Kato M, Kato Y, Nakamura T, Sugiyama Y
Graduate School of Pharmaceutical Sciences, University of Tokyo, Hongo, Bunkyo-ku, Tokyo, Japan.
J Pharmacol Exp Ther. 1999 Jul;290(1):373-9.
A steady-state pharmacokinetic analysis was performed to investigate the overall elimination and extraction of hepatocyte growth factor (HGF) by its target organs, including liver, kidney, and lung, during its constant i.v. infusion in rats. The plasma clearance of HGF became saturated as the steady-state plasma concentration (Cpss) increased, but complete saturation was not achieved, even when the Cpss ( approximately 1000 pM) was much higher than the dissociation constant for the HGF receptor (20-40 pM), which has been identified as one of the major clearance sites for HGF. This result suggests that 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 to 60%, whereas the HGF extraction both in kidney and lung was always less than 10%. Hepatic clearance accounted for approximately 70% of the plasma clearance at any Cpss. Thus, the present study shows that HGF in circulating plasma is efficiently extracted by the liver compared with other HGF target organs, the liver being involved in 70% of the overall elimination both under linear and nonlinear conditions. Biliary excretion of HGF was observed, but this accounted for only 0.1 to 0. 2% of the infusion rate, indicating that the nonlysosomal pathway of HGF, which avoids the lysosomal enzymes and transcytoses HGF directly into the bile, is very minor indeed.
进行了稳态药代动力学分析，以研究在大鼠持续静脉输注肝细胞生长因子（HGF）期间，其靶器官（包括肝脏、肾脏和肺）对HGF的整体消除和摄取情况。随着稳态血浆浓度（Cpss）升高，HGF的血浆清除率达到饱和，但即使Cpss（约1000 pM）远高于已被确定为HGF主要清除位点之一的HGF受体解离常数（20 - 40 pM），也未实现完全饱和。该结果表明，除了受体介导的内吞作用外，还存在一种低亲和力、高容量的清除机制参与其从体内的消除。通过测定循环血液和肝静脉中的HGF浓度评估，HGF的肝摄取率为40%至60%，而肾脏和肺中的HGF摄取率始终低于10%。在任何Cpss下，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，循环血浆中的HGF能被肝脏有效摄取，在线性和非线性条件下，肝脏参与了约70%的整体消除。观察到了HGF的胆汁排泄，但这仅占输注速率的0.1%至0.2%，表明HGF的非溶酶体途径（该途径避免溶酶体酶并将HGF直接转运至胆汁中）实际上非常少。
