Kinetic analysis of the elimination process of human epidermal growth factor (hEGF) in rats

Pharmacokinetic study of human epidermal growth factor (hEGF) in rats was performed in vivo. The hepatic extraction ratio (EH) of [125I]hEGF, determined from the difference between the artery and the hepatic vein plasma concentrations at steady state, was 0.19. The hepatic clearance (CLH:7.56 ml/min/kg body wt), calculated by multiplying EH by the hepatic plasma flow rate (QP,H), was approximately 70% of the total body clearance (CLtot: 10.8 ml/min/kg body wt), which was determined from the steady-state arterial plasma concentration and the infusion rate. These results indicated that the liver is the main organ responsible for the removal of [125I]hEGF from the systemic circulation in rats. The renal extraction ratio (ER) of [125I]hEGF was half of that of [14C]inulin; this may have resulted from the plasma protein binding of [125I]hEGF, which was approximately 50% as determined by the charcoal adsorption method and the equilibrium gel-filtration method. The renal clearance (CLR:2.65 ml/min/kg body wt), calculated by multiplying ER by the renal plasma flow rate (QPR), was approximately 17% of the CLtot (15.6 ml/min/kg body wt), indicating a minor contribution of CLR to CLtot compared with that of CLH to CLtot. The CLR of [125I]hEGF calculated from the urinary excretion data was one-tenth of that calculated from the plasma concentration difference between the femoral artery and the renal vein at steady state. These results suggest that the bulk of [125I]hEGF cleared from the plasma by the kidney may have been metabolized further in the renal tubules before appearing in the urine.