液质联用法测定人血浆中多潘立酮的浓度及其药代动力学的研究
摘要
本试验建立了液相色谱-串联质谱联用法(LC/MS/MS)测定了10名健康受试者单剂量口服试验制剂多潘立酮片剂(西安杨森制药有限公司生产)10 mg后,人血浆中不同时刻多潘立酮的浓度,绘制出了血药浓度-时间曲线。根据不同时刻的血药浓度数据,采用Topfit 2.0软件求算出主要的药代动力学参数。
试验中选用曲马多作为内标物,血浆样品经液-液萃取后,以甲醇:0.5%氨水(80:20,v/v)为流动相,采用Zorbax XDB-C8柱分离,通过API 4000型三重四极杆串联质谱仪以MRM方式进行检测。与国内外相关文献报导的检测方法相比,本试验所建立的LC/MS/MS法更为灵敏、快速且专属性强,更为重要的一点,本法仅需100μl的血浆样品即可进行定量分析,大大地减少了健康受试者所受的损伤,提高了受试者的顺应性。本方法线性范围为0.3-100 ng/ml,最低定量浓度为0.3 ng/ml,方法确证结果表明,本方法具有良好的精密度与准确度、提取回收率和稳定性,适合多潘立酮的人体药代动力学研究。
10名健康受试者单剂量口服试验制剂多潘立酮片剂10 mg后,血浆中多潘立酮的Tmax为0.60±0.30 h(平均值±标准差,下同);Cmax为11.20±4.83 ng/ml;t1/2为8.52±0.99 h;采用梯形法计算,AUC0-36分别为44.35±12.65 ng·h/ml,AUC0-∞分别为46.44±13.71 ng·h/ml。
OBJECTIVE: To develop a LC/MS/MS method for the determination of domperidone in human plasma and to study its pharmacokinetics in healthy volunteers .
METHOD: The analyte was extracted from plasma samples by liquid-liquid extraction, separated through a Zorbax XDB-C8 column and detected by tandem mass spectrometry with an electrospray ionization interface. The concentrations of domperidone in human plasma samples at different time points were determined by LC/MS/MS and the plasma concentrations-time profiles were obtained. The pharmacokinetic parameters were described by the obtained data. RESULTS: The assay was linear over the concentration range of 0.3?100 ng/ml with a limit of quantitation (LOQ) of 0.3 ng/ml. The inter- and intra-day precision and accuracy were within±15%. The main pharmacokinetic parameters were as follows: Cmax was 11.20±4.83 ng/ml occurring at 0.60±0.30 h, the mean plasma elimination half-life (t1/2) was 8.52±0.99 h and the AUC0?36 and AUC0?∞were 44.35±12.65 and 46.44±13.71 ng.h/ml, respectively.
CONCLUSION: The LC/MS/MS method was suitable for the pharmacokinetic study of domperidone in human with the advantage of specificity, sensitivity, accuracy and high speed.
试验中选用曲马多作为内标物,血浆样品经液-液萃取后,以甲醇:0.5%氨水(80:20,v/v)为流动相,采用Zorbax XDB-C8柱分离,通过API 4000型三重四极杆串联质谱仪以MRM方式进行检测。与国内外相关文献报导的检测方法相比,本试验所建立的LC/MS/MS法更为灵敏、快速且专属性强,更为重要的一点,本法仅需100μl的血浆样品即可进行定量分析,大大地减少了健康受试者所受的损伤,提高了受试者的顺应性。本方法线性范围为0.3-100 ng/ml,最低定量浓度为0.3 ng/ml,方法确证结果表明,本方法具有良好的精密度与准确度、提取回收率和稳定性,适合多潘立酮的人体药代动力学研究。
10名健康受试者单剂量口服试验制剂多潘立酮片剂10 mg后,血浆中多潘立酮的Tmax为0.60±0.30 h(平均值±标准差,下同);Cmax为11.20±4.83 ng/ml;t1/2为8.52±0.99 h;采用梯形法计算,AUC0-36分别为44.35±12.65 ng·h/ml,AUC0-∞分别为46.44±13.71 ng·h/ml。
OBJECTIVE: To develop a LC/MS/MS method for the determination of domperidone in human plasma and to study its pharmacokinetics in healthy volunteers .
