摘要
目的研究聚乙二醇化重组人粒细胞集落刺激因子(PEG-rhG-CSF)在动物体内的药代动力学与组织分布。方法猕猴给予不同剂量(30、100和300μg/kg)的PEG-rhG-CSF,酶联免疫吸附法(ELISA)测定猕猴血浆中PEG-rhG-CSF浓度;[^(125)I]标记示踪法结合分子排阻色潽法观察PEG-rhG-CSF在Wistar大鼠各组织中的分布情况。结果猕猴单次sc PEG-rhG-CSF后血药浓度及系统暴露随给药剂量呈非线性增加。低、中、高剂量组达峰时间(T_(max))为6.67~12.00h,全身清除率(CL)顺序减小,药-时曲线下面积(AUC)与给药剂量不成正比。sc给药的绝对生物利用度为47.5%。与临床使用剂量的rhG-CSF(10μg/kg)相比,猕猴sc中剂量PEG-rhG-CSF后C_(max)、AUC分别为(1671±357)μg/L和(45156±9407)(μg·h)/L,均明显高于rhG-CSF组(P<0.05);PEG-rhG-CSF组的T_(1/2β)为(13±3)h,较rhG-CSF组的T_(1/2β)(1.52±0.08)h显著增加(P<0.05);而CL为(2.3±0.5)ml/(h·kg),较rhG-CSF组的CL(19.6±2.4)ml/(h·kg)显著降低(P<0.01)。大鼠sc[^(125)I]PEG-rhG-CSF后血清、肾、肺等组织放射性较高,2 h血清原形药物浓度达峰,肺、肠道、膀胱等组织在给药后分布较慢,8 h放射性达峰值。尿液中主要为小分子[^(125)I]降解代谢产物;未观察到药物与血浆蛋白的结合。结论将rhG-CSF进行PEG化修饰可以显著降低系统清除率,延长体内半衰期,增加药物暴露,可达到长效目的。药物主要分布于血管床,并代谢为小分子从泌尿系统排泄,不易透过血脑屏障。
Objective To study the pharmacokinetics and tissue distribution of pegylated recombinant human granulocyte colony-stimulating factor(PEG-rhG-CSF)in animals.Methods Rhesus monkeys were administered PEG-rhG-CSF at various doses(30,100 and 300μg/kg).Enzyme-linked immunosorbent assay(ELISA)was used to determine the concentrations of PEG-rhG-CSF in plasma of rhesus monkeys.[^(125)I]labeled tracing method combined with size exclusion chromatography method was utilized to investigate tissue distribution of PEG-rhG-CSF in Wistar rats.Results After Rhesus monkeys were given PEG-rhG-CSF by subcutaneous administration,the concentration and systemic exposure level in plasma increased as non-linear kinetics following with the dosage.The peak time(T_(max))was between 6.67-12.00 h.Among the groups of PEG-rhG-CSF 30,100 and 300μg/kg,the clearance(CL)decreased in turn,and area under curve(AUC)was out of direct proportion to the dosage.The absolute bioavailability was 47.5%after sc administration.After given PEG-rhG-CSF 100μg/kg,the maximum concentration(C_(max)),AUC were(1671±357)μg/L and(45156±9407)(μg·h)/L,respectively,which were obviously higher than that of rhG-CSF group with clinical dosage 10μg/kg(P 0.05).T_(1/2β)of PEG-rhG-CSF group was(13±3)h,which was significantly increased compared with that of rhG-CSF group which was(1.52±0.08)h(P 0.05).Meanwhile,CL of PEG-rhG-CSF group was(2.3±0.5)ml/(h·kg),which was significantly lower thall than of rhG-CSF group with(19.6±2.4)ml/(h·kg)(P 0.01).Total radioactivity in serum,kindey and lung was high in rats given[^(125)I]PEG-rhG-CSF.The concentration of intact[^(125)I]PEG-rhG-CSF in serum reached the maximum at 2 h,while other tissues,like lung,stool in bowel and urinary bladder,were distributed slowly after administration,in which the radioactive concentrations arrived the maximum at 8 h.Micromolecular metabolites of[^(125)I]PEG-rhG-CSF were mainly existed in the urine.The conjugation of drug and plasma protein was not observed.Conclusion rhG-CSF modified with PEG can decrease the systemic clearance,prolong the circulating half-life,elevate in vivo exposure level,achieve the purpose of prolonged action.The drug is mainly distributed over vascular bed and metabolized to micromolecule excreting by urinary system.PEG-rhG-CSF is difficult to permeate through the blood-brain barrier.
作者
李娜
欧伦
陈方
孙效
邹佳
董立厚
王清清
宋海峰
LI Na;OU Lun;CHEN Fang;SUN Xiao;ZOU Jia;DONG Li-hou;WANG Qing-qing;SONG Hai-feng(Institute of Radiation Medicine,Academy of Military Medical Sciences,Beijing 100850,China;Fengtai Comprehensive Warehouse Medical Supply Station,PLA General Logistics Department,Beijing 100071,China)
出处
《国际药学研究杂志》
CAS
2011年第4期306-311,共6页
Journal of International Pharmaceutical Research
基金
国家科技重大专项临床前药物代谢技术平台资助项目(2009ZX09304-004)
