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首页> 外文期刊>Pharmacological research: The official journal of The Italian Pharmacological Society >Evidence that the granulocyte colony-stimulating factor (G-CSF) receptor plays a role in the pharmacokinetics of G-CSF and PegG-CSF using a G-CSF-R KO model.
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Evidence that the granulocyte colony-stimulating factor (G-CSF) receptor plays a role in the pharmacokinetics of G-CSF and PegG-CSF using a G-CSF-R KO model.

机译：使用G-CSF-R KO模型，粒细胞集落刺激因子（G-CSF）受体在G-CSF和PegG-CSF的药代动力学中起作用的证据。

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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 100microgkg(-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 100microgkg(-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.
机译：聚乙二醇与非格司亭的共价结合产生了新的聚乙二醇非格司亭分子，其半衰期比非格司亭更长。非格司亭和聚乙二醇非格司亭的清除均可能涉及粒细胞集落模拟因子（G-CSF）受体结合，但尚未在具有和未具有功能性G-CSF受体的小鼠中比较这些药物的药代动力学。我们力求阐明使用野生型（WT）小鼠或具有非功能性G-CSF-R的小鼠（敲除，KO）的受体介导的非格司亭和吡非司亭清除的作用。我们向WT和KO小鼠静脉注射单剂量的非格司亭或培非司亭（10或100microgkg（-1））。通过酶联免疫吸附测定（ELISA）在预设时间点测量血浆蛋白水平，并计算AUC，MRT，CL，V（d）和T（1/2）。当与野生型小鼠比较时，G-CSF-R KO小鼠的AUC明显更大，MRT更长，T（1/2）更长，清除率更低。动物是否接受10或100microgkg（-1），是否接受非格司亭或聚乙二醇非格司亭，都是这种情况。 WT和KO小鼠的蛋白质分布体积相同。但是，吡非司亭给药后的V（d）比非格司亭给药后大。在WT和KO小鼠中，增加Figrastim或pegfilgrastim的剂量会导致AUC成比例增加。功能性G-CSF-R是非格司亭和聚乙二醇非格司亭血浆清除的重要机制。

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