聚乙二醇化重组新型人白细胞介素-6的药代动力学研究

PHARMACOKINETICS OF PEGYLATED RECOMBINAN NEW HUMAN INTERLEUKIN-6(PEG-rhIL-6)

以双相氯胺-T法标记,应用125I示踪技术对新研制的聚乙二醇化重组人白细胞介素-6(PEG-rhIL-6)的药代动力学进行研究,试验选取不分雌雄30只SD大鼠,随机分成6个组,1～3组皮下注射给药,剂量分别为40μg/kg(高剂量组),20μg/kg(中剂量组)和3μg/kg(低剂量组),4～6组静脉注射给药(剂量同1～3组)。所有组动物给药后分别在0.03、0.08、0.17、0.33、0.67、1、2、4、6、8、24、48和72h断尾采血,采用125I同位素示踪法检测血药浓度,应用3P87软件进行房室模型拟合。结果显示,高、中、低3个剂量皮下注射消除相半衰期(t1/2ke)(20.41、21.53、19.77)和分布相半衰期(t1/2ka)(10.44、11.26、11.37)都高于静脉注射消除相半衰期(t1/2β)(17.54、18.78、17.81)和分布相半衰期(t1/2α)(1.93、1.60、1.78);皮下注射表观分布容积(平均694.96mL/kg)大于静脉注射(平均115.26mL/kg),表明皮下给125I-PEG-rhIL-6后,在体内维持的药理活性时间比较长,且经皮下注射药物排泄慢。试验为临床用药提供了理论依据。

In this study,the newly developed Pegylated recombinan human Interleukin-6（PEG-rhIL-6） was investigated.With ^125I labeled PEG-rhIL-6 by two-phase chloramine-T method.Thirty of the SD rats were randomly divided into 6 groups（group 1,2,3,4,5 and 6,respectively）,with 5 animals（3 males and 2 females） each group.Group 1,2,and 3 were injected subcutaneously with125I-PEG-rhIL-6 at the dose of 40,20 and 3μg/kg,respectively.Group 4,5,and 6 were injected intravenously with125I-PEG-rhIL-6 with the same dose level,respectively.Blood samples were collected at different time intervals after injection.The plasma concentration（ng/ml）of125I-PEG-rhIL-6 were determined by125I isotope tracing method and then assessed with 3P87 software to obtain the pharmacokinetic parameters.Results clearly showed that 1/2ke（20.41,21.53,19.77）and t1/2ka（10.44,11.26,11.37）of group1-3 are higher number than t1/2β（17.54,18.78,17.81）and t1/2α（1.93,1.60,1.78）of grou4-6,The pharmacological activity of125I-PEG-rhIL-6 maintain longer time by subcutaneous injection;The pharmacokinetic of V/Fc after sc（694.96ml/kg）is higher than those after iv（115.26ml/kg）,which showed that the excretion speed of125I-PEG-rhIL-6 given by sc was slowly.The above results obtained indicated that the pharmacokinetic characteristics of125I-PEG-rhIL-6 would provide important information for clinical application and the subcutaneous injection is better.