Pharmacokinetic analysis of the injured organ-specific targeting of hepatocyte growth factor

肝细胞生长因子损伤器官特异性靶向药代动力学分析

• 批准号: 11672138
• 负责人: KATO Yukio
• 金额: $ 2.3万
• 依托单位: Graduate School of Pharmaceutical Sciences, The University of Tokyo
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 1999
• 资助国家: 日本
• 起止时间: 1999 至 2000
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-11672138/
• 关键词: Hepatocyte growth factor; Cytokine; Pharmacokinetics; Drug Delivery System; Homeostasis; Clearance

Hepatocyte growth factor (HGF) is the potent mitogen for many types of epithelial cells and, therefore, is expected to be developed as therapeutics for the injured organs including the liver, kidney and lung. However, such a wide range of its biological activity for many types of cells may result in the side effects in the clinical stage. In the present study a steady-state pharmacokinetic analysis was performed to investigate the overall elimination and extraction of HGF by its target organs, including liver, kidney, and lung, during its constant intravenous infusion in rats. The plasma clearance of HGF became saturated as the steady-state plasma increased, but complete saturation was not achieved, even when the plasma concentration was much higher than the dissociation constant for the HGF receptor. Therefore, there is a low-affinity and high-capacity clearance mechanism, other than receptor-mediated endocytosis, involved in its elimination from the body. The hepatic extraction ratio of HGF, assessed by determining the HGF concentration in both the circulating blood and hepatic vein, was 40-60% while the HGF extraction both in kidney and lung was always less than 10%. Hepatic clearance accounted for approximately 70% of the plasma clearance. Thus, the present study shows that HGF in circulating plasma is efficiently extracted by the liver, compared with other HGF target organs. To observe the injured organ-specific biological activity the precursor (a single-chain form) of HGF was intravenously administered in the liver or kidney injured rats. The mitogenic activity assessed as the lableling index after injection of a single chain form was observed only in the injured organ whereas HGF exhibited its activity both in normal and injured organs. Thus, this approach may be one of the methods to observe its organ-specific activity in vivo.

肝细胞生长因子（HGF）是多种上皮细胞的有效促细胞分裂剂，因此有望被开发为治疗肝、肾和肺等受损器官的药物。然而，其对多种细胞的广泛生物活性可能会导致临床阶段的副作用。在本研究中，进行了稳态药代动力学分析，以研究 HGF 在大鼠持续静脉输注过程中被靶器官（包括肝、肾和肺）的总体消除和提取情况。随着稳态血浆增加，HGF 的血浆清除率变得饱和，但即使血浆浓度远高于 HGF 受体的解离常数，也没有达到完全饱和。因此，除了受体介导的内吞作用之外，还有一种低亲和力和高容量的清除机制参与其从体内的消除。通过测定循环血和肝静脉中的HGF浓度评估，HGF的肝脏提取率为40-60%，而肾脏和肺中的HGF提取率始终低于10%。肝脏清除率约占血浆清除率的70%。因此，本研究表明，与其他 HGF 靶器官相比，肝脏可以有效地提取循环血浆中的 HGF。为了观察受损器官特异性的生物活性，将 HGF 前体（单链形式）静脉注射到肝脏或肾脏损伤的大鼠中。仅在受损器官中观察到注射单链形式后评估为标记指数的促有丝分裂活性，而HGF在正常和受损器官中均表现出其活性。因此，该方法可能是观察其体内器官特异性活性的方法之一。

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