Abstract
The pharmacokinetics of recombinant human insulin-like growth factor-I (rhIGF-I) was examined in normal and hypophysectomized (Hypox) rats after i.v. administration. The plasma concentration of rhIGF-I administered i.v. (0.32, 1.0 and 3.2 mg/kg) declined biexponentially in both normal and Hypox rats. Half-lives of the β-phase were not significantly different among the doses examined in both animal groups, but were shorter in Hypox rats. In Hypox rats, the values of the area under the plasma concentration-time curve, the mean residence time, the variance of residence time and the apparent volume of distribution at steady-state decreased, while the total body clearance (CLtotal) increased. The distribution of rhIGF-I after i.v. administration (1.0 mg/kg) was examined in normal rats. High distribution to the kidney was observed at early time points (5 min and 1 h), but no significant distribution was found in other tissues. The ligation of renal vasculature greatly reduced the CLtotal, suggesting that the kidney is the main elimination organ. In spite of the rapid distribution of rhIGF-I to the kidney, the urinary excretion of intact rhIGF-I was negligible. Thus, the metabolism of rhIGF-I in the kidney was examined in vitro, and the results showed extensive metabolism in the brush border and lysosomal fractions 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. However, since unbound rhIGF-I and the 50 kDa complex were eliminated rapidly through the kidney, most of the rhIGF-I in the plasma was present as the 150kDa complex later on. The lack of 150kDa complex in the plasma of Hypox rats might be the reason why the CLtotal of rhIGF-I is greater in Hypox rats than in normal rats.
