Department of Orthopaedics, Xijing Hospital, Fourth Military Medical University, Shaanxi, China.
J Chromatogr B Analyt Technol Biomed Life Sci. 2010 Feb 15;878(5-6):551-6. doi: 10.1016/j.jchromb.2009.12.030. Epub 2010 Jan 6.
A simple, rapid and accurate liquid chromatography-tandem mass spectrometry (LC-MS/MS) method has been developed and validated for the determination of mildronate in human plasma. Following a simple protein precipitation with methanol, the analyte was separated on a C(18) column by isocratic elution with methanol and 10 mM ammonium acetate (55:45; v/v), and then analyzed by mass spectrometry in the positive ion MRM mode. Good linearity was achieved over a wide range of 0.01-20 microg/mL. The intra- and inter-batch precisions (as RSD, %) were less than 7.1%. The average extraction recovery was 87.5%. The method described above has been used, for the first time, to reveal the pharmacokinetics of mildronate injection in healthy subjects. After single intravenously administration of 250, 500 and 1000 mg mildronate, the elimination half-life (t(1/2)) were (5.56+/-1.55), (6.46+/-1.07) and (6.55+/-1.17) h, respectively. The Student-Newman-Keuls test results showed that peak plasma concentration (C(max)) and the area under the plasma concentration versus time curve from time 0 to 24h (AUC(0-24)) were both linearly related to dose. The pharmacokinetics of mildronate fitted the linear dynamic feature over the dose range studied. The essential pharmacokinetic parameters of multidoses administration intravenously (500 mg, b.i.d) were as follows: t(1/2) was (15.34+/-3.14) h; C(max) was (25.50+/-3.63) microg/mL; AUC(0-24) was (58.56+/-5.57) mgh/L. The t(1/2) and AUC of multidoses administration intravenously were different from those of single-dose administration significantly. These findings suggested that accumulation of mildronate in plasma occurred.
建立并验证了一种用于人血浆中米屈肼的测定的简单、快速和准确的液相色谱-串联质谱（LC-MS/MS）方法。样品经甲醇沉淀蛋白后，以甲醇和 10 mM 乙酸铵（55:45，v/v）为流动相，在 C(18)柱上进行等度洗脱，然后采用正离子 MRM 模式进行质谱分析。米屈肼在 0.01-20 μg/mL 范围内呈良好的线性。批内和批间精密度（RSD，%）均小于 7.1%。平均提取回收率为 87.5%。该方法已首次用于揭示健康受试者中单次静脉注射米屈肼后的药代动力学。单次静脉注射 250、500 和 1000 mg 米屈肼后，消除半衰期（t(1/2)）分别为（5.56+/-1.55）、（6.46+/-1.07）和（6.55+/-1.17）h。Student-Newman-Keuls 检验结果表明，峰血浆浓度（C(max)）和 0 至 24 h 时的血浆浓度-时间曲线下面积（AUC(0-24)）均与剂量呈线性相关。米屈肼的药代动力学在研究剂量范围内呈线性动力学特征。静脉注射（500 mg，bid）多剂量给药的基本药代动力学参数如下：t(1/2)为（15.34+/-3.14）h；C(max)为（25.50+/-3.63）μg/mL；AUC(0-24)为（58.56+/-5.57）mgh/L。静脉注射多剂量给药的 t(1/2)和 AUC 与单次给药显著不同。这些发现表明米屈肼在血浆中发生了蓄积。
