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

肝细胞生长因子（HGF）是许多类型上皮细胞的有效丝裂原，因此有望开发作为肝、肾和肺等损伤器官的治疗药物。然而，由于其对多种类型细胞具有广泛的生物活性，在临床阶段可能会产生副作用。本研究通过稳态药代动力学分析，研究了HGF在大鼠持续静脉输注过程中被其靶器官（包括肝、肾和肺）整体清除和提取的情况。随着稳态血浆浓度的增加，HGF的血浆清除率达到饱和，但即使血浆浓度远高于HGF受体的解离常数，也不能达到完全饱和。因此，除了受体介导的内吞作用外，还有一种低亲和力和高容量的清除机制参与了其从体内的清除。通过测定循环血液和肝静脉中HGF的浓度，肝脏中HGF的提取率为40-60%，而肾脏和肺中HGF的提取率均小于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，肝脏可有效地提取循环血浆中的HGF。为了观察肝、肾损伤大鼠体内HGF前体（单链形式）的损伤器官特异性生物活性。以单链形式注射后的有丝分裂活性作为标记指数仅在损伤器官中观察到，而HGF在正常和损伤器官中均表现出活性。因此，这种方法可能是在体内观察其器官特异性活性的方法之一。

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.