Veng-Pedersen P, Widness J A, Pereira L M, Schmidt R L, Lowe L S
College of Pharmacy, Division of Pharmaceutics, University of Iowa, Iowa City, IA 52242, USA. veng@uiowa-edu
Biopharm Drug Dispos. 1999 May;20(4):217-23. doi: 10.1002/(sici)1099-081x(199905)20:4<217::aid-bdd177>3.0.co;2-6.
The primary mechanism of erythropoietin's (EPO) in vivo elimination and the tissue, or tissues, responsible are unknown. Previous studies indicating that EPO pharmacokinetic (PK) behaviour is nonlinear suggest that EPO elimination takes place by a saturable mechanism. A versatile PK system analysis, the Disposition Decomposition Analysis (DDA), capable of quantification of the Michaelis-Menten parameters, V(m) and k(m) was used to analyze and compare EPO's PK behaviour in newborn sheep and preterm infants. Lambs and infants both demonstrated nonlinear PK behaviour appropriately analyzed with DDA. Compared to preterm infants, lambs had significantly greater (p<0.05) elimination capacity as determined by the V(m) (2789+/-525 versus 1767+/-250 mU/mL per h (mean+/-S.E.), respectively), and larger extrapolated linear clearances (116+/-19.1 versus 21.3+/-1.75 mL/kg per h, respectively) (p<0.01). Lambs also demonstrated significantly larger (p<0.01) degrees of nonlinearity as judged by smaller mean k(m) values (2142+/-258 versus 6796+/-1.007 mU/mL, respectively). Of note, although the DDA does not distinguish what the mechanism of EPO elimination is, enzymatic degradation and receptor-mediated cellular internalization are two possibilities. The in vivo DDA-derived k(m) values were similar to reported in vitro binding affinity k(d) data for erythroid progenitors and cell lines having EPO-R's, i.e. 240-2400 mU/mL. The present study's demonstration that EPO's nonlinear PK behaviour in both sheep and humans can be analyzed by the DDA methodology indicates that the sheep model may be used in invasive studies needed to further characterize the mechanism of EPO elimination.
促红细胞生成素（EPO）在体内消除的主要机制以及负责消除的组织尚不清楚。先前的研究表明EPO的药代动力学（PK）行为是非线性的，这表明EPO的消除是通过一种可饱和机制进行的。一种通用的PK系统分析方法，即处置分解分析（DDA），能够对米氏参数V（m）和k（m）进行量化，用于分析和比较新生绵羊和早产儿中EPO的PK行为。羔羊和婴儿均表现出非线性PK行为，可用DDA进行适当分析。与早产儿相比，羔羊的消除能力显著更强（p<0.05），这由V（m）确定（分别为2789±525与1767±250 mU/mL每小时（平均值±标准误）），并且外推线性清除率更大（分别为116±19.1与21.3±1.75 mL/kg每小时）（p<0.01）。根据较小的平均k（m）值判断，羔羊的非线性程度也显著更大（p<0.01）（分别为2142±258与6796±1.007 mU/mL）。值得注意的是，尽管DDA无法区分EPO消除的机制是什么，但酶促降解和受体介导的细胞内化是两种可能的机制。体内DDA得出的k（m）值与报道的具有EPO-R的红系祖细胞和细胞系的体外结合亲和力k（d）数据相似，即240 - 2400 mU/mL。本研究证明，绵羊和人类中EPO的非线性PK行为均可通过DDA方法进行分析，这表明绵羊模型可用于进一步表征EPO消除机制所需的侵入性研究。
