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目的建立beagle犬血浆中及SD大鼠组织中多西他赛的浓度测定方法,并对新剂型及原有剂型多西他赛药代动力学及组织分布特点进行比较。方法采取双处理、两周期随机交叉的实验设计,观察了在相同剂量(1.0或2.5 mg/kg)下注射用多西他赛和原剂型多西他赛注射液在beagle犬体内的药代动力学差异;观察了两种剂型在大鼠组织中分布的差异;建立了液相色谱-三重串联四级杆质谱联用(QQQ LC-MS)法,测定不同时间的两种剂型多西他赛血浆浓度。结果血浆样品在2～500μg/L范围内呈线性,最低检测限为2μg/L。血浆药物浓度在5、50和500μg/L,日间精密度分别为3.9%、7.0%和5.3%,回收率范围为89.2%～101.1%。血浆样品3日内,萃取样品3个月内稳定性良好。新剂型与原有剂型的药代动力学重要参数差异均有统计学意义(P<0.05),组织学分布可观察到差异。结论建立方法灵敏可靠,满足测定要求。与原剂型相比,在相同剂量下新剂型在血浆中的暴露较低,但是在组织器官中的分布更多,尤其在肺脏中分布更多,持续时间更长。
Objective To establish a method for the determination of docetaxel in beagle dogs plasma and in SD rats and to compare the pharmacokinetics and tissue distribution characteristics of the new and original formulations of docetaxel. Methods The experimental design of two-treatment and two-period random crossover was used to observe the pharmacokinetics of docetaxel and docetaxel injection in beagle dogs at the same dose (1.0 or 2.5 mg / kg) Differences in the distribution of the two formulations were observed in rats. A liquid chromatographic-triple quadrupole mass spectrometry (QQQ LC-MS) method was established for the determination of two formulations of docetaxel Plasma concentration. Results The plasma samples were linear in the range of 2 ~ 500μg / L with the detection limit of 2μg / L. The plasma drug concentrations were at 5, 50 and 500 μg / L. The intra-day precision was 3.9%, 7.0% and 5.3%, respectively. The recoveries ranged from 89.2% to 101.1%. Plasma samples within 3 days, the extraction of samples within 3 months of good stability. There were significant differences in the pharmacokinetics parameters between the new dosage form and the original dosage form (P <0.05), and histological distribution was observed. Conclusion The method is sensitive and reliable and meets the requirements of determination. Compared to the original dosage form, the new dosage form is less exposed in plasma at the same dosage but more distributed in tissues and organs, especially in the lungs, for longer durations.