液相色谱-串联质谱法测定枸地氯雷他定在大鼠体内的浓度及其药动学

Determination of desloratadine citrate disodium in rat and pharmacokinetic study by LC-MS/MS

目的建立测定大鼠血浆和尿液中枸地氯雷他定的液相色谱-串联质谱（LC-MS／MS）法，并将其应用于枸地氯雷他定在大鼠体内的药动学研究。方法12只成年健康SD大鼠，随机分成两组。各6只，分别单剂量尾静脉注射枸地氯雷他定0．5mg·kg-1和灌胃枸地氯雷他定2mg·kg-1后，于一定时间点采集血浆或尿液，取生物样品50μL经液液萃取后，以甲醇-0．1％甲酸水溶液（70：30，V/V形）为流动相，选用Diamonsil5uC18色谱柱（4．6mm×100mm，5μm）分离，采用电喷雾离子化进行正离子检测。用于定量分析的离子反应分别为m/z311→259（构地氯雷他定）和m/z327→270（氯氮平）。使用WinNonlin软件计算药动学参数。结果单剂量静脉注射枸地氯雷他定0．5mg·kg-1和单剂量灌胃枸地氯雷他定2mg·kg-1的主要药动学参数：ρmax分别为（457．00±49．76）和（17．25±4．09）μg·L-1，AUC0-∞分别为（128．80±19．40）和（107．38±10．74）μg·h·L-1，t1/2分别为（3．47±0．27）和（5．33±0．22）h，MRT分别为（4．19±0．62）和（7．22±0．39）h，绝对生物利用度为20．86％；0～72h的尿药累积排泄率分别为（1．19±0．21）％和（0．38±0．11）％。结论建立的液质联用测定构地氯雷他定在血浆和尿液样品的方法，专属灵敏快速，适用于大鼠药动学研究。

AIM To develop a liquid chromatography-tandem mass spectrometric （LC-MS/MS） method for determination of desloratadine citrate disodium （DCD） concentration in plasma and urine, and to investigate the pharmacokinetics of DCE in rats. METHODS Twelve SD rats were divided randomly into two groups （each group n = 6） , and tail intravenously infused with single dose of DCD 0.5 mg. kg-1 and intragastrically administrated with single dose of DCE 2 mg. kg-1, respectively. Plasma or urine samples were collected at the appointed time. The concentration of DCD was determined with an aliquot of 50 μL biological sample treated by liquid-liquid extraction. The separation was performed on a Diamonsil 5u C18 （4.6 mm × 100 mm, 5 μm） column with the mobile phase consisting of methol-0.1% formic acid water solution （70 ： 30, V/V）. A tandem mass spectrometer equipped with electrospray ionization source was used as a detector and operated in the positive ion mod. The ion reactions for quantitative analysis were as follows： m/z 311→259 （DCD） and m/z 327→270 （cozapine）. The pharmacokinetic parameters were calculated by WinNonlin software. RESULTS The main pharmacokinetic paramters of rats with intravenous administration of DCD 0.5 mg .kg-1 or intragastric administration of DCD 2 mg.kg-1 were as follows：ρmax（457.00 ± 49.76） and （17.25 ± 4.09） μg.L-1, AUC0-∞ （128.80 ±19.40） and （107.38 ± 10.74） μg.h.L-1, t1/2 （3.47 ±0.27） and （5.33 ± 0.22） h, MRT （4.19 ± 0.62） and （7.22 ± 0.39） h. The absolute bioavailability was 20.86%. The accumulative excretion rate of DCD through urine in 72 h were （1.19 ± 0.21）% and （0.38 _±0.11）%, respectively. CONCLUSION The established LC-MS/MS method is sensitive, accurate and fast for the pharmacokinetic study of DCD in plasma and urine of rats.