METHOD: The analyte was extracted from plasma samples by liquid-liquid extraction, separated through a Zorbax XDB-C8 column and detected by tandem mass spectrometry with an electrospray ionization interface. The concentrations of domperidone in human plasma samples at different time points were determined by LC/MS/MS and the plasma concentrations-time profiles were obtained. The pharmacokinetic parameters were described by the obtained data. RESULTS: The assay was linear over the concentration range of 0.3?100 ng/ml with a limit of quantitation (LOQ) of 0.3 ng/ml. The inter- and intra-day precision and accuracy were within±15%. The main pharmacokinetic parameters were as follows: Cmax was 11.20±4.83 ng/ml occurring at 0.60±0.30 h, the mean plasma elimination half-life (t1/2) was 8.52±0.99 h and the AUC0?36 and AUC0?∞were 44.35±12.65 and 46.44±13.71 ng.h/ml, respectively.
CONCLUSION: The LC/MS/MS method was suitable for the pharmacokinetic study of domperidone in human with the advantage of specificity, sensitivity, accuracy and high speed.
引文
[1] 卫生部药典委员会. 中华人民共和国药典. 二部. 2000年版.
[2] 黄跃, 许鲁宁. 多潘立酮治疗8650例反流性食道炎和功能性消化不良的不良反应[J]. 中国新药与临床杂志, 1997, 16(3): 148-150.
[3] 朱人敏, 汪芳裕, 金鑫鑫等. 马来酸多潘立酮治疗功能性消化不良63例的II期临床试验[J]. 中国新药与临床杂志, 2005, 24(9): 697-700.
[4] Takahashi T, Kurosawa S, Wiley JW, et al. Mechanism for the gastrokinetic action of domperidone. In vitro studies in guinea pigs [J]. Gastroenterology, 1991, 101: 703-710.
[5] 李柏泉, 刘迎利. 多虑平和多潘立酮治疗功能性消化不良60例疗效观察[J]. 中国实用内科杂志, 2002, 22(3): 179.
[6] 许国铭, 邹多武, 侯晓华等. 多潘立酮及铝碳酸镁治疗胆汁反流性胃炎多中心临床观察[J]. 中华消化杂志, 2003, 23(5): 275-278.
[7] 郭建强, 李轶忻, 刘斌. 多潘立酮对慢性胃炎病人餐后近端胃容受性舒张的作用及临床意义[J]. 中华消化杂志, 2005, 25(3): 181-182.
[8] 孙振华, 李宝山, 陈梅. 多潘立酮、盐酸多塞平联合治疗功能性消化不良的疗效观察[J]. 中华消化杂志, 2003, 23(1): 55-56.
[9] 王国琪, 郑伟. 法莫替丁、呋喃唑酮、多潘立酮联合治疗胃、十二指肠溃疡72例分析[J]. 中国综合临床, 2006, 22(2): 113.
[10] Maton PN. Profile and assessment of GERD pharmacotherapy [J]. Cleve Clin J Med, 2003, 70(5): S51-S70.
[11] 从莉萍. 多潘立酮联合多塞平治疗功能性消化不良疗效观察[J]. 山东医学, 2006, 46(31): 32.
[12] 喻昌利, 高捷, 魏剑芬等. 抗胃食管反流药物治疗支气管哮喘合并胃食管反流的临床研究[J]. 临床荟萃, 2006, 21(20): 1502-1503.
[13] 寇继光, 钟敏华, 郑晓清等. 氟西汀联合多潘立酮治疗功能性消化不良的临床研究[J]. 新药学, 2004, 35(2): 85-86.
[14] 尹建明, 王敏, 张岑等. 奥美拉唑联合多潘立酮递减法治疗反流性食管炎疗效观察[J]. 临床荟萃, 2006, 22(4): 268.
