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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。
Objective To establish a sensitive and specific method for simultaneous determination of thionorphine and its metabolite glucuronide in beagle dogs plasma. Methods The concentrations of archetypes and metabolites in Beagle dogs were determined by HPLC-MS / MS and the pharmacokinetic parameters were analyzed in Beagle dogs. Results The linear range of thienorphine and metabolites was 0.02 ~ 50 ng / ml and 0.2 ~ 500 ng / ml, the lower limit of quantification was 0.02 ng / ml and 0.2 ng / ml respectively. The intra- and inter-day precision was less than 9% The recoveries are both greater than 60% and provide good stability during sample storage, handling and analysis. After a single oral dose of thienorphine 0.2, 0.6, 1.8 mg / kg, the prototype Cmax were 1.42,2.08,4.82 ng / ml, AUC was 8.60, 13.24 and 26.10μg.h / L, Tmax was about 0.55 ~ 0.65 h, t1 / 2 was 10 ~ 13 h and MRT was about 10 ~ 12 h. The Cmax of its metabolite (thienorphine glucuronic acid conjugate) were 1.78,5.03,7.09μg / L, 9.37,22.34,41.40μg.h / L, Tmax was 0.47-1.1 h, t1 / 2 was 18-40 h, MRT was 11-17 h. Beagle dogs oral 0.2 mg / kg thienorphine bioavailability of 12.65%. Conclusions This study firstly reported the pharmacokinetics of thienorphine and its glucuronic acid conjugates in beagle dogs, which showed that the absorption and conversion of the drug in beagle dogs were rapid. The low, middle and high levels of thienorphine hydrochloride The three prototypes and their glucuronic acid conjugates pharmacokinetic process were in accordance with the first-order absorption two-compartment model.