替硝唑、达克罗宁和氯己定在大鼠体内的毒代动力学及组织分布研究

目的:研究替硝唑、达克罗宁和氯己定在大鼠体内的毒代动力学及组织分布。方法:采用HPLCMS/MS法,测定单次和多次给药后大鼠血浆和组织样品中替硝唑、达克罗宁和氯己定的浓度,计算毒代动力学参数。生物样品采用固相萃取预处理;采用Phenomenex Gemini C₁₈(50 mm×2.0 mm, 5μm)色谱柱,以甲醇-10 mmol·L^-1甲酸铵-甲酸(56:44:0.2)为流动相,流速0.2 mL·min^-1,柱温25℃,甲磺酸酚妥拉明为内标;通过电喷雾离子化四极杆串联质谱,以正离子多反应监测方式(MRM)检测。结果:单次给药后替硝唑、达克罗宁和氯己定在大鼠体内符合二室模型,主要毒代动力学参数包括:t_1/2为6.32、5.88和8.92 h; T_max为1.06、0.56和0.63 h; C_max为3142.6、164.79和144.20 ng·mL^-1; AUC_0-t为26604.53、1200.03和816.39 ng·h·mL^-1。多次给药后替硝唑在血浆和脑组织,氯己定在血浆和肾组织,达克罗宁在脑和肝组织中有少量分布。结论:涂膜剂经皮给药后,替硝唑、达克罗宁和氯己定吸收快、分布迅速、消除较快、蓄积时间短。

Objective:To study toxicokinetics and tissue distribution of tinidazole, dyclonine and chlorhexidine in rats. Methods:HPLC-MS/MS method was used to determine the concentration of tinidazole, dyclonine and chlorhexidine in rat plasma and tissues, and toxicokinetics parameters were analyzed. The biological specimens were pretreated by solid phase extraction(SPE)method. Separation was achieved on a Phenomenex Gemini C₁₈ column(50 mm×2.0 mm, 5μm)using an isocratic mobile phase system composed of methanol-ammonium formate(10 mmol·L^-1)-formic acid(56:44:0.2)at a flow rate of 0.2 mL·min^-1. Analytes were determined by tandem mass spectrometry with electrospray positive ionization and multiple-reaction monitoring(MRM) mode. Results:Tinidazole, dyclonine and chlorhexidine in single dosing was correspondent to a twocompartment model. The main toxicokinetics parameters of tinidazole, dyclonine and chlorhexidine were as follows respectively:t_1/26.32 h,5.88 h and 8.92 h; T_max 1.06 h, 0.56 h and 0.63 h; C_max 3142.6 ng·mL^-1,164.79 ng·mL^-1 and 144.20 ng·mL^-1; AUC_0-t 26604.53 ng·h·mL^-1, 1200.03 ng·h·mL^-1 and 816.39 ng·h·mL^-1. After multiple administrations of tinidazole in plasma and brain, chlorhexidine in plasma and kidney, dyclonine in brain and liver, there still left a small quantity of distribution. Conclusion:Tinidazole, dyclonine and chlorhexidine were absorbed, distributed and eliminated quickly and the accumulation time was short after skin administration.