Abstract
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(∼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.
Footnotes
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Send reprint requests to: Yuichi Sugiyama, Department of Biopharmaceutics, Graduate School of Pharmaceutical Sciences, University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan. E-mail:sugiyama{at}seizai.f.u-tokyo.ac.jp
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↵1 This study was supported in part by a grant-in-aid for scientific research provided by the Ministry of Education, Science and Culture of Japan.
- Abbreviations:
- HGF
- hepatocyte growth factor
- Cp
- plasma concentration
- EIA
- enzyme-immunoassay
- CLuptake
- tissue uptake clearance
- CLp
- plasma clearance
- Eh
- extraction ratio in the liver,Er, extraction ratio in the kidney
- R0
- infusion rate
- Cpss
- steady-state concentration in circulating plasma
- Chvss
- steady-state concentration in hepatic vein
- Crvss
- steady-state concentration in renal vein
- Crass
- steady-state concentration in right atrium
- CLh
- hepatic clearance
- CLr
- renal clearance
- Qh
- hepatic plasma flow rate
- Qr
- renal plasma flow rate
- CLns
- nonsaturable elimination clearance
- Received July 31, 1998.
- Accepted March 11, 1999.
- The American Society for Pharmacology and Experimental Therapeutics
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