LC-MS/MS法测定人血浆中甲麦角新碱浓度及药代动力学研究
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摘要
目的建立LC-MS/MS测定人血浆中甲麦角新碱浓度,并用于马来酸甲麦角新碱的药代动力学研究。方法以6-羟基黄酮为内标,色谱柱为Waters Xterra C18(2. 1 mm×100 mm,3. 5μm),流动相为0. 05%乙酸水溶液,有机相为甲醇-乙腈(80∶20)混合溶液,梯度洗脱,流速为0. 3 m L·min-1;整个分析时间12 min。样品经电喷雾离子源电离为正离子化后,通过质谱仪多反应监测模式下测定甲麦角新碱(m/z 340. 3→223. 2)和内标(m/z 239. 2→129. 1)的浓度。血浆样品采用液液萃取法提取。结果血浆中甲麦角新碱浓度线性范围为0. 1～20. 0 ng·m L-1,定量下限为0. 1 ng·m L~(-1),日内、日间精密度CV均小于15%。血浆样品室温放置4 h,反复冻融(-70℃) 3次及长期稳定性4个月的情况下均稳定。样品再分析(ISR)实验室准确度符合要求。多次给药甲麦角新碱在体内无蓄积。结论本文的分析方法特异性高,灵敏准确,可用于受试者空腹口服马来酸甲麦角新碱片0. 125,0. 25和0. 5 mg后血浆样品中甲麦角新碱的药代动力学研究。
Objective To establish a LC-MS/MS method for pharmacokinetics study of methylergonovine in healthy Chinese volunteers after single and multiple-dose administration of methylergonovine maleate tablets. Methods 6-hydroxyflavone was used as internal standard.The separation was achieved on a Waters Xterra C18( 2. 1 mm × 100 mm,3. 5 μm) with a mobile phase consisting of 0. 05% ammonium acetate and methanol-acetonitrile( 80 ∶ 20) solution. At a flow rate of 0. 3 m L·min~(-1) within 12 min. Methylergonovine and 6-hydroxyflavone were measured by ESI in positive electron mode using multiple reaction monitoring( MRM). The extracted ions monitored following MRM transitions were m/z 340. 3 →223. 2 for methylergonovine and m/z 239. 2 →129. 1 for 6-hydroxyflavone. Plasma samples were pretreated by liquid-liquid extraction. Results The calibration curve was linear within the range of 0. 1-20. 0 ng·m L~(-1). The Lower limit of quantitation was 0. 1 ng·m L~(-1) and CV% of intra-and inter-day were less than 15%. The plasma samples were stable at room temperature( 25 ℃) for 4 h,at-70℃ for 4 months and during three freeze-thaw cycles. There was no accumulationafter ultiple-dose of methylergonovine maleate tablets.Conclusion The method was proved to be accurate and sensitive suitable for the pharmacokinetics of methylergonovine in volunteers after oral administration of 0. 125,0. 25,0. 5 mg methylergonovine maleate tablets.
Objective To establish a LC-MS/MS method for pharmacokinetics study of methylergonovine in healthy Chinese volunteers after single and multiple-dose administration of methylergonovine maleate tablets. Methods 6-hydroxyflavone was used as internal standard.The separation was achieved on a Waters Xterra C18( 2. 1 mm × 100 mm,3. 5 μm) with a mobile phase consisting of 0. 05% ammonium acetate and methanol-acetonitrile( 80 ∶ 20) solution. At a flow rate of 0. 3 m L·min~(-1) within 12 min. Methylergonovine and 6-hydroxyflavone were measured by ESI in positive electron mode using multiple reaction monitoring( MRM). The extracted ions monitored following MRM transitions were m/z 340. 3 →223. 2 for methylergonovine and m/z 239. 2 →129. 1 for 6-hydroxyflavone. Plasma samples were pretreated by liquid-liquid extraction. Results The calibration curve was linear within the range of 0. 1-20. 0 ng·m L~(-1). The Lower limit of quantitation was 0. 1 ng·m L~(-1) and CV% of intra-and inter-day were less than 15%. The plasma samples were stable at room temperature( 25 ℃) for 4 h,at-70℃ for 4 months and during three freeze-thaw cycles. There was no accumulationafter ultiple-dose of methylergonovine maleate tablets.Conclusion The method was proved to be accurate and sensitive suitable for the pharmacokinetics of methylergonovine in volunteers after oral administration of 0. 125,0. 25,0. 5 mg methylergonovine maleate tablets.
引文
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[6]DE GROOT A N,VREE T B,HEKSTER Y A,et al.Comparison of the bioavailability and pharmacokinetics of oral methylergometrine in men and women[J].Int J Clin Pharmacol Ther,1995,33(6):328-332.
[7]NAKAMICHI T,YAWATA A,HOJO H,et al.Monitoring of methylergometrine in human breast milk by solid-phase extraction and high-performance liquid chromatography with fluorimetric detection[J].Pharmazie,2012,67(6):482-484.
[2]盛玉成,何迎春,杨娟,等.药代动力学比例化剂量反应关系的研究方法及其线性评价[J].中国临床药理学杂志,2010,26(5):376-381.
[3]MNTYLR KLEIMOLA T KANTO J.Methylergometrine(methylergonovine)concentrations in the human plasma and urine[J].Int JClin Pharmacol Biopharm,1978,16(6):254-257.
[4]VOGEL D,BURKHARDT T,RENTSCH K,et al.Misoprostol versus methylergometrine:pharmacokinetics in human milk[J].Am JObstet Gynecol,2004,191(6):2168-2173.
[5]赵恒利,李岩,方增军,等.LC-MS/MS法测定血浆中马来酸甲麦角新碱及其人体药代动力学研究[J].药物分析杂志,2018,38(3):393-398.
[6]DE GROOT A N,VREE T B,HEKSTER Y A,et al.Comparison of the bioavailability and pharmacokinetics of oral methylergometrine in men and women[J].Int J Clin Pharmacol Ther,1995,33(6):328-332.
[7]NAKAMICHI T,YAWATA A,HOJO H,et al.Monitoring of methylergometrine in human breast milk by solid-phase extraction and high-performance liquid chromatography with fluorimetric detection[J].Pharmazie,2012,67(6):482-484.