雷公藤内酯醇在Beagle犬体内的药代动力学

Pharmacokinetics of triptolide in Beagle dogs

雷公藤内酯醇（triptolide，TP）是雷公藤的主要有效成分之一。研究不同剂量TP在Beagle犬灌胃给药时的绝对生物利用度和药代动力学，可望为其临床研究提供参考。以泼尼松龙作内标，用乙酸乙酯液液萃取，建立LC—APCI／MS选择性离子监测方法测定血浆TP浓度。Beagle犬分别静脉注射TP0．05mg·kg^-1、灌胃TP0．05，0．08和0．1mg·kg^-1。进行药代动力学和绝对生物利用度研究。结果表明，TP在1—200ng·mL^-1呈良好线性关系（r=0．9997），批内和批间精密度RSD均小于10％，准确度在95．0％～105．0％，提取回收率大于75％。静注0．05mg·kg^-1 TP后，T1/2β为（2．5±0．8）h。3个剂量灌胃组，Tmax,T1/2α和T1/2β,经检验无统计学差异。AUC和Cmax与剂量之间线性相关。灌胃0．05mg·kg^-1后，TP在Beagle犬体内绝对生物利用度为（75±17）％。可见，LC—APCI／MS法灵敏、可靠、专属性强，可用来测定Beagle犬血浆TP的浓度；TP在Beagle犬体内消除较快，灌胃给药生物利用度较高。

The aim of this paper is to develop and validate a rapid and sensitive LC-APCI/MS method for the determination of triptolide （TP） in plasma and to study the pharmacokinetic properties of TP in Beagle dogs. Sample preparation consisted of liquid-liquid extraction of interests with ethyl acetate from dog plasma. The analytes and internal standard prednisolone were well separated on a Zorbax Extend-C18 analytical column. Plasma TP was detected by selected-ion monitoring （SIM） of LC-APCI/MS as its deprotonated molecular ions [ M - H ]^ - at m/z 358.9. Pharmacokinetic studies were undertaken in dogs following an iv dose of 0.05 mg·kg^-1 of TP or an ig dose of 0.05, 0.08, 0. 1 mg·kg^-1, separately. The pharmacokinetic parameters were calculated by DAS software. Calibration curves were linear over the concentration range of 1 -200 mg·kg^-1 of TP with the within- and between-batch precisions less than 10%. The within and between-batch accuracy was 95.0% to 105.0%. Recovery of LC-MS method for TP in plasma was over 75%. The T1/2β was （2.5 ±0.8） h after intravenous administration of TP at the dose of 0.05 mg ·kg^-1. There were no significant differences in Tmax,T1/2α and T1/2β among the three ig dosage groups. AUC and Cmax increased proportionally with doses. The absolute bioavailability of TP after ig administration of 0.05 mg · kg^-1 was （75 ± 17）%. The LC-MS method for determination of triptolide in dog plasma was sensitive and rapid. It was showed that the elimination of triptolide was rapid. The absolute bioavailability of triptolide given orally was high.