高脂餐对多潘立酮在中国健康受试者体内药代动力学行为的影响
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摘要
目的研究高脂餐对多潘立酮片在中国健康受试者体内药代动力学行为的影响。方法采用随机、开放、双周期交叉试验设计,17名健康受试者各自在空腹及高脂餐后30 min后单剂量口服多潘立酮片1片(规格:10 mg/片),于给药前及给药后0.17、0.33、0.5、0.75、1、1.5、2、2.5、3、4、6、8、10、12、24、48 h收集血液样品并提取血浆,血浆样品经蛋白沉淀法处理后采用LC-MS/MS法进行检测,使用DAS 3.2.2计算主要药代动力学参数,使用SPSS 24软件对主要药代动力学参数进行统计分析。结果人血浆中多潘立酮在0.104～40.0μg/L范围内线性关系良好;受试者空腹及高脂餐后口服多潘立酮片后的主要药代动力学数据为:Cmax分别为(18.41±6.96)及(14.52±5.79)μg/L,Tmax分别为(0.70±0.33)及(1.70±1.10)h,T1/2分别为(10.48±2.01)及(9.52±1.33)h,AUC0-t分别为(62.96±21.71)及(78.25±17.74)μg·h/L,AUC0-∞分别为(65.34±22.13)及(80.10±17.87)μg·h/L。对空腹与高脂餐后给药的主要药动学参数采用配对t检验进行统计分析,两者Cmax及T1/2无显著性差异,高脂餐组Tmax明显延后(P<0.01),AUC显著升高(P<0.05)。结论高脂饮食可显著延后多潘立酮的达峰时间,并可明显提高多潘立酮的生物利用度。
Objective To investigate the effect of high-fat meal on the pharmacokinetics of domperidone(Dom)in healthy Chinese volunteers after single oral dose of Dom tablet. Methods According to a random opening,two-period crossover design,17 healthy volunteers received a 10 mg dose of Dom tablet before and after a high-fat meal. The blood sample was collected prior to dosing and at the 0.17,0.33,0.5,0.75,1,1.5,2,2.5,3,4,6,8,10,12,24,and 48 h of dosing. The plasma samples were prepared by the protein precipitation method. The concentrations of Dom in plasma were determined by LC-MS/MS. The main pharmacokinetic parameters were calculated with the DAS 3.2.2 software. The statistical analysis was carried out with the SPSS 24 software. Results The calibration curve of Dom in human plasma showed a good linearity within the concentration range of 0.104-40.0 μg/L. The main pharmacokinetic parameters for the Dom dosed before and after a high-fat meal were as follows:Cmax(18.41±6.96)and(14.52±5.79)μg/L,Tmax(0.70±0.33)and(1.70±1.1)h,T1/2(10.48±2.01)and(9.52±1.33)h,AUC0-t(62.96±21.71)and(78.25±17.74)μg·h/L,and AUC0-∞(65.34±22.13)and(80.10±17.87)μg·h/L,respectively. The paired-sample t-test was performed for the statistical analysis of the pharmacokinetic parameters for the fasting and high-fat meal groups. There was no significant difference in Cmaxand T1/2,while the difference in Tmax(P<0.01),AUC0-tand AUC0-∞(P<0.05)were significant,all between the two groups. Conclusions High-fat meal could significantly delay the time to reach maximal concentration of Dom and increase the bioavailability of Dom.