[15] 郭建强, 谷成明. 多潘立酮的作用机制及临床应用新进展[J]. 中华内科杂志, 2001, 40(1): 58-61.
[16] 张云丽, 范锦辉, 刘艳凤等. 中西医结合治疗中重度反流性食管炎的探讨[J]. 中国综合临床, 2007, 23(1): 10-11.
[17] 卢永福. 唯泰颗粒联合多潘立酮治疗残胃炎的疗效观察[J]. 陕西医学杂志, 2005, 34(11): 1414-1415.
[18] Brogden RN, Carmine AA, Heel RC, et al. Domperidone, a review of its pharmacological activity, pharmacokinetics and therapeutic efficacy in the symptomatic treatment of chronic dyspepsia and as an antiemetic [J]. Drugs, 1982, 24: 360-600.
[19] Bradette M, Pare P, Douville P, et al. Visceral perception in health and functional dyspepsia. Crossover study of gastric distension with placebo and domperidone [J]. Dig Dis., 1991, 36: 52-58.
[20] 迟阿鲁, 李爱军, 孟庆秀. 促动力药多潘立酮、西沙比利的特点和不良反应[J]. 山东医学, 2004, 44(19): 75-76.
[21] 石刚, 吴硕东. 促胃肠动力药的作用机制及临床应用研究进展[J]. 世界华人消化杂志, 2006, 14(2): 189-196.
[22] Mastai R, Grande L, Bosch J, et al. Effects of metoclopramide and domperidone on azygos venous blood flow in patients with cirrhosis and portal hypertension [J]. Hepatology, 1986, 6: 1244-1247.
[23] 冀明. 功能性消化不良[J]. 中华内科杂志, 2000, 39(9): 645-646.
[24] 李淑德. 多潘立酮片治疗功能性消化不良的临床研究[J]. 中华消化杂志, 2003, 3(4): 220-222.
[25] Veldhuyzen van Zanten SJ, Jones MJ, Verlinden M, et al. Efficacy of cisapride and domperidone in functional dyspepsia: a meta-analysis [J]. Am J Gastroenterol, 2001, 96: 689-696.
[26] Finney JS, Kinnersley N, Hughes M, et al. Meta-analysis of antisecretory and gastronkinetic compounds in functional dyspepsia [J]. J Clin Gastroenterol, 1998, 26: 312-320.
[27] Grande L, Lacima G, Ros E, et al. Lack of effect of metoclopramide and domperidone on esophageal peristalsis and esophageal acid clearance in reflux esophagitis. A randomized, double-blind study [J]. Dig Dis Sci, 1992, 37: 583-588.
[28] Yin C.H., John L, Colaizzi, et al. Pharmacokinetics and dose proportionality of domperidone in healthy volunteers [J]. J Clin Pharmacol, 1986, 26: 628-632.
[29] Wang W., He S.P., Liu S.P., et al. Study on bioavailability of domperidone [J]. Chin J Clin Pharmacol, 1992, 8(1): 25-31.
[30] Maria Kobylinska, Kamila Kobylinska. High-performance liquid chromatographic analysis for the determination of domperidone in human plasma [J]. J. Chromatogr B, 2000, 744: 207-212.
[31] Yamamoto K, Hagino M, Kotaki H, et al. Quantitative determination of domperidone in rat plasma by high- performance liquid chromatography with fluorescence detection [J]. J. Chromatogr B, 1998, 720: 251-255.
[32] 柴栋, 方翼, 裴斐等. 单剂量口服多潘立酮片在健康人体的生物等效性[J]. 中国临床药理学杂志, 2005, 21(3): 190-193.
[33] Zavitsanos AP, Macdonald C, Basscoo E, et al. Determination of domperidone in human serum and human breast milk by high- performance liquid chromatography-electrospray mass spectrometry [J]. J.Chromatogr B, 1999, 730: 9-24.
[34] Smit MJ, Sutherland FCW, Hundt HKL, et al. Rapid and sensitive liquid chromatography-tandem mass spectrometry method for the quantitation of domperidone in human plasma [J]. J. Chromatogr A, 2002, 949: 65-70.
