Kotto-Kome Anne C, Fox Samuel E, Lu Wenge, Yang Bing-Bing, Christensen Robert D, Calhoun Darlene A
All Children's Hospital, Children's Research Institute, University of South Florida, 140 Seventh Avenue South CRI Room 2006, St. Petersburg, FL 33701, USA.
Pharmacol Res. 2004 Jul;50(1):55-8. doi: 10.1016/j.phrs.2003.12.011.
The covalent attachment of polyethylene glycol to filgrastim results in a new molecule pegfilgrastim, which has a significantly longer half-life than filgrastim. It is likely that the clearance of both filgrastim and pegfilgrastim involves granulocyte colony simulating factor (G-CSF) receptor binding, but the pharmacokinetics of these drugs have not been compared in mice with and without a functional G-CSF receptor. We sought to clarify the role of receptor-mediated clearance of filgrastim and pegfilgrastim using wild-type (WT) mice or mice with a non-functional G-CSF-R (knockout, KO). We administered single doses of filgrastim or pegfilgrastim (10 or 100 microg kg(-1)) intravenously to WT and KO mice. Plasma levels of protein were measured by enzyme-linked immunosorbent assay (ELISA) at preset time points, and AUC, MRT, CL, V(d), and T(1/2) were calculated. When compared with WT mice, the G-CSF-R KO mice had significantly greater AUC, longer MRT, longer T(1/2), and lower clearance. This was the case whether animals received 10 or 100 microg kg(-1) and whether they received filgrastim or pegfilgrastim. The volume of protein distribution was identical among WT and KO mice. However, the V(d) was larger after pegfilgrastim dosing than after filgrastim dosing. In both WT and KO mice, increasing the dose of figrastim or pegfilgrastim resulted in a proportional increase in the AUC. A functional G-CSF-R is an important mechanism in the plasma clearance of both filgrastim and pegfilgrastim.
聚乙二醇与非格司亭的共价连接产生了一种新分子培非格司亭，其半衰期比非格司亭显著更长。非格司亭和培非格司亭的清除可能都涉及粒细胞集落刺激因子（G-CSF）受体结合，但尚未在具有和不具有功能性G-CSF受体的小鼠中比较这些药物的药代动力学。我们试图使用野生型（WT）小鼠或具有无功能G-CSF-R（基因敲除，KO）的小鼠来阐明受体介导的非格司亭和培非格司亭清除的作用。我们向WT和KO小鼠静脉内单剂量给药非格司亭或培非格司亭（10或100μg kg⁻¹）。在预设时间点通过酶联免疫吸附测定（ELISA）测量血浆蛋白水平，并计算AUC、MRT、CL、V(d)和T(1/2)。与WT小鼠相比，G-CSF-R KO小鼠具有显著更大的AUC、更长的MRT、更长的T(1/2)和更低的清除率。无论动物接受10还是100μg kg⁻¹，以及接受非格司亭还是培非格司亭，都是如此。WT和KO小鼠之间的蛋白分布体积相同。然而，培非格司亭给药后的V(d)比非格司亭给药后的更大。在WT和KO小鼠中，增加非格司亭或培非格司亭的剂量都会导致AUC成比例增加。功能性G-CSF-R是血浆清除非格司亭和培非格司亭的重要机制。