Objective To investigate the effect of high-fat meal on the pharmacokinetics of domperidone(Dom)in healthy Chinese volunteers after single oral dose of Dom tablet. Methods According to a random opening,two-period crossover design,17 healthy volunteers received a 10 mg dose of Dom tablet before and after a high-fat meal. The blood sample was collected prior to dosing and at the 0.17,0.33,0.5,0.75,1,1.5,2,2.5,3,4,6,8,10,12,24,and 48 h of dosing. The plasma samples were prepared by the protein precipitation method. The concentrations of Dom in plasma were determined by LC-MS/MS. The main pharmacokinetic parameters were calculated with the DAS 3.2.2 software. The statistical analysis was carried out with the SPSS 24 software. Results The calibration curve of Dom in human plasma showed a good linearity within the concentration range of 0.104-40.0 μg/L. The main pharmacokinetic parameters for the Dom dosed before and after a high-fat meal were as follows:Cmax(18.41±6.96)and(14.52±5.79)μg/L,Tmax(0.70±0.33)and(1.70±1.1)h,T1/2(10.48±2.01)and(9.52±1.33)h,AUC0-t(62.96±21.71)and(78.25±17.74)μg·h/L,and AUC0-∞(65.34±22.13)and(80.10±17.87)μg·h/L,respectively. The paired-sample t-test was performed for the statistical analysis of the pharmacokinetic parameters for the fasting and high-fat meal groups. There was no significant difference in Cmaxand T1/2,while the difference in Tmax(P<0.01),AUC0-tand AUC0-∞(P<0.05)were significant,all between the two groups. Conclusions High-fat meal could significantly delay the time to reach maximal concentration of Dom and increase the bioavailability of Dom.
引文
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[8]余鹏,阳国平,冉黎灵,等. LC-MS/MS法测定人血浆中多潘立酮的浓度[J].药物分析杂志,2011,31(4):619-624.
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[13] Hussein R,Lockyer M,Yusuf A,et al. Bioequivalence assessment of two domperidone tablet formulations[J]. Acta Pharmacol Sin,2007,57(5):269.
[14] Wang X,Qin F,Jing L,et al. Development and validation of UPLC-MS/MS method for determination of domperidone in human plasma and its pharmacokinetic application[J]. Biomed Chromatogr,2013,27(3):371-376.
[15]张欣,戴青,陈勇川,等. HPLC法检测人血浆中多潘立酮浓度及其药代动力学研究[J].中国医药导刊,2011,13(5):908-909.
[16] Zhang Y,Chen X,Dai X,et al. Influence of omeprazole on pharmacokinetics of domperidone given as free base and maleate salt in healthy Chinese patients[J]. Acta Pharmacol Sin,2007,28(8):1243-1246.
[17] Khan A,Lqbal Z,Khadra I,et al. Simultaneous determination of domperidone and itopride in pharmaceuticals and human plasma using RP-HPLC/UV detection:method development,validation and application of the method in in-vivo evaluation of fast dispersible tablets[J]. J Pharm Biomed Anal,2016,121:6-12.
[18] Heykants J,Hendriks R,Mwuldermans W,et al. On the pharmacokinetics of domperidone in animals and manⅣ. The pharmacokinetics of intravenous domperidone and its bioavailability in man following intramuscular,oral and rectal administration[J]. Eur J Drug Metab Ph,1981,6(1):61-70.
[19]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):343-346.
[20]国家药典委员会.生物样品定量分析验证指导原则[S].北京:中华人民共和国药典(2015年版).附录9012:363-368.
[21] Huang YC,Colaizzi JL,Bierman RH,et al. Pharmacokinetics and dose proportionality of domperidone in healthy volunteers[J]. J Clin Pharmacol,1986,26(8):628-632.
[22] Charman WN,Porter CJH,Mithani S,et al. Physicochemical and physiological mechanisms for the effects of food on drug absorption:the role of lipids and pH[J]. J Pharm Sci-us,1997,86(3):269-282.
[23] Rocha CMG,Barbosa MM. QT interval prolongation associated with the oral use of domperidone in an infant[J]. Pediatr Cardiol,2005,26(5):720-723.
[24] Ward BA,Morocho A,Kandil A,et al. Characterization of human cytochrome P450 enzymes catalyzing domperidone N-dealkylation and hydroxylation in vitro[J]. Br J Clin Pharmacol,2004,58(3):277-287.
[2] Laduron PM,Leysen JE. Domperidone,a specific in vitro dopamine antagonist,devoid of in vivo central dopaminergic activity[J]. Biochem Pharmacol,1979,28(14):2161-2165.
[3] European Medicines Agency,Pharmacovigilance Risk Assessment Committee. Domperidone assessment report[EB/OL].(2014)[2018-11-12]. http://www.ema.europa.eu/docs/en_GB/document_library/Referrals_document/Domperidone_31/Recommendation_provided_by_Pharmacovigilance_Risk_Assessment_Committee/WC500168926.pdf
[4] Kobylińska M,Kobylińska K. High-performance liquid chromatographic analysis for the determination of domperidone in human plasma[J]. J Chromatogr B,2000,744(1):207-212.
