Bcl-2反义硫代磷酸寡脱氧核苷酸KS0604在猕猴和小鼠的药动学(英文)  

Pharmacokinetics of a phosphorothioate antisense bcl-2 oligonucleotide(KS0604)in rhesus monkeys and mice

作　　者：王诗鸿[1,2] 王清清[2] 董增祥[2] 欧伦[2] 季颖[2] 王婧[2] 宋海峰[2] 刘秀文[2] 

机构地区：[1]中国人民解放军188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药理毒理研究室,北京100850

出　　处：《中国新药与临床杂志》2010年第8期581-589,共9页Chinese Journal of New Drugs and Clinical Remedies

摘　　要：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。AIM To investigate the pharmacokinetic profile of a antisense oligonucleotide （KS0604）. METHODS A dual solid phase extraction pretreatment method coupling with non-gel sieving capillary electrophoresis analysis method was used for determination of KS0604. The pharmacokinetic behavior of KS0604 after iv, gtt administration （5, 15 and 45 mg·kg^-1） in rhesus monkeys, and iv （10, 30 and 90 mg·kg^-1） in mice was investigated. The comparing study was conducted after iv or iv gtt administration at dose of 15 mg·kg^-1 in rhesus monkeys. RESULTS In rhesus monkeys, the concentration-time data were fit well to a two or three compartment model. The increase of cmax was proportional to dosage, the same as the AUC（0-inf） and AUC （0-t） . The t1/2 was less than 1 h and was similar between the iv and iv gtt administration rhesus monkey groups. Following administration in mice, the concentration-time data are fit well to a two compartment model. KS0604 was rapidly cleared with a t1/2 of 17.17-34.63 min and was no longer detected at 4 h post dosing. AUC and Cmaxcexhibited a linear increase proportional to dose. CONCLUSION KS0604 showed linear pharmacokinetics in rhesus monkeys and mice over the investigated dose range. The pharmacokinetic parameters were similar with iv and iv, gtt routes of administration.

关 键 词：药动学 寡核苷酸类 反义 毛细管电泳 固相萃取 恒河猴 小鼠 KS0604 

分 类 号：R969.1[医药卫生—药理学]