Kuwabara T, Kobayashi S, Sugiyama Y
Pharmaceutical Research Laboratories, Kyowa Hakko Kogyo Co., Ltd., Shizuoka, Japan.
Drug Metab Rev. 1996 Nov;28(4):625-58. doi: 10.3109/03602539608994020.
Granulocyte colony-stimulating factor (G-CSF), a hematopoietic growth factor, is a clinically effective drug used to promote neutrophil recovery in patients with chemo- or radiotherapy-induced neutropenia. We have reviewed the pharmacokinetic and pharmacodynamic properties of three kinds of G-CSFs: E. coli derived G-CSF, CHO-derived G-CSF, and mutein G-CSF. The clearances of G-CSFs are saturable and autoinducible in experimental animals and humans. That is, the systemic clearances of G-CSFs decrease as the dose injected increases and approaches a constant value. Both saturable and nonsaturable processes are involved in G-CSF elimination. Also, the systemic clearances of G-CSFs are increased by repeated administration of G-CSF. Although the relative bioavailability of G-CSFs after subcutaneous administration is approximately 60%, the increase in peripheral white blood cells or neutrophils is greater than that after intravenous administration at the same dose. The effects of G-CSFs seem to be time dependent rather than AUC dependent, considering that mean residence time of G-CSFs in the plasma is longer after subcutaneous administration than that after intravenous administration. There is a slight difference in the pharmacokinetics of E-coli- and CHO-G-CSF although they seem to be pharmacologically equivalent. The correlation between G-CSF clearance and peripheral neutrophil counts in the patients suggests that G-CSF receptors contribute to G-CSF clearance. Quantitative pharmacokinetic analysis using mutein G-CSF shows that the G-CSF receptor plays a major role in saturable G-CSF clearance, and that this saturable process accounts for approximately 80% of the total clearance at low doses. That is, the degradation following the receptor-mediated endocytosis in bone marrow might be a major clearance system of G-CSF at a physiological blood level. The G-CSF receptor in bone marrow might work not only as a signal transducer for differentiation and proliferation of granulopoietic precurcer cells but as a regulator of G-CSF levels in blood. In addition, at high doses, glomerular filtration in the kidneys is the major process for nonsaturable G-CSF clearance. At present, polyethylene glycol derivatives of G-CSF are being developed to reduce the frequency of G-CSF administration.
粒细胞集落刺激因子（G-CSF）是一种造血生长因子，是临床上用于促进化疗或放疗引起的中性粒细胞减少患者中性粒细胞恢复的有效药物。我们综述了三种G-CSF的药代动力学和药效学特性：大肠杆菌来源的G-CSF、中国仓鼠卵巢细胞（CHO）来源的G-CSF和突变体G-CSF。在实验动物和人类中，G-CSF的清除是可饱和且自身诱导的。也就是说，G-CSF的全身清除率随着注射剂量的增加而降低，并趋于一个恒定值。G-CSF的消除涉及可饱和和不饱和过程。此外，重复给予G-CSF会增加其全身清除率。尽管皮下注射后G-CSF的相对生物利用度约为60%，但相同剂量下外周白细胞或中性粒细胞的增加幅度大于静脉注射。考虑到皮下注射后G-CSF在血浆中的平均驻留时间比静脉注射后长，G-CSF的作用似乎与时间有关而非与血药浓度-时间曲线下面积（AUC）有关。大肠杆菌来源的G-CSF和CHO来源的G-CSF在药代动力学上有细微差异，尽管它们在药理学上似乎等效。患者中G-CSF清除率与外周中性粒细胞计数之间的相关性表明，G-CSF受体参与了G-CSF的清除。使用突变体G-CSF进行的定量药代动力学分析表明，G-CSF受体在可饱和G-CSF清除中起主要作用，并且在低剂量时，这种可饱和过程约占总清除率的80%。也就是说，在生理血药浓度下，骨髓中受体介导的内吞作用后的降解可能是G-CSF的主要清除系统。骨髓中的G-CSF受体可能不仅作为粒细胞前体细胞分化和增殖的信号转导器，还作为血液中G-CSF水平的调节剂。此外，在高剂量时，肾脏中的肾小球滤过是不饱和G-CSF清除率的主要过程。目前，正在开发G-CSF的聚乙二醇衍生物以减少G-CSF的给药频率。