[5] Yoshizato T,Tsutsumi K,Kotegawa T,et al. Determination of domperidone in human plasma using high performance liquid chromatography with fluorescence detection for clinical application[J]. J Chromatogr B,2014,961:86-90.
[6] Wu MS,Gao L,Cai XH,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.
[7] Zhang D,Chen K,Teng Y,et al. Determination of domperidone in human plasma using liquid chromatography coupled to tandem mass spectrometry and its pharmacokinetic study[J]. Arzneimittel-Forsch,2012,62(3):128-133.
[8]余鹏,阳国平,冉黎灵,等. LC-MS/MS法测定人血浆中多潘立酮的浓度[J].药物分析杂志,2011,31(4):619-624.
[9] Helmy SA,Bedaiwy HM. Pharmacokinetics and comparative bioavailability of domperidone suspension and tablet formulations in healthy adult subjects[J]. Clin Pharm Drug Dev,2014,3(2):126-131.
[10]李忠亮,王晓波,宋晓楠,等.多潘立酮片在健康人体的相对生物利用度与生物等效性[J].解放军药学学报,2009,25(1):26-29.
[11]何佩贞.多潘立酮片人体生物等效性研究[J].药物与人,2014,27(2):7-7.
[12]于洋,张小丽,王建,等.液相色谱-质谱联用法测定人血浆中多潘立酮[J].药物分析杂志,2007,27(5):677-680.
[13] Hussein R,Lockyer M,Yusuf A,et al. Bioequivalence assessment of two domperidone tablet formulations[J]. Acta Pharmacol Sin,2007,57(5):269.
[14] Wang X,Qin F,Jing L,et al. Development and validation of UPLC-MS/MS method for determination of domperidone in human plasma and its pharmacokinetic application[J]. Biomed Chromatogr,2013,27(3):371-376.
[15]张欣,戴青,陈勇川,等. HPLC法检测人血浆中多潘立酮浓度及其药代动力学研究[J].中国医药导刊,2011,13(5):908-909.
[16] Zhang Y,Chen X,Dai X,et al. Influence of omeprazole on pharmacokinetics of domperidone given as free base and maleate salt in healthy Chinese patients[J]. Acta Pharmacol Sin,2007,28(8):1243-1246.
[17] Khan A,Lqbal Z,Khadra I,et al. Simultaneous determination of domperidone and itopride in pharmaceuticals and human plasma using RP-HPLC/UV detection:method development,validation and application of the method in in-vivo evaluation of fast dispersible tablets[J]. J Pharm Biomed Anal,2016,121:6-12.
[18] Heykants J,Hendriks R,Mwuldermans W,et al. On the pharmacokinetics of domperidone in animals and manⅣ. The pharmacokinetics of intravenous domperidone and its bioavailability in man following intramuscular,oral and rectal administration[J]. Eur J Drug Metab Ph,1981,6(1):61-70.
[19]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):343-346.
[20]国家药典委员会.生物样品定量分析验证指导原则[S].北京:中华人民共和国药典(2015年版).附录9012:363-368.
[21] Huang YC,Colaizzi JL,Bierman RH,et al. Pharmacokinetics and dose proportionality of domperidone in healthy volunteers[J]. J Clin Pharmacol,1986,26(8):628-632.
[22] Charman WN,Porter CJH,Mithani S,et al. Physicochemical and physiological mechanisms for the effects of food on drug absorption:the role of lipids and pH[J]. J Pharm Sci-us,1997,86(3):269-282.
[23] Rocha CMG,Barbosa MM. QT interval prolongation associated with the oral use of domperidone in an infant[J]. Pediatr Cardiol,2005,26(5):720-723.
[24] Ward BA,Morocho A,Kandil A,et al. Characterization of human cytochrome P450 enzymes catalyzing domperidone N-dealkylation and hydroxylation in vitro[J]. Br J Clin Pharmacol,2004,58(3):277-287.