clopidogrel added to aspirin before percutaneous coronary intervention on the risk associated with C-reactive protein [J]. American Journal of Cardiology, 2001,88:672-674.
[17]Steinbubl SR, Berger PB, Mann JT, et al. Early and sustain dual oral antiplatelet therapy following percutaneous coronary intervention:a randomized controlled trial [J]. Journal of the American Medical Association,2002,288:2411-2420.
[18]罗心平,施海明,倪唤春,等.负荷剂量的氯吡格雷在38例急性心肌梗死直接支架术中的应用[J].中国新药与临床杂志,2004,23：667-670.
[19]Fraker TD Jr, Fihn SD,2002 Chronic Stable Angina Writing Committee, et al.2007 chronic angina focused update of the ACC/AHA 2002 guidelines for the management of patients with chronic stable angina:a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines Writing Group to develop the focused update of the 2002 guidelines for the management of patients with chronic stable angina [J]. Journal of the American College of Cardiology,2007,50: 2264-2274.
[20]Patti G, Colonna G, Pasceri V, et al. Randomized trial of high loading dose of clopidogrel for reduction of periprocedural myocardial infarction in patients undergoing coronary intervention. Results from the ARMYDA-2 (Antiplatelet therapy for Reduction of Myocardial Damage during Angioplasty) study. Circulation,2005 Mar 6.
[21]王应志,吕吉元,王睿.氯吡格雷抵抗与临床应用[J].中西医结合心脑血管病杂志,2006.
[22]P Lagorce, Y Perez, J Ortiz, et al. Assay method for the carboxylic acid metabolite of clopidogrel in human plasma by gas chromatography-mass spectrometry [J]. Journal of Chromatography B,1998,720:107-117.
[23]D Taubert, A Kastrati, S Harlfinger, et al. Pharmacokinetics of clopidogrel after administration of hish loading dose [J]. Thrombosis and Haemostasis,2004,92:311.
[24]A Lainesse, Y Ozalp, H Wong, et al. Bioequivalence Study of Clopidogrel Bisulfate Film-coated Tablets [J], Arzneimittel-Forschung/Drug Research,2004,54:600.
[25]Ramakrishna VS Nirogi, Vishwottam N Kandikere, Manoj Shukla, et al. Quantification of clopidogrel in human plasma by sensitive liquid chromatography/tandem mass spectrometry [J]. Rapid Communications in Mass Spectrometry,2006,20:1695-1700.
[26]Ksycinska H, Rudzki P, Bukowska-Kiliszek M, et al. Determination of clopidogrel metabolite (SR26334) in human by LC-MS [J]. Journal of Pharmaceutical and Biomedical Analysis,2006,41(2):533.
[27]A Robinson, J Hillis, C Neal, et al. The validation of a bioanalytical method for the determination of clopidogrel in human plasma [J]. Journal of Chromatography B,2007,848:344-354.
[28]Reist M, Roy-De Vos M, Montseny JP. Very slow chiral inversion of clopidogrel in rats:a pharmacokinetics and mechanistic investigation [J]. Drug Metabolism and Disposition 2000,28(12):1405.
[29]D Agbaba, D Antic, S Filipic. A simple and sensitive TLC method for determination of clopidogrel and its impurity SR 26334 in pharmaceutical products [J]. Acta Chromatographica,2007,18:199-206.
[30]Singh SS, Sharma K, Barot D, et al. Estimation of carboxylic acid metabolite of clopidogrel in Wister rat plasma by HPLC and its application to a pharmacokinetic study [J]. Journal of Chromatography B,2005, 821:173.
[31]Effat Souri, Hassan Jalalizadeh, Abbas Kebriaee-Zadeh, et al. Validated HPLC method for determination of carboxylic acid metabolite of clopidogrel in human plasma and its application to a pharmacokinetic study [J]. Biomedical Chromatography,2006,20:1309-1314.
[32]Gholamreza Bahrami, Bahareh Mohammadia, Sajjad Sisakhtnezhad. High-performance liquid chromatographic determination of inactive carboxylic acid metabolite of clopidogrel in human serum: Application to a bioequivalence study [J]. Journal of Chromatography B,2008,864:168-172.
[33]国家食品药品监督管理局.化学药物制剂人体生物利用度和生物等效性研究技术指导原则.2005年3月.
[34]国家食品药品监督管理局.化学药物和生物制品临床试验的生物统计学技术指导原则.2005年3月.
[35]A Mitakos, I Panderi. A validated LC method for the determination of clopidogrel in pharmaceutical preparations [J]. Journal of Pharmaceutical and Biomedical Analysis.2002,28:43-438.
[36]L Dal Bo, F Verga, A MaTzo. Determination of ticlopidine in human plasma by high performance liquid chromatography and ultraviolet absorbance detection [J]. Journal of Chromatography B,1995,665: 404-409.
[37]PLAVIXR-clopidogrel bisulfate tablets. http://products.sanofi-aventis.us/plavix/plavix.html.
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