反义寡核苷酸生物分布及药代动力学研究  

BIODISTRIBUTION AND PHARMACOKINETICS OF PHOSPHOROTHIOATE ANTISENSE OLIGODEOXYNUCLEOTIDE IN MICE

作　　者：黄爱琼[1] 姚志强[2] 周永兴[2] 

机构地区：[1]解放军第476医院,福州市350002 [2]第四军医大学唐都医院

出　　处：《实用肝脏病杂志》1999年第3期131-133,共3页Journal of Practical Hepatology

基　　金：国家自然科学基金资助(NO.39200116)

摘　　要：目的 研究反义寡核苷酸在小鼠体内的生物分布及药代动力学。方法 用γ-32 p-ATP标记15聚硫代磷酸反义寡核苷酸(S-asON),36只小鼠分12组,以30mg/kg体重剂量经尾静脉一次性给小鼠注射,每24小时收集尿液和粪便;分别在5min、15min、30min及1h、2h、3h、4.5h、12h、24h、48h和72h放血杀死3只小鼠,取各器官组织匀浆,用液体闪烁计数测定cpm值。结果 S-asON广泛分布于全身各器官,肝、肾聚积浓度较高,血浆消除曲线可用药代动力学二室模型描述,其t_(a1/2)为0.12 h,t_(β1/2)为46.2h,曲线下面积(AUC)为1776.4μg/ml×h。最大浓度(C_(max))为129.7μg/ml,表观分布容积(Vd)为4.6ml,血浆清除率(CL)为0.07 ml/h,尿液为主要排出途径,24 h排出28.2％,72h排出43.9％,粪便排出量少。结论 反义寡核苷酸分布于全身各器官,药代动力学符合二室模型,尿液为其主要排出途径。Objective To study the biodistribution and pharmacokinetics of antisense oligodeoxynu- cleotide. Methods S-asON was labelled at 5'end with γ-32 P-ATP.Thirty-six mice were intravenously injected with S-asON at a sigle dose of 30mg/kg bodyweight. Urine and feces were completely collected every 24h. Three mice was killed by exsangui nation at 12 time points: ie. 5min、15min、30min、60min;and 2h、3h、4. 5h、8h、12h、24h、48h and 72h. Organs were removed and the tissues were weighted and homogenized. The total radioactivities in each tissue specimen and body fluid were determined by liquid scintillation spectrometry. Results A wide tissue distribution of S-asON was observed with the majority of radioactivity in kidney、liver、lung、large and small intestine、thymus、pancreas、heart、 stomach、muscle and testes. The distribution of S-asON in the animal body was consistent with a two-compartment model with tα1/2 of 0. 12h and tβ1/2 of 46. 2h. The S-asON was eliminated mainly by urine(28. 2% at 24h and 43.9% at 72h). Fecal excretion was small. Conclusions A wide tissue distribution of S-asON could be described by a two-compartment model. Urine is the major eliminantion pathway.

关 键 词：反义寡核苷酸 生物分布 药代动力学 小鼠 

分 类 号：R96[医药卫生—药理学]