[35] Wu M.S., Gao L., Cai X.H., et al. Determination of domperidone in human plasma by LC-MS and its pharmacokinetics in healthy Chinese volunteers [J]. Acta Pharmacol Sin, 2002, 23(3): 285-288.
[36] 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[J]. 药物分析杂志, 1996,16(5): 306-312.
[37] Karnes HT, March C. Precision, accuracy, and data acceptance criteria in biopharmaceutical analysis. [J] Pharm Res., 1993, 10: 1420-1421.
[38] SFDA. 化学药品制剂人体药代动力学研究指导原则,2005.
[2] 黄跃, 许鲁宁. 多潘立酮治疗8650例反流性食道炎和功能性消化不良的不良反应[J]. 中国新药与临床杂志, 1997, 16(3): 148-150.
[3] 朱人敏, 汪芳裕, 金鑫鑫等. 马来酸多潘立酮治疗功能性消化不良63例的II期临床试验[J]. 中国新药与临床杂志, 2005, 24(9): 697-700.
[4] Takahashi T, Kurosawa S, Wiley JW, et al. Mechanism for the gastrokinetic action of domperidone. In vitro studies in guinea pigs [J]. Gastroenterology, 1991, 101: 703-710.
[5] 李柏泉, 刘迎利. 多虑平和多潘立酮治疗功能性消化不良60例疗效观察[J]. 中国实用内科杂志, 2002, 22(3): 179.
[6] 许国铭, 邹多武, 侯晓华等. 多潘立酮及铝碳酸镁治疗胆汁反流性胃炎多中心临床观察[J]. 中华消化杂志, 2003, 23(5): 275-278.
[7] 郭建强, 李轶忻, 刘斌. 多潘立酮对慢性胃炎病人餐后近端胃容受性舒张的作用及临床意义[J]. 中华消化杂志, 2005, 25(3): 181-182.
[8] 孙振华, 李宝山, 陈梅. 多潘立酮、盐酸多塞平联合治疗功能性消化不良的疗效观察[J]. 中华消化杂志, 2003, 23(1): 55-56.
[9] 王国琪, 郑伟. 法莫替丁、呋喃唑酮、多潘立酮联合治疗胃、十二指肠溃疡72例分析[J]. 中国综合临床, 2006, 22(2): 113.
[10] Maton PN. Profile and assessment of GERD pharmacotherapy [J]. Cleve Clin J Med, 2003, 70(5): S51-S70.
[11] 从莉萍. 多潘立酮联合多塞平治疗功能性消化不良疗效观察[J]. 山东医学, 2006, 46(31): 32.
[12] 喻昌利, 高捷, 魏剑芬等. 抗胃食管反流药物治疗支气管哮喘合并胃食管反流的临床研究[J]. 临床荟萃, 2006, 21(20): 1502-1503.
[13] 寇继光, 钟敏华, 郑晓清等. 氟西汀联合多潘立酮治疗功能性消化不良的临床研究[J]. 新药学, 2004, 35(2): 85-86.
[14] 尹建明, 王敏, 张岑等. 奥美拉唑联合多潘立酮递减法治疗反流性食管炎疗效观察[J]. 临床荟萃, 2006, 22(4): 268.
[15] 郭建强, 谷成明. 多潘立酮的作用机制及临床应用新进展[J]. 中华内科杂志, 2001, 40(1): 58-61.
[16] 张云丽, 范锦辉, 刘艳凤等. 中西医结合治疗中重度反流性食管炎的探讨[J]. 中国综合临床, 2007, 23(1): 10-11.
[17] 卢永福. 唯泰颗粒联合多潘立酮治疗残胃炎的疗效观察[J]. 陕西医学杂志, 2005, 34(11): 1414-1415.
[18] Brogden RN, Carmine AA, Heel RC, et al. Domperidone, a review of its pharmacological activity, pharmacokinetics and therapeutic efficacy in the symptomatic treatment of chronic dyspepsia and as an antiemetic [J]. Drugs, 1982, 24: 360-600.
