犬血浆中决奈达隆及其代谢物SR35021的LC-MS/MS法测定

Determination of Dronedarone and Its Metabolite SR35021 in Dog Plasma by LC-MS/MS

建立了LC-MS/MS法同时测定Beagle犬血浆中的决奈达隆及其N-去丁基代谢物SR35021,并考察了盐酸决奈达隆片在Beagle犬内的药动学。采用C_(18)色谱柱,以乙腈-甲醇-5 mmol/L乙酸铵溶液-甲酸(55:10:35:0.07)为流动相,大气压化学电离源,多反应监测(MRM)方式,正离子检测。用于定量分析的离子反应分别为m/z 557→100(决奈达隆)、m/z 501→114(代谢物SR35021)和m/z 449→252(内标,托伐普坦)。血浆中决奈达隆及其代谢物SR35021均在0.2～200 ng/ml浓度范围内线性关系良好。两者的日内和日间RSD均小于10%。主要药动学参数如下:c_(max)(495±208)和(61.6±15.9)ng/ml;t_(max)(1 67±0.61)和(1.75±0.42)h;t_(1/2)(5 92±0.59)和(3.01±0.60)h:AUC_(0-t)(2 785±1 409)和(325±137)ng·h·ml;AUC_(0-(?))(2 793±1 412)和(328±136)ng·h·m1。

A LC-MS/MS method was established for the simultaneous determination of dronedarone and its N-debutyl metabolite SR35021 in Beagle dog plasma,and the pharmacokinetics of dronedarone hydrochloride tablets were investigated.A C_(18) column was used,with acetonitrile-methanol-5 mmol/L ammonium acetate solution-formic acid (55:10:35:0.07) as the mobile phase.A tandem mass spectrometer equipped with atmospheric pressure chemical ionization source was used as detector and operated in the positive ion mode.Quantification was performed using multiple reaction monitoring(MRM) of the transitions m/z 557→100(dronedarone),m/z 501→114(metabolite SR35021) and m/z 449→252(tolvaptan,the internal reference).The calibration curves of two analytes were linear in the range of 0.2-200 ng/ml.The intra-day and inter-day RSDs were less than 10%.The pharmacokinetics of dronedarone and SR35021were as follows:c_(max)(495±208) and(61.6±15.9) ng/ml,t_(max)(1.67±0.61) and(1.75±0.42) h,t_(1/2)(5.92±0.59) and(3.01±0.60) h,AUC_(0-t)(2 785±1 409) and(325±137) ng·h·ml^(-1),AUC_(0-∞)(2 793±1 412) and(328±136) ng·h·ml^(-1).