噻吩诺啡及其活性代谢产物的药代动力学研究

目的建立灵敏、专一的可同时测定比格犬血浆中噻吩诺啡及其代谢产物葡萄糖醛酸结合物含量的方法。方法采用HPLC-MS/MS法测定比格犬血中原型和代谢产物的浓度,分析在比格犬中的药代动力学参数。结果噻吩诺啡和代谢产物线性范围分别为0.02～50 ng/ml和0.2～500 ng/ml,定量下限分别为0.02 ng/ml和0.2 ng/ml,日内和日间精密度均小于9%,回收率均大于60%,在样品贮存、处理和分析过程中稳定性良好。比格犬单次口服噻吩诺啡0.2、0.6、1.8 mg/kg后,原型的Cmax分别为1.42、2.08、4.82 ng/ml,AUC分别为8.60、13.24和26.10μg.h/L,Tmax约为0.55～0.65 h,t1/2为10～13 h,MRT约为10～12 h;其代谢产物(噻吩诺啡葡萄糖醛酸结合物)的Cmax分别为1.78、5.03、7.09μg/L,AUC分别为9.37、22.34、41.40μg.h/L,Tmax为0.47～1.1 h,t1/2为18～40 h,MRT在11～17 h。比格犬口服0.2 mg/kg噻吩诺啡生物利用度为12.65%。结论本研究首次报道了噻吩诺啡及其葡萄糖醛酸结合物在比格犬中药代动力学研究,证明药物在犬体内的吸收和转化较快,单次口服盐酸噻吩诺啡低、中、高3种剂量后原型及其葡萄糖醛酸结合物药代动力学过程均符合一级吸收二房室模型。

Simultaneous Determination of Thienorphine and Its Active Metabolite Thienorphine-glucuronide by HPLC-MS/MS and Application to Pharmacokinetic Studies

Objective To develop a simple,sensitive and rapid method for the simultaneous quantification of thienorphine and thienorphine glucuronide conjugate in dog plasma.Methods HPLC-MS/MS method was established to determine the concentration of thienorphine and its metabolite in dog plasma.Results There was a linear calibration curve over the concentration range of 0.02-50 ng/ml for thienorphine and 0.2-500 ng/ml for thienorphine glucuronide conjugate,respectively.LOQ of thienorphine and thienorphine glucuronide conjugate was 0.02 and 0.2 ng/ml,respectively.The intra-and inter-batch precision was less than 9% and their recovery exceeded 60%.The concentration-time profiles of thienorphine and thienorphine glucuronide in blood were analyzed following a single oral administration of 0.2,0.6,1.8 mg/kg thienorphine to dogs.The average peak concentration for thienorphine was 1.42,2.08,4.82 ng/ml,respectively and the mean AUC was 8.60,13.24,26.10 μg·h/L,respectively.The value of Tmax,t1/2 and MRT time for thienorphine was ranged from 0.55 to 0.65 h,from 10 to 13 h,from 10 to 12 h,respectively.The average peak concentration for thienorphine glucuronide was 1.78,5.03,7.09 ng/ml,and the mean AUC was 9.37,22.34,41.40 μg · h/L,respectively.The value of Tmax,t1/2 and MRT for thienorphine glucuronide ranged from 0.47 to 1.1 h,from 18 to 40 h,from 11 to 17 h.The absolute bioavailability of 0.2 mg/kg thienorphine orally administered to dogs was about 12.65%.Conclusion The concentration-time profiles of thienorphine and thienorphine glucuronide in blood follow an open two-compartment model with firstorder absorption following a single oral administration of 0.2,0.6,1.8 mg / kg thienorphine to dogs.Thienorphine is quickly absorbed and biotransformated into thienorphine glucuronide conjugate.