Pharmacokinetic modeling of hepatocyte growth factor in experimental animals and humans
Pharmacokinetic modeling of hepatocyte growth factor in experimental animals and humans
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实验动物和人类肝细胞生长因子的药代动力学模型
DOI：
10.1002/jps.23337
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发表时间：
2013
期刊：
影响因子：
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通讯作者：
Tomoko Sugiura et al.
中科院分区：
文献类型：
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作者：
Mami Tsume;et al.;松尾 勲 他;松尾 勲 他;Piao X;Tomoko Sugiura et al.
肝细胞生长因子（HGF）正在开发用于治疗肾衰竭。本研究旨在阐明肾衰竭时HGF药代动力学的变化，并建立适用于单次和重复给药的药代动力学模型。甘油诱导的急性肾衰竭小鼠的血浆浓度曲线与正常小鼠相似，表明肾脏对HGF的全身清除贡献极小。然而，在这两种情况下，荧光素-4-异氰酸酯标记的HGF在肾小管中的蓄积表明肾脏中发生了HGF的有效内吞作用。构建了包括血浆和肝脏隔室的药代动力学模型，纳入了用于结合和随后内吞HGF的高亲和力和低亲和力受体，因为HGF通过特异性受体c-Met和肝素样物质消除。该模型很好地解释了动物和人体推注后检查的所有剂量下的血浆浓度曲线，以及啮齿动物输注期间的血浆浓度曲线。它包括受HGF负调控的受体外化，可以解释猴重复给药期间谷浓度逐渐增加的原因。HGF的总体药代动力学特征受至少两种受体的控制，并通过该药代动力学模型得到很好的描述，这将有助于临床试验的安全管理。
Hepatocyte growth factor (HGF) is under development for treatment of renal failure. This study was designed to clarify changes in HGF pharmacokinetics in renal failure and to establish a pharmacokinetic model applicable to single and repeated doses. The plasma concentration profile in mice with glycerol‐induced acute renal failure was similar to that in normal mice, indicating a minimal contribution of kidney to systemic clearance of HGF. Nevertheless, accumulation of fluorescein‐4‐isocyanate‐labeled HGF in renal tubules in both cases suggests the occurrence of efficient endocytosis of HGF in kidney. A pharmacokinetic model including plasma and liver compartments was constructed, incorporating both high‐ and low‐affinity receptors for association and subsequent endocytosis of HGF because HGF is eliminated via specific receptor c‐Met and heparin‐like substance. The model well explained the plasma concentration profiles at all doses examined after bolus injection in animals and humans, and those during infusion in rodents. It includes externalization of receptors, which is negatively regulated by HGF, and can explain the gradual increase in trough concentration during repeated dosing in monkeys. Overall pharmacokinetic profiles of HGF are governed by at least two receptors and are well described by this pharmacokinetic model, which should assist in safe management of clinical trials.