Kinetic analysis of the disposition of insulin-like growth factor 1 in healthy volunteers.
OBJECTIVE
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.
Mizuno
N
N
Graduate School of Pharmaceutical Sciences, University of Tokyo, Japan.
Kato
Y
Y
Iwamoto
M
M
Urae
A
A
Amamoto
T
T
Niwa
T
T
Sugiyama
Y
Y
D000328:Adult; D000465:Algorithms; D001798:Blood Proteins / Q000378:metabolism; D006801:Humans; D007334:Insulin-Like Growth Factor I / Q000493:pharmacokinetics*; D008297:Male; D008954:Models, Biological; D011485:Protein Binding; D011863:Radioimmunoassay; D014018:Tissue Distribution
D001798:Blood Proteins; D007334:Insulin-Like Growth Factor I