School of Pharmacy, The Chinese University of Hong Kong, HKSAR, China.
Phase I Clinical Trial Center, Taihe Hospital, Hubei University of Medicine, Shiyan, China.
Br J Pharmacol. 2024 Aug;181(16):2833-2850. doi: 10.1111/bph.16396. Epub 2024 Apr 23.
Our previous study reported that erythroferrone (ERFE), a newly identified hormone produced by erythroblasts, responded to recombinant human erythropoietin (rHuEPO) sensitively but its dynamics was complicated by double peaks and circadian rhythm. This study intends to elucidate the underlying mechanisms for the double peaks of ERFE dynamics and further determine whether early ERFE measurements can predict haemoglobin responses to rHuEPO.
By using the purified recombinant rat ERFE protein and investigating its deposition in rats, the production of ERFE was deconvoluted. To explore the role of iron in ERFE production, we monitored short-term changes of iron status after injection of rHuEPO or deferiprone. Pharmacokinetic/pharmacodynamic (PK/PD) modelling was used to confirm the mechanisms and examine the predictive ability of ERFE for long-term haemoglobin responses.
The rRatERFE protein was successfully purified. The production of ERFE was deconvoluted and showed two independent peaks (2 and 8 h). Transient iron decrease was observed at 4 h after rHuEPO injection and deferiprone induced significant increases of ERFE. Based on this mechanism, the PK/PD model could characterize the complex dynamics of ERFE. In addition, the model predictions further revealed a stronger correlation between ERFE and haemoglobin peak values than that for observed values.
The complex dynamics of ERFE should be composited by an immediate release and transient iron deficiency-mediated secondary production of ERFE. The early peak values of ERFE, which occur within a few hours, can predict haemoglobin responses several weeks after ESA treatment.
我们之前的研究报告称，红系生成素（erythroferrone，ERFE）是一种新发现的由红细胞生成素产生的激素，对重组人红细胞生成素（recombinant human erythropoietin，rHuEPO）反应敏感，但由于双峰和昼夜节律，其动态变化较为复杂。本研究旨在阐明 ERFE 动态双峰的潜在机制，并进一步确定早期 ERFE 测量是否可以预测对 rHuEPO 的血红蛋白反应。
通过使用纯化的重组大鼠 ERFE 蛋白并研究其在大鼠中的沉积情况，我们对 ERFE 的产生进行了剖析。为了探讨铁在 ERFE 产生中的作用，我们监测了 rHuEPO 或去铁酮注射后铁状态的短期变化。药代动力学/药效动力学（pharmacokinetic/pharmacodynamic，PK/PD）模型用于确认机制，并检查 ERFE 对长期血红蛋白反应的预测能力。
成功纯化了 rRatERFE 蛋白。对 ERFE 的产生进行了剖析，显示出两个独立的峰值（2 和 8 小时）。rHuEPO 注射后 4 小时观察到短暂的铁减少，而去铁酮诱导 ERFE 显著增加。基于该机制，PK/PD 模型可以描述 ERFE 的复杂动态。此外，模型预测进一步揭示了 ERFE 与血红蛋白峰值之间的相关性强于观察值。
ERFE 的复杂动态应由即刻释放和短暂铁缺乏介导的 ERFE 二次产生组成。ESA 治疗数周后，在几小时内出现的早期 ERFE 峰值可以预测血红蛋白反应。
