Chapel S H, Veng-Pedersen P, Schmidt R L, Widness J A
The Colleges of Pharmacy, Department of Pediatrics, The University of Iowa, Iowa City, USA.
J Pharmacol Exp Ther. 2000 Oct;295(1):346-51.
The pharmacodynamics (PD) of the reticulocyte response resulting from phlebotomy-induced erythropoietin (EPO) was investigated in adult sheep. The anemia caused by the controlled phlebotomy (Hb < 4 g/dl, t = 0) resulted in a rapid increase in EPO with peak concentrations from 200 to 1400 mU/ml at 0.5 to 3 days generating a delayed reticulocyte response with peak levels from 9.3 to 14.1% at 2.5 to 5.1 days. The PD EPO-reticulocyte relationship is well described by a simple kinetic model involving 3 relevant physiologic parameters: T(1) = lag-time (0.73 +/- 0.32 days, mean +/- S.D.), T(2) = reticulocyte maturation time (5.61 +/- 1.41 days), and k = EPO efficacy coefficient (0.052 +/- 0.048% g/dl mU/ml/day). Accordingly, 0.52% reticulocytes at 10 g/dl Hb level are generated per day at an EPO concentration of 100 mU/ml. The difference between the T(2) parameter in this study and the maturation time reported for humans may be due to interspecies differences or different technique and experimental conditions. The PD transduction appears largely linear in the observed EPO concentration range, indicating a full utilization of EPO without any significant PD saturation. Also, the EPO concentration versus time profiles resulting from the phlebotomy were similar to exogenous EPO profiles resulting from s.c. therapeutic dosing. This study supports the hypothesis that s.c. EPO dosing is more efficacious than i.v. dosing.
在成年绵羊中研究了放血诱导的促红细胞生成素（EPO）所引起的网织红细胞反应的药效学（PD）。控制性放血（Hb < 4 g/dl，t = 0）所导致的贫血使EPO迅速增加，在0.5至3天时峰值浓度为200至1400 mU/ml，产生延迟的网织红细胞反应，在2.5至5.1天时峰值水平为9.3%至14.1%。EPO-网织红细胞关系的PD可用一个涉及3个相关生理参数的简单动力学模型很好地描述：T(1)=延迟时间（0.73±0.32天，平均值±标准差），T(2)=网织红细胞成熟时间（5.61±1.41天），以及k = EPO效能系数（0.052±0.048% g/dl mU/ml/天）。因此，在EPO浓度为100 mU/ml时，每天在Hb水平为10 g/dl时产生0.52%的网织红细胞。本研究中T(2)参数与报道的人类成熟时间之间的差异可能是由于种间差异或不同的技术和实验条件。在观察到的EPO浓度范围内，PD转导在很大程度上呈线性，表明EPO得到充分利用，没有任何明显的PD饱和。此外，放血所导致的EPO浓度随时间变化曲线与皮下治疗给药所产生的外源性EPO曲线相似。本研究支持皮下注射EPO给药比静脉注射给药更有效的假说。
