PURPOSE: Insulin-like growth factor 1 (IGF-1) is predominantly bound to its specific binding proteins (IGFBPs) in circulating plasma. In the present study, pharmacokinetic analysis of IGF-1 was performed in healthy volunteers to characterize the effect of interactions with IGFBPs on IGF-1 disposition. METHODS: Plasma concentration profiles of both free and bound IGF-1 were examined at several doses. An in vitro plasma protein binding was also analyzed. RESULTS: The total body clearance (CLtotal) for the free IGF-1 was much higher than the creatinine clearance, suggesting that the major elimination pathway is by a route other than renal glomerular filtration. The CLtotal for the free IGF-1 exhibited a dose-dependent reduction whereas that for the sum of unbound and bound IGF-1 increased on increasing the dose. The data obtained fitted closely a one-compartment model that involved the binding and dissociation of IGF-1, as well as its biosynthesis and elimination. The estimated parameters suggest that IGF-1 exhibits high affinity binding to IGFBPs. the rate-limiting step in the overall elimination being the dissociation from IGFBPs. CONCLUSIONS: The saturation of both the plasma protein binding and elimination accounts for the nonlinear pharmacokinetic profile. The binding to IGFBPs markedly limits both the distribution and elimination of IGF-1.
PURPOSE:Insulin-like growth factor 1 (IGF-1) is predominantly bound to its specific binding proteins (IGFBPs) in circulating plasma. In the present study, pharmacokinetic analysis of IGF-1 was performed in healthy volunteers to characterize the effect of interactions with IGFBPs on IGF-1 disposition. METHODS: Plasma concentration profiles of both free and bound IGF-1 were examined at several doses. An in vitro plasma protein binding was also analyzed. RESULTS: The total body clearance (CLtotal) for the free IGF-1 was much higher than the creatinine clearance, suggesting that the major elimination pathway is by a route other than renal glomerular filtration. The CLtotal for the free IGF-1 exhibited a dose-dependent reduction whereas that for the sum of unbound and bound IGF-1 increased on increasing the dose. The data obtained fitted closely a one-compartment model that involved the binding and dissociation of IGF-1, as well as its biosynthesis and elimination. The estimated parameters suggest that IGF-1 exhibits high affinity binding to IGFBPs. the rate-limiting step in the overall elimination being the dissociation from IGFBPs. CONCLUSIONS: The saturation of both the plasma protein binding and elimination accounts for the nonlinear pharmacokinetic profile. The binding to IGFBPs markedly limits both the distribution and elimination of IGF-1.
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