Dose-Dependent Plasma Clearance of Human Epidermal Growth Factor in Rats

Abstract

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 μg/kg. In rats in which down-regulation of EGF receptors caused a reduction in their number (50% below the normal level) (group 1), the CLtotalof hEGF was decreased only at a medium dose (100 μg/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), CLtotalwas 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), CLtotalwas decreased at all hEGF doses examined, and the decrease at a low hEGF dose (50 μg/kg) was proportional to the hepatic blood flow. The decreases of CLtotalat 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. Above results indicate that (a) the CLtotalof hEGF at the lower dose is regulated mainly by hepatic blood flow, (b) at the medium dose, both hepatic blood flow and EGF receptor number affect the CLtotal, and, (c) at the higher dose (>500 μg/kg), the contribution of the saturable uptake of hEGF by tissues to CLtotalbecomes lower, and CLtotalwill be mainly comprised of the extrahepatic clearance.