DISPOSITION KINETICS OF HUMAN EPIDERMAL GROWTH-FACTOR (HEGF1-53) AND ITS TRUNCATED FRAGMENT (HEGF1-48) IN RATS

Clearance of human epidermal growth factor (hEGF1-53) has been propose d to be mediated by a receptor pathway involving a typical cascade of ligand-receptor endocytosis and lysosomal degradation. Deletion of the C-terminal pentapeptide from hEGF1-53, which yields hEGF1-48, is know n to be associated with a marked reduction in receptor binding, We def ined the intravenous (iv)-bolus (acute exposure) and the iv-infusion ( prolonged exposure) pharmacokinetics of hEGF1-53 and hEGF1-48 in rats to investigate the impact of the deletion of C-terminal pentapeptide o n the EGF clearance using a validated, sensitive ELISA method for quan titation of the peptides in plasma, Both peptides at the low iv bolus dose of 10 mu g/kg were cleared from plasma with unusually high cleara nces (CL(tot): 128 +/- 31 ml/min/kg for hEGF1-53 and 168 +/- 47 ml/min /kg for hEGF1-48), which are virtually complete within 4-min postdose, and the difference in the overall pharmacokinetics is of minor signif icance. A 10-fold increase in bolus dose to 100 mu g/kg decreased clea rances 3- to 6-fold, indicating a nonlinear kinetics for both peptides ; however, hEGF1-48 was cleared (52 +/- 11 ml/min/kg) 2.5-fold faster than hEGF1-53, A similar nonlinear kinetics was also noticed for both peptides when they were administered by a 2-hr iv infusion at 30 and 3 00 mu g/kg doses, hEGF1-48 at the low and high infusion doses was clea red at 126 +/- 16 and 33.7 +/- 14.5 ml/min/kg, respectively, which are 4-fold greater than the corresponding clearance rates of hEGF1-53. Th ese observations suggest that a) deletion of C-terminal pentapeptide i s associated with a faster clearance of the growth factor and b) the r eceptor clearance pathway may be more sensitive to saturation with hEG F1-53 than with hEGF1-48 at low microgram dose levels, hEGF1-53 at the low infusion dose of 30 mu g/kg was cleared (32.1 +/- 6.2 ml/min/kg) 4-fold slower in comparison with the low bolus dose of 10 mu g/kg, ind icating a remarkable injection mode-dependent disposition kinetics for hEGF1-53, which does not exist for hEGF1-48. The overall results sugg est that deletion of C-terminal pentapeptide leads to faster clearance of the growth factor, and the degree of the impact of deletion of C-t erminal pentapeptide on the global pharmacokinetics is also dependent on the length of exposure of the receptor to the ligand. The negative relationship between receptor binding and plasma clearance for the two peptides remains to be elucidated at the molecular and receptor level s.