Kunimasa J I, Itoga Y, Yasuhara M, Hori R, Inui K I
Department of Pharmacy, Kyoto University Hospital, Kyoto University, Japan.
J Pharm Pharmacol. 1999 Jul;51(7):777-82. doi: 10.1211/0022357991773131.
A new derivative of recombinant human granulocyte colony-stimulating factor (rhG-CSF) has been synthesized by conjugating rhG-CSF to poly(styrene-co-maleic acid) (poly(styrene-co-maleic acid)-rhG-CSF) to try to avoid glomerular filtration and thus potentiate the neutrophil-proliferating activity of rhG-CSF. Poly(styrene-co-maleic acid)-rhG-CSF was highly bound to bovine serum albumin (BSA) and the molecular weight of the poly(styrene-co-maleic acid)-rhG-CSF-BSA complex was estimated to be about 90000 by gel filtration. Intravenous administration of poly(styrene-co-maleic acid)-rhG-CSF to normal rats resulted in a dose-dependent increase in neutrophil count. The neutrophil-proliferating activity of poly(styrene-co-maleic acid)-rhG-CSF was about 10 times greater than that of rhG-CSF. After intravenous injection at a dose of 5 microg protein kg(-1) the total clearance of rhG-CSF fell from 71.0 to 32.1 mLh(-1) kg(-1) following poly(styrene-co-maleic acid) modification. An isolated perfusion study in rat kidney showed that the filtered fraction of rhG-CSF was reduced by conjugation with poly(styrene-co-maleic acid). These results suggest that poly(styrene-co-maleic acid)-conjugation can potentiate the neutrophil-proliferating activity of rhG-CSF by reducing, at least in part, its renal clearance.
通过将重组人粒细胞集落刺激因子（rhG-CSF）与聚（苯乙烯-共-马来酸）结合（聚（苯乙烯-共-马来酸）-rhG-CSF）合成了一种新型rhG-CSF衍生物，试图避免肾小球滤过，从而增强rhG-CSF的中性粒细胞增殖活性。聚（苯乙烯-共-马来酸）-rhG-CSF与牛血清白蛋白（BSA）高度结合，通过凝胶过滤法估计聚（苯乙烯-共-马来酸）-rhG-CSF-BSA复合物的分子量约为90000。对正常大鼠静脉注射聚（苯乙烯-共-马来酸）-rhG-CSF导致中性粒细胞计数呈剂量依赖性增加。聚（苯乙烯-共-马来酸）-rhG-CSF的中性粒细胞增殖活性约为rhG-CSF的10倍。在以5μg蛋白kg⁻¹的剂量静脉注射后，经聚（苯乙烯-共-马来酸）修饰后rhG-CSF的总清除率从71.0降至32.1 mL h⁻¹ kg⁻¹。大鼠肾脏的离体灌注研究表明，rhG-CSF与聚（苯乙烯-共-马来酸）结合后滤过分数降低。这些结果表明，聚（苯乙烯-共-马来酸）结合可以通过至少部分降低rhG-CSF的肾清除率来增强其中性粒细胞增殖活性。
