氢氯噻嗪在小鼠体内的组织分布及药动学研究

Tissue distribution and pharmacokinetics of hydrochlorothiazide in mice by HPLC-MS/MS

目的建立小鼠血浆及组织中氢氯噻嗪浓度测定的HPLC—MS／MS方法，研究氢氯噻嗪在小鼠体内的组织分布及药动学。方法在血浆样品及组织样品中加入内标布洛芬，分别采用乙醚和乙酸乙酯提取处理，以甲醇-水-氨水（90：10：1）为流动相，用C18柱分离，采用电喷雾电离源（Turbo Ionspray），负离子方式检测，扫描方式为多反应监测（MRM）。以此方法测定72只雄性健康小鼠给予氢氯噻嗪后10个时间点的血浆及组织样品，并采用DAS2．0药动学程序计算主要药动学参数。结果氢氯噻嗪在血浆中线性范围为5．0～1000μg·L^-1，在组织中线性范围为0．05～50．0μg·g^-1,日内、日间RSD均〈15％。小鼠灌胃给予氢氯噻嗪后快速分布在各组织中，其中胃、肠、肝分布最多，心分布最少。结论本法快速、准确、专属、灵敏。氢氯噻嗪灌胃给药后吸收快，消除半衰期长，组织分布广泛。

Objective To establish an LC-MS/MS method for the determination of hydrochlorothiazide in mice plasma and tissue, and to study pharrnacokinetics and tissue distribution of hydrochlorothiazide. Methyls The test drug and internal standard ibuprofen were extracted from plasma samples and tissue samples by ether and ethyl acetate respectively, chromatgraphed on a C18 column. The mobile phase consisted of methanol-wate- ammonia water （90 ： 10 ： 1 ）. Detection was performed on a triple quadrupole tandem mass spectrometer via turbo ionspray source in the negative mode. Hydrochlorothiazide in the plasma and tissue of healthy male mice was deterimined using DAS 2.0 pharmacokinetic program to calculate pharmacokinetic parameters. Results The linear calibration curves were obtained at 5.0- 1000 μg·L^-1 and 0. 05- 50.0 μg·L^-1 in the plasma samples and tissue samples. The intra-and inter-run precisions were lower than 15% in terms of relative standard deviation. After a single dose of the 13 mg·L^-1 hydrochlorothiazide to mice, it was rapidly and extensively distributed to all tissues, especially in the stomach, intestines, and liver. Conehtsion This method is fast, sensitive and accurate. Hydrochlorothiazide is rapidly absorbed with long half life and extensive distribution.