Kinetic analysis of the disposition of insulin-like growth factor 1 in healthy volunteers

Purpose. Insulin-like growth factor 1 (IGF-1) is predominantly bound to its specific binding proteins (IGFBPs) in circulating plasma. In the present s tudy, pharmacokinetic analysis of IGF-1 was performed in healthy volunteers to characterize the effect of interactions with IGFBPs on IGF-1 dispositio n. Methods. Plasma concentration profiles of both free and bound IGF-1 were ex amined at several doses. An in vitro plasma protein binding was also analyz ed. Results. The total body clearance (CLtotal) for the free IGF-1 was much hig her than the creatinine clearance, suggesting that the major elimination pa thway is by a route other than renal glomerular filtration. The CLtotal for the free IGF-I exhibited a dose-dependent reduction whereas that for the s um of unbound and bound IGF-I increased on increasing the dose. The data ob tained fitted closely a one-compartment model that involved the binding and dissociation of IGF-I, as well as its biosynthesis and elimination. The es timated parameters suggest that IGF-1 exhibits high affinity binding to IGF BPs, the rate-limiting step in the overall elimination being the dissociati on from IGFBPs. Conclusions. The saturation of both the plasma protein binding and eliminat ion accounts for the nonlinear pharmacokinetic profile. The binding to IGFB Ps markedly limits both the distribution and elimination of IGF-1.