Dose-dependent plasma clearance of human epidermal growth factor in rats.
Exogenously administered human epidermal growth factor (hEGF) shows a marked dose-dependent plasma disposition in rats. In the present study, total plasma clearance (CLtotal) of hEGF was examined from the viewpoint of hepatic blood flow and accessible EGF receptors in a dosing range of hEGF from 30 to 1000 micrograms/kg. In rats in which down-regulation of EGF receptors caused a reduction in their number (50% below the normal level) (group 1), the CLtotal of hEGF was decreased only at a medium dose (100 micrograms/kg) compared to those in normal rats. In rats in which hepatic intoxication with carbon tetrachloride caused 50% reduction of both EGF receptor number and hepatic blood flow (group 2), CLtotal was decreased at low and medium hEGF doses. The decrease at a low hEGF dose was proportional to the decrease in the hepatic blood flow. In rats with reduced hepatic blood flow caused by hypothermia (group 3), CLtotal was decreased at all hEGF doses examined, and the decrease at a low hEGF dose (50 micrograms/kg) was proportional to the hepatic blood flow. The decreases of CLtotal at a medium hEGF dose in groups 1, 2 and 3 were well accounted for by the decrease of hepatic blood flow and/or EGF receptor number in a well-stirred model.(ABSTRACT TRUNCATED AT 250 WORDS)
Murakami
T
T
Institute of Pharmaceutical Sciences, Hiroshima University School of Medicine, Japan.
Misaki
M
M
Masuda
S
S
Higashi
Y
Y
Fuwa
T
T
Yata
N
N
D000818:Animals; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D004815:Epidermal Growth Factor / Q000097:blood*; D066246:ErbB Receptors / Q000378:metabolism; D006801:Humans; D007124:Immunoenzyme Techniques; D008099:Liver / Q000098:blood supply / Q000378:metabolism / Q000648:ultrastructure; D008102:Liver Circulation / Q000502:physiology; D008297:Male; D008954:Models, Biological; D010446:Peptide Fragments / Q000032:analysis; D051381:Rats; D017207:Rats, Sprague-Dawley
D010446:Peptide Fragments; D004815:Epidermal Growth Factor; D066246:ErbB Receptors