The pharmacokinetics of free insulin-like growth factor-I in healthy subjects.
In a randomized cross-over study in five healthy males we compared 75-min constant i.v. infusion of saline, low-dose recombinant human (rh) insulin-like growth factor-I (rhIGF-I; 1.5 microg/kg/h) and high-dose rhIGF-I (9.0 microg/kg/h). Serum samples were analysed for ultrafiltered free IGF-I (fIGF-I), total IGF-I (tIGF-I), tIGF-II and IGF-binding protein-1 (IGFBP-1) and -3. Free and total IGF-I were unchanged during saline infusion. Low-dose rhIGF-I caused a small increment in fIGF-I [+41%, from 0.64 +/- 0.19 (mean +/- SEM) to 0.90 +/- 0.25 microg/l;P< 0.05] and tIGF-I (+9%, from 220 +/- 31 to 239 +/- 33 microg/l;P< 0.05). High-dose rhIGF-I increased tIGF-I by 40% (from 227 +/- 36 to 329 +/- 31 microg/l;P< 0.05), and fIGF-I by 11.5 times (from 0.56 +/- 0.20 to 6.46 +/- 1.39 microg/l;P< 0.05). The pharmacokinetic profile of fIGF-I was calculated after high-dose IGF-I only. The disappearance of fIGF-I followed first order kinetics with an apparent half-life of 14.4 +/- 1.0 [11.2-17.1 (range)] min. The clearance was estimated to 52 +/- 20 (16-128) ml/min/kg and the volume of distribution to 1102 +/- 464 (388-2899) ml/kg. In the three experiments, there were no differences in IGFBP-1, and tIGF-II and IGFBP-3 remained unchanged. In conclusion, fIGF-I remained within the physiological range after low-dose rhIGF-I, whereas high-dose rhIGF-I resulted in supraphysiological concentrations. Since the half-life estimates for each subject were remarkably similar, this parameter most likely does not explain the observed variation in clearance and volume of distribution of fIGF-I. Instead, differences in the circulating and cellular IGF-I binding capacity may be of importance.
Frystyk
J
J
Institute of Experimental Clinical Research, Medical Research Laboratories and Medical Department M, Aarhus University Hospital, Aarhus, Denmark. jan@frystyk.dk
Hussain
M
M
Skjaerbaek
C
C
Pørksen
N
N
Froesch
E R
ER
Orskov
H
H
D000328:Adult; D018592:Cross-Over Studies; D006801:Humans; D007334:Insulin-Like Growth Factor I / Q000008:administration & dosage / Q000493:pharmacokinetics*; D016014:Linear Models; D008297:Male; D011994:Recombinant Proteins / Q000378:metabolism; D012965:Sodium Chloride / Q000494:pharmacology; D013997:Time Factors
D011994:Recombinant Proteins; D012965:Sodium Chloride; D007334:Insulin-Like Growth Factor I