聚乙二醇化重组人粒细胞集落刺激因子的药代动力学与组织分布研究

目的 研究聚乙二醇化重组人粒细胞集落刺激因子(PEG-rhG-CSF)在动物体内的药代动力学与组织分布.方法 猕猴给予不同剂量(30、100和300μg/kg)的PEG-rhG-CSF,酶联免疫吸附法(ELISA)测定猕猴血浆中PEG-rhG-CSF浓度;(125)I]标记示踪法结合分子排阻色潜法观察PEG-rhG-...

Pharmacokinetics and tissue distribution of pegylated recombinant human granulocyte colony-stimulating factor

Objective To study the pharmacokinetics and tissue distribution of pegylated recombinant human granulocyte colony-stimulating factor （PEG-rhG-CSF） in animals. Methods Rhesus monkeys were administered PEG-rhG-CSF at various doses （30, 100 and 300 μg/kg）. Enzyme-linked immunosorbent assay （ELISA） was used to determine the concentrations of PEG-rhG-CSF in plasma of rhesus monkeys. ［¹²⁵I］ labeled tracing method combined with size exclusion chromatography method was utilized to investigate tissue distribution of PEG-rhG-CSF in Wistar rats. Results After Rhesus monkeys were given PEG-rhG-CSF by subcutaneous administration, the concentration and systemic exposure level in plasma increased as non-linear kinetics following with the dosage. The peak time （Tmax） was between 6.67-12.00 h. Among the groups of PEG-rhG-CSF 30, 100 and 300 μg/kg, the clearance （CL） decreased in turn, and area under curve （AUC） was out of direct proportion to the dosage. The absolute bioavailability was 47.5 % after sc administration. After given PEG-rhG-CSF 100 μg/kg, the maximum concentration （C_max）, AUC were（1671 ± 357）μg/L and（45 156 ± 9407）（μg·h）/L, respectively, which were obviously higher than that of rhG-CSF group with clinical dosage 10 μg/kg （P< 0.05）. T_1/2β of PEG-rhG-CSF group was（13 ± 3） h, which was significantly increased compared with that of rhG-CSF group which was（1.52 ± 0.08） h （P< 0.05）. Meanwhile, CL of PEG-rhG-CSF group was（2.3 ± 0.5） ml/（h·kg）, which was significantly lower thall than of rhG-CSF group with（19.6 ± 2.4） ml/（h·kg） （P< 0.01）. Total radioactivity in serum, kindey and lung was high in rats given ［¹²⁵I］ PEG-rhG-CSF. The concentration of intact ［¹²⁵I］ PEG-rhG-CSF in serum reached the maximum at 2 h, while other tissues, like lung, stool in bowel and urinary bladder, were distributed slowly after administration, in which the radioactive concentrations arrived the maximum at 8 h. Micromolecular metabolites of ［¹²⁵I］ PEG-rhG-CSF were mainly existed in the urine. The conjugation of drug and plasma protein was not observed. Conclusion rhG-CSF modified with PEG can decrease the systemic clearance, prolong the circulating half-life, elevate in vivo exposure level, achieve the purpose of prolonged action. The drug is mainly distributed over vascular bed and metabolized to micromolecule excreting by urinary system. PEG-rhG-CSF is difficult to permeate through the blood-brain barrier.