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研究反义寡核苷酸药物癌泰得(cantide)及其代谢产物在猕猴体内的药代动力学特征。通过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的癌泰得及其代谢产物的血药浓度,并计算药代动力学参数。研究比较了猕猴单次静脉滴注不同剂量(8,16,24 mg.kg-1)癌泰得后血浆中原形药物及其代谢产物M1和M2的药代动力学行为。猕猴经静脉滴注给药后,癌泰得在血浆中消除迅速,末端t1/2为57.91～77.97 min,其Cmax、AUC0-inf和AUC0-t与给药剂量的线性相关系数(r)分别为0.991 8、0.956 8和0.977 3。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。原形药物及其代谢产物M1和M2的CLs分别为1.60～2.19、5.92～8.58和6.07～8.78 mL.min-1.kg-1。结果表明癌泰得原形及其代谢产物的Cmax、AUC0-inf和AUC0-t均随给药剂量增加而增加。代谢产物的清除率大于原形药物,且代谢产物在高剂量组表现为MRT明显延长,末端消除相半衰期亦增大。
To investigate the pharmacokinetic profile of cantide and its metabolites of the antisense oligonucleotide in rhesus monkeys. The plasma concentrations of CTC and its metabolites in macaque plasma were determined by two-step solid-phase extraction coupled with gel-free screening capillary electrophoresis and the pharmacokinetic parameters were calculated. The pharmacokinetics of the prototype drugs and their metabolites M1 and M2 in plasma of macaque monkeys after a single intravenous infusion of different dosages (8, 16, and 24 mg.kg-1) were compared. After intravenous drip administration of Cynomolgus monkey, Citalot was rapidly eliminated in the plasma, the terminal t1 / 2 was 57.91 ~ 77.97 min, and the linear correlation coefficients (r) of Cmax, AUC0-inf and AUC0-t 0.991 8, 0.9556 8 and 0.977 3. Metabolites followed the prototype drug peak concentration, and the peak concentrations were significantly lower than the prototype drug. The CLs of prototype drugs and their metabolites M1 and M2 were 1.60-2.19, 5.92-8.58 and 6.07-8.78 mL.min-1.kg-1, respectively. The results showed that the Ctata, AUC0-inf and AUC0-t of the original form and its metabolites were increased with the increase of the dose. Metabolites clearance rate than prototype drugs, and metabolites in the high-dose group was significantly prolonged MRT, terminal elimination phase half-life also increased.