反义寡核苷酸药物癌泰得及其代谢产物的猕猴体内药代动力学研究  

Pharmacokinetics of cantide,an antisense oligonucleotide,and its metabolites in rhesus monkeys

作　　者：王秀中 王诗鸿 宋海峰[2] 王清清[2] 王升启[2] 

机构地区：[1]解放军第一八八医院,广东潮州521000 [2]军事医学科学院放射与辐射医学研究所,北京100850

出　　处：《药学学报》2011年第11期1370-1373,共4页Acta Pharmaceutica Sinica

基　　金：国家高技术研究发展计划(863计划)资助项目(2007AA021602);"重大新药创制"科技重大专项资助项目(2009ZX09503-021);国家自然科学基金资助项目(39870879)

摘　　要：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 study the pharmacokinetics of cantide,an antisense oligonucleotide,and its metabolites after iv gtt administration in rhesus monkeys,a dual solid phase extraction pretreatment method coupling 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.The pharmacokinetic behavior of cantide and its metabolites（M1 and M2） after iv gtt administration（8,16 and 24 mg·kg-1） in rhesus monkeys were investigated.After iv gtt administration of cantide to rhesus monkeys,cantide in plasma was eliminated rapidly and the terminal elimination half-life（t1/2） was 57.91-77.97 min,the correlation coefficients（r） to the dose of Cmax,AUC0-inf and AUC0-t of the prototype was 0.991 8,0.956 8 and 0.977 3,respectively.The metabolites of cantide reached the Cmax following cantide immediately and the Cmax of metabolites were lower than that of the prototype.The CLs of cantide and its metabolites（M1 and M2） were 1.60-2.19,5.92-8.58 and 6.07-8.78 mL-min-1·kg-1,respectively.So,it is concluded that the Cmax of cantide and its metabolites increased with the dose,which is the same as their AUC0-inf and AUC0-t.The CLs of metabolites were higher than that of the prototype.The MRT and t1/2 of metabolites in the high dose group increased obviously.

关 键 词：反义寡核苷酸 癌泰得 代谢产物 

分 类 号：R969.1[医药卫生—药理学]