聚乙二醇化新型集成干扰素注射液大鼠药物代谢动力学研究

摘要

目的 研究聚乙二醇化新型集成干扰素(pegylated consensus interferon,PEG-cIFN)注射液在大鼠体内的药代动力学特征,并与非聚乙二醇化的集成干扰素(consensus interferon,cIFN)进行比较.方法 大鼠分别单次皮下注射不同剂量PEG-cIFN(7、14和28 μg/kg)和cIFN(7 μg/kg),采用酶联免疫分析法测定不同时间血清药物浓度,实验数据以DAS 3.0药动程序拟合并计算药动参数.结果 大鼠分别单次皮下注射PEG-cIFN低、中和高3个剂量组后,峰浓度(the peak concentration,Cmax)和药时曲线下面积(the area under the serum concentration-time curve,AUC)随剂量增加呈更大比例增大,清除率(clearance,CL)随剂量增大而降低;达峰时间(the time to reach peak concentration,Tmax)和消除半衰期(elimination half life,t1/2β)与剂量呈非相关,且较为恒定(10~20 h);相同剂量下的PEG-cIFN较cIFN t1/2β延长15倍;CL降低10倍;Tmax滞后约10倍;AUC增加8倍,而Cmax降低近1倍.结论 上述研究结果表明,PEG化后的IFN确实能改善和提高药代动力学/药效动力学特性,延长半衰期,降低清除率,增加暴露量,减小血清峰-谷浓度比率,延缓药物体内作用时间,具有长效作用.%Objective To characterize the parmacokinetics of a novel pegylated consensus interferon(PEG-IFN-SA) following a single subcutaneous administration to rat, compared with those of non-PEG modified IFN-SA. Methods The rats were randomly assigned into four groups in which the rats were given PEG-IFN-SA at doses of 7, 14 and 28 μg/kg, and IFN-SA at a dose of 7 μg/kg, respectively. The serum concentrations of PEG-IFN-SA and IFN-SA were determined using an enzyme-linked immunosorbent assay ( ELISA). The pharmacokinetic parameters were calculated by DAS 3. 0 software. Results The rats treated with PEG-IFN-SA following single s. c. administration at doses of 7, 14, and 28 μg/kg, a greater than proportional increase in both the peak concentration(Cmax) and the area under the concentration-time curve( AUC) for PEG-IFN-SA was observed with increasing dose, while the rate of clearance decreased. Both the time to reach peak concentration (Tmax) and serum elimination half life(t|/2o) did not display markedly dose-dependence and were relatively consistent in the range of 10 — 20 h. The pegylated protein exhibited improved pharmaco kinetic properties compared to IFN-SA at an identical dose, with a 15-fold increase in t1/2β , and a 10-fold decrease in serum clearance(CL) , as well as a 10-fold increase in Tmax, respectively. In addition, AUC of PEG-IFN-SA was approximately 8-fold greater, while Cmax was approximately half that of IFN-SA. Conclusion These findings demonstrate that pegylation of IFN-SA results in more desirable pharmacokinetic properties, prolonged biological half-life, decreased system clearance, enhanced drug exposure, reduced serum peak-to-trough concentration ratio and increased in vivo duration of antiviral efficacy compared to unmodified IFN-SA.