The pharmacokinetics, tissue localization, and metabolic processing of recombinant human hepatocyte growth factor after intravenous administration in rats.
Hepatocyte growth factor (HGF) is a pluripotent mitogen thought to be involved in liver regeneration. It is synthesized as a single chain promitogen and requires proteolytic processing to a two-chain heterodimeric form for biological activity. The pharmacokinetics and tissue distribution of radioiodinated single chain recombinant human HGF ([125I]rhuHGF) were studied in male Sprague-Dawley rats after an iv bolus dose. Pharmacokinetic parameters were determined from trichloroacetic acid-precipitable radioactivity in serum samples. There was a rapid distribution phase (t1/2 alpha = 3.1 min) and a slower elimination phase (t1/2 beta = 114 min). Tissue distribution was assessed by whole body autoradiography 5, 60, and 1440 min after an iv bolus dose. rhuHGF rapidly distributed to the liver, kidney, adrenal gland, and spleen. The importance of the liver in the rapid clearance and subsequent conversion of single chain pro-rhuHGF to the mitogenically active two-chain form was demonstrated using an isolated rat liver perfusion system. TCA-precipitable radioactivity excreted into the bile (1.0 +/- 0.1%) and released into the venous effluent (38.9 +/- 6.1%) was monitored for 60 min after a portal vein injection. The appearance of radioactivity in both the bile and venous effluent was maximal between 20-35 min. Further characterization of the reduced samples by sodium dodecyl sulfate-polyacrylamide gel electrophoresis and autoradiography revealed that the two-chain form of [125I]rhuHGF was the predominant form after hepatic perfusion. These studies suggest that the liver plays a major role in the rapid clearance and subsequent activation of pro-rhuHGF in vivo.
Zioncheck
T F
TF
Department of Pharmacology, Genentech, Inc., South San Francisco, California 94080.
Richardson
L
L
DeGuzman
G G
GG
Modi
N B
NB
Hansen
S E
SE
Godowski
P J
PJ
D000818:Animals; D001345:Autoradiography; D001646:Bile / Q000378:metabolism; D001769:Blood / Q000378:metabolism; D016466:CHO Cells; D006224:Cricetinae; D005341:Fibrinolysin / Q000378:metabolism; D017228:Hepatocyte Growth Factor / Q000737:chemistry / Q000378:metabolism* / Q000493:pharmacokinetics*; D006801:Humans; D066298:In Vitro Techniques; D007275:Injections, Intravenous; D007457:Iodine Radioisotopes; D008099:Liver / Q000378:metabolism; D008297:Male; D010477:Perfusion; D051381:Rats; D017207:Rats, Sprague-Dawley; D011994:Recombinant Proteins; D014018:Tissue Distribution
D007457:Iodine Radioisotopes; D011994:Recombinant Proteins; D017228:Hepatocyte Growth Factor; D005341:Fibrinolysin