猕猴多次给药后癌泰得原形及其代谢产物的药代动力学研究

Pharmacokinetics of cantide and its metabolites after multiple administration in rhesus monkeys

目的:研究猕猴经多次静脉滴注反义寡核苷酸药物癌泰得后原形药物及其代谢产物的药代动力学特征。方法:每天静脉滴注8 mg.kg-1癌泰得1次,连续7 d。采用两步固相萃取法结合无胶筛分毛细管电泳技术测定猕猴血浆中癌泰得及其代谢产物M1和M2的血药浓度,并计算其药代动力学参数。结果:给药后,猕猴血浆中癌泰得被迅速消除,首末次给药后原形药物的末端t1/2分别为(57.91±23.64)和(57.45±24.38)min,其峰浓度分别为(72.21±8.68)和(58.34±17.39)μg.mL-1。代谢产物紧随原形药物之后达到峰浓度,且峰浓度均明显低于原形药物。首末次给药后原形药物及代谢产物的血浆药物浓度和药代动力学参数均无统计学显著差异。结论:癌泰得多次给药后在猕猴体内的药代动力学行为没有明显改变,无药物蓄积或诱导代谢现象。

Objective： To investigate the pharmacokinetics of cantide,an antisense oligonucleotide,and its metabolites after multiple administration in rhesus monkeys.Methods： The pharmacokinetic behaviors of cantide and its metabolites（M1 and M2） were investigated after intravenous infusion of 8 mg·kg^-1cantide per day for 7 days in rhesus monkeys.A dual solid phase extraction pretreatment method coupled with non-gel sieving capillary electrophoresis analysis method was used for determination of cantide and its metabolites in plasma,and their pharmacokinetic parameters were calculated.Results： After intravenous infusion of cantide to rhesus monkeys,cantide in plasma was eliminated rapidly.The first and last terminal elimination half-life（t1/2） of cantide was（57.91±23.64） min and（57.45±24.38） min,and their Cmax was（72.21±8.68） and（58.34±17.39） μg·mL-1,respectively.The metabolites of cantide reached the Cmax immediately following cantide Cmax,and the metabolite Cmax was lower than that of the prototype.There was no statistical significant difference in plasma concentrations of cantide and its metabolites and in their pharmacokinetic parameters after multiple administration in rhesus monkeys.Conclusion： The pharmacokinetic behaviors of cantide do not change after multiple administration in rhesus monkeys,without accumulation and inducting metabolism of cantide.