LC-MS/MS法同时测定人血浆中盐酸二甲双胍和罗格列酮浓度及其药代动力学

Simultaneous determination of metformin and rosiglitazone in human plasma by LC-MS/MS and the pharmacokinetics studies

目的：建立LC-MS/MS同时测定人血浆中盐酸二甲双胍及罗格列酮浓度的方法,测定志愿者单次和多次顿服二甲双胍罗格列酮胶囊后盐酸二甲双胍和罗格列酮的血药浓度,估算其药代动力学参数。方法：血浆中加入盐酸苯乙双胍为内标,经乙腈沉淀蛋白,取上清直接进行LC-MS/MS测定。色谱柱为Phenomenex Luna CN 100A（150 mm×2.0 mm ID）,流动相为CH3OH-30 mmol/L NH4Ac,pH 5.0（80∶20）,流速为0.2 mL/min;ESI-MS/MS选择性反应正离子检测。临床试验方案采用拉丁方试验设计。结果：盐酸二甲双胍和罗格列酮的血浆线性范围分别为5-3 000 ng/mL和1.5-500 ng/mL,检测限均为1ng/mL。测定了12名志愿者单次和多次顿服二甲双胍罗格列酮胶囊后的血药浓度经时过程。结论：本方法操作简单,专属性强,灵敏度高,准确性好。盐酸二甲双胍和罗格列酮体内动力学行为符合线性药物动力学特征。

Aim：To establish an LC-MS/MS method to study the pharmacokinetics of metfonnin and rosiglitazone in human plasma. Methods： After adding phenfonnin, the internal standard, plasma samples were precipitated by acetonitrile and the supernatant was injected onto LC-MS/MS system. The chromatographic system consisted of Phenomenex Luna CN 100A column（ 150 mm ×2.0 mm ID）and the mobile phase of CH3OH-NH4Ac（30 mmol/L, pH 5.0） （80：20） at a flow rate of 0.2 mL/min. According to the crossover design using latin square, 12 volunteers orally received test capsules in single and multiple-dosing and plasma concentrations of metformin and rosiglitazone were determined by the validated method. Pharmacokinetic parameters of the two species were estimated. Results： The method exhibited linear ranges of from 5 to 3 000 ng/mL and 1.5 to 500 ng/mL with a correlation coefficient of 0.999 5 and 0. 999 2 for metfonnin and rosiglitazone, respectively. The limit of detection was 1 ng/mL for both metfonnin and rosiglitazone. The concentration-time curves of metfonnin and rosiglitazone were best fitted to a two-compartment open model. Conclusion： The method is simple, sensitive and rapid. The absorption and disposition of metformin and rosiglitazone in human body follow the first order kinetics.