具有长循环特性的麦冬多糖聚乙二醇修饰物的体内药代动力学研究

Pharmacokinetics of a long-circulating PEGylated Radix Ophiopogonis polysaccharide

研究具有长循环特性的麦冬多糖聚乙二醇修饰物在不同给药剂量和给药途径时大鼠体内的药代动力学行为。利用麦冬多糖活化羟基与mPEG-NH2的端氨基之间的温和反应制备麦冬多糖PEG结合物(嫁接度为1.03,PEG分子质量为20 kD)。将异硫氰酸荧光素预标记与高效凝胶渗透色谱法结合用于测定血样中结合物浓度。结果表明,静脉注射和皮下注射给药(9、20、50 mg.kg 1)后,结合物的消除行为基本不变,给药剂量与药时曲线下面积(AUC)均呈良好的线性关系。皮下注射给药后,结合物的绝对生物利用度约为56%,体内平均滞留时间(52.1 h)较静脉注射给药增加了2.4倍。在本剂量范围内,结合物呈现线性动力学特征,皮下注射给药有望成为该结合物理想的给药途径。

The pharmacokinetics of a long-circulating PEGylated Radix Ophiopogonis polysaccharide（ROP） was investigated in rats following iv or sc administration at three dose levels（9,20,50 mg kg 1）.A moderate coupling reaction between the hydroxyl-activated ROP and the amino-terminated mPEG was chosen to produce PEGylate ROP.The grafting degree of the prepared conjugate was 1.03,and the molecular mass of mPEG used was 20 kDa.High-performance gel permeation chromatorgraphy with fluorescein isothiocyanate prelabeling was established to determine levels of the conjugate in plasma.The results showed that the elimination half-life of the conjugate following sc administration was basically identical to that after iv administration.An accurate linear correlation was observed between administration doses and areas under the curve of plasma conjugate level vs time profile,regardless of the administration route.The absolute bioavailability of the conjugate following sc administration was approximately 56%,and the mean in vivo residence time was 52.1 h,increased 2.4 times compared to those of iv administration.In general,linear pharmacokinetics was observed for the conjugate within the dose range studied,and sc should be a promising administration route for the conjugate.