基因重组人粒-巨噬细胞集落刺激因子/白细胞介素-3融合蛋白在猕猴中的药代动力学

Pharmacokinetics of recombinant human granulocyte-macrophage colony stimulating factor/interleukin-3 fusion protein in rhesus monkeys

目的 研究重组人粒 /巨噬细胞集落刺激因子 白细胞介素 3融合蛋白 (PIXY32 1)在猕猴中的药动学。方法 12 5I 标记结合反相高效液相和酸沉淀法。结果 12 5I PIXY32 1纯度为 94 5 % ,标记前后PIXY32 1对TF 1细胞增殖的ED50 分别为 0 12 5和 0 119μg·L-1。12 5I PIXY32 1在体内迅速降解。iv和sc后末端T1/ 2 相近 ,为 6 6～ 8 2h。AUC随sc剂量增大 ,全身清除率ClS 相近 ,sc生物利用度6 3 %± 2 1%。泌尿系统浓度最高 ,胆汁其次 ,骨髓和脾脏高于其它组织略低于血清 ,脑内最低。主要经尿排泄 ,少部分在尿中以原型排出。结论 猕猴sc12 5I PIXY32 12 0～ 80 μg·kg-1后为线性药代动力学。肾脏在12 5I PIXY32

AIM To study the pharmacokinetics of recombinant human granulocyte macrophage colony stimulating factor / interleukin 3 fusion protein (PIXY321) in rhesus monkeys. METHODS 125 I label combined with reversed phase high performance liquid chromatography (RHPLC). RESULTS The purity of 125 I PIXY321 was 94 5%. The EC 50 to stimulate the growth of TF 1 cell by PIXY321 were 0 125 and 0 119 μg·L -1 , respectively, before and after 125 I labeled. 125 I PIXY321 was degraded within body rapidly. Concentration time profile after iv of 20 μg·kg -1 of 125 I PIXY321 was fitted with 2 comparamental model. T 1/2 α was (0 11±0 05) h. T 1/2 β was (6 6±1 1) h. T 1/2 β were (0 44±0 37) h, (0 57±0 22) h, and (0 90±0 36) h, respectively. T peak were (2 4±0 2) h, (2 4±0 5) h, and (2 6±0 5) h, respectively. Within dosage ranges AUC increased with dose and Cl S were similar. Bioavailability after sc was 63%±21%. Rapid biodegradation was found in plasma. Distribution profiles of TCA perceptible radioactivity was as follows: the highest level was found in urinary system. Levels in bile enteric system, bone marrow and spleen were near to that in plasma, and level in brain was the lowest. The major route of excretion was urinary system. CONCLUSION The linear pharmacokinetics is found after sc of 20, 40 and 80 μg·kg -1 of 125 I PIXY321 in rhesus monkeys. Kidney is the major organ for biodegradation.