DISPOSITION OF RECOMBINANT HUMAN INSULIN-LIKE GROWTH FACTOR-I IN NORMAL AND HYPOPHYSECTOMIZED RATS

The pharmacokinetics of recombinant human insulin-like growth factor-I (rhIGF-I) was examined in normal and hypophysectomized (Hyper) rats a fter i.v. administration. The plasma concentration of rhIGF-I administ ered i.v. (0.32, 1.0 and 3.2 mg/kg) declined biexponentially in both n ormal and Hypox rats. Half-lives of the beta-phase were not significan tly different among the doses examined in both animal groups, but were shorter in Hypox rats. In Hypox rats, the values of the area under th e plasma concentration-time curve, the mean residence time, the varian ce of residence time and the apparent volume of distribution at steady -state decreased, while the total body clearance (CL(total)) increased . The distribution of rhIGF-I after i.v. administration (1.0 mg/kg) wa s examined in normal rats. High distribution to the kidney was observe d at early time points (5 min and 1 h), but no significant distributio n was found in other tissues. The ligation of renal vasculature greatl y reduced the CL(total), suggesting that the kidney is the main elimin ation organ. In spite of the rapid distribution of rhIGF-I to the kidn ey, the urinary excretion of intact rhIGF-I was negligible. Thus, the metabolism of rhIGF-I in the kidney was examined in vitro, and the res ults showed extensive metabolism in the brush border and lysosomal fra ctions of tubular cells. In the plasma of normal rats, rhIGF-I formed the 50 kDa complex first, and the 150 kDa complex was formed slowly. H owever, since unbound rhIGF-I and the 50 kDa complex were eliminated r apidly through the kidney, most of the rhIGF-I in the plasma was prese nt as the 150 kDa complex later on. The lack of 150 kDa complex in the plasma of Hypox rats might be the reason why the CL(total) of rhIGF-I is greater in Hypox rats than in normal rats.