[19] Bradette M, Pare P, Douville P, et al. Visceral perception in health and functional dyspepsia. Crossover study of gastric distension with placebo and domperidone [J]. Dig Dis., 1991, 36: 52-58.
[20] 迟阿鲁, 李爱军, 孟庆秀. 促动力药多潘立酮、西沙比利的特点和不良反应[J]. 山东医学, 2004, 44(19): 75-76.
[21] 石刚, 吴硕东. 促胃肠动力药的作用机制及临床应用研究进展[J]. 世界华人消化杂志, 2006, 14(2): 189-196.
[22] Mastai R, Grande L, Bosch J, et al. Effects of metoclopramide and domperidone on azygos venous blood flow in patients with cirrhosis and portal hypertension [J]. Hepatology, 1986, 6: 1244-1247.
[23] 冀明. 功能性消化不良[J]. 中华内科杂志, 2000, 39(9): 645-646.
[24] 李淑德. 多潘立酮片治疗功能性消化不良的临床研究[J]. 中华消化杂志, 2003, 3(4): 220-222.
[25] Veldhuyzen van Zanten SJ, Jones MJ, Verlinden M, et al. Efficacy of cisapride and domperidone in functional dyspepsia: a meta-analysis [J]. Am J Gastroenterol, 2001, 96: 689-696.
[26] Finney JS, Kinnersley N, Hughes M, et al. Meta-analysis of antisecretory and gastronkinetic compounds in functional dyspepsia [J]. J Clin Gastroenterol, 1998, 26: 312-320.
[27] Grande L, Lacima G, Ros E, et al. Lack of effect of metoclopramide and domperidone on esophageal peristalsis and esophageal acid clearance in reflux esophagitis. A randomized, double-blind study [J]. Dig Dis Sci, 1992, 37: 583-588.
[28] Yin C.H., John L, Colaizzi, et al. Pharmacokinetics and dose proportionality of domperidone in healthy volunteers [J]. J Clin Pharmacol, 1986, 26: 628-632.
[29] Wang W., He S.P., Liu S.P., et al. Study on bioavailability of domperidone [J]. Chin J Clin Pharmacol, 1992, 8(1): 25-31.
[30] Maria Kobylinska, Kamila Kobylinska. High-performance liquid chromatographic analysis for the determination of domperidone in human plasma [J]. J. Chromatogr B, 2000, 744: 207-212.
[31] Yamamoto K, Hagino M, Kotaki H, et al. Quantitative determination of domperidone in rat plasma by high- performance liquid chromatography with fluorescence detection [J]. J. Chromatogr B, 1998, 720: 251-255.
[32] 柴栋, 方翼, 裴斐等. 单剂量口服多潘立酮片在健康人体的生物等效性[J]. 中国临床药理学杂志, 2005, 21(3): 190-193.
[33] Zavitsanos AP, Macdonald C, Basscoo E, et al. Determination of domperidone in human serum and human breast milk by high- performance liquid chromatography-electrospray mass spectrometry [J]. J.Chromatogr B, 1999, 730: 9-24.
[34] Smit MJ, Sutherland FCW, Hundt HKL, et al. Rapid and sensitive liquid chromatography-tandem mass spectrometry method for the quantitation of domperidone in human plasma [J]. J. Chromatogr A, 2002, 949: 65-70.
[35] Wu M.S., Gao L., Cai X.H., et al. Determination of domperidone in human plasma by LC-MS and its pharmacokinetics in healthy Chinese volunteers [J]. Acta Pharmacol Sin, 2002, 23(3): 285-288.
[36] 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[J]. 药物分析杂志, 1996,16(5): 306-312.
[37] Karnes HT, March C. Precision, accuracy, and data acceptance criteria in biopharmaceutical analysis. [J] Pharm Res., 1993, 10: 1420-1421.
[38] SFDA. 化学药品制剂人体药代动力学研究指导原则,2005.