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目的研究反义核苷酸KS0604的药动学。方法建立基于离子交换和反相分配原理的两步固相萃取法,并采用非胶筛分毛细管电泳技术分析猕猴和小鼠血浆中的KS0604。观察猕猴静脉滴注(5,15和45mg·kg-1)和小鼠静脉注射(10,30和90mg·kg-1)给药后的药动学。结果猕猴给药后,药时曲线符合二室或三室模型,cmax、AUC(0～inf)和AUC(0～t)随给药剂量的增加而增加,静脉注射和静脉滴注后的末端t1/2相似,均小于1h。小鼠给药后,药时曲线符合二室模型,KS0604在血浆中消除迅速,末端t1/2为17.17～34.63min,给药后4h血药浓度低于定量下限,cmax、AUC(0～inf)和AUC(0～t)随给药剂量的增加而增加。结论在研究剂量范围内,KS0604在猕猴中表现为线性药动学,而小鼠中表现为非线性药动学。猕猴静脉注射和静脉滴注给药后的药动学参数相似。
Objective To study the pharmacokinetics of antisense nucleotide KS0604. Methods A two-step SPE was established based on the principle of ion exchange and reversed phase partitioning. KS0604 in the plasma of macaque and mouse was analyzed by non-gel-sieving capillary electrophoresis. The pharmacokinetics of Rhesus monkeys after intravenous drip (5, 15 and 45 mg · kg-1) and intravenous injection (10, 30 and 90 mg · kg-1) were observed. Results After administration, the pharmacokinetics curve of the rhesus macaque conformed to the two-compartment or three-compartment model. The cmax, AUC (0 ~ inf) and AUC (0 ~ t) increased with the increase of the dosage. After the intravenous injection and the intravenous infusion, / 2 Similar, both less than 1h. After administration to mice, the drug-time curve conformed to the two-compartment model. KS0604 was rapidly eliminated from the plasma and the terminal t1 / 2 was 17.17-34.63 min. The plasma concentration of the KS0604 was lower than the lower limit of quantitation at 4 hours after administration, ) And AUC (0 ~ t) increased with increasing dose. Conclusion KS0604 showed linear pharmacokinetics in macaques and non-linear pharmacokinetics in mice over the study dose range. Pharmacokinetic parameters of rhesus monkeys after intravenous injection and intravenous drip administration were similar.