PHARMACOKINETICS OF RECOMBINANT HUMAN INSULIN-LIKE GROWTH-FACTOR-I INDIABETIC RATS

Pharmacokinetics of recombinant human insulin-like growth factor-I (rh IGF-I) was investigated after iv administration (0.32, 1.0, and 3.2 mg /kg) to normal and streptozotocin-induced diabetic rats, rhIGF-I was e liminated from plasma biexponentially in both normal and diabetic rats , Plasma concentrations of rhIGF-I were lower at almost all the time p oints examined in diabetic rats than in normal rats. The pharmacokinet ic parameters of total body clearance (CLtotal), mean residence time ( MRT), and elimination rate constant (k(el)) indicated that rhIGF-I dis appeared more rapidly In diabetic rats than in normal rats at any dosa ge. The amounts of IGF binding proteins (IGFBPs) in plasma were assess ed by determining the endogenous IGF-I and. Levels of the 150 kDa comp lex, a ternary complex of IGF-I with IGFPB-3 and an acid-labile subuni t, the 50 kDa complex, a complex of IGF-I with IGFBP-2, were found to be lower in diabetic rats than in normal rats, Fractions af rhIGF-I fr ee and bound to the binding proteins were estimated by gel chromatogra phic separation of rhIGF-I in plasma after iv administration, and the pharmacokinetics of free and bound rhIGF-I was analyzed independently, Plasma concentrations of free and bound rhIGF-I were lower in diabeti c rats than in normal rats, especially the concentrations of the 150 k Da complex were much lower. The reduced IGFBP-3 would be responsible f or the faster elimination of rhIGF-I in diabetic rats.