Disposition of recombinant human insulin-like growth factor-I in normal and hypophysectomized rats.
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 beta-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.(ABSTRACT TRUNCATED AT 250 WORDS)
Kimura
T
T
Faculty of Pharmaceutical Sciences, Okayama University, Japan.
Kanzaki
Y
Y
Matsumoto
Y
Y
Mandai
M
M
Kurosaki
Y
Y
Nakayama
T
T
D000818:Animals; D001798:Blood Proteins / Q000378:metabolism; D002352:Carrier Proteins / Q000097:blood; D002850:Chromatography, Gel; D006207:Half-Life; D006801:Humans; D007016:Hypophysectomy; D066298:In Vitro Techniques; D007275:Injections, Intravenous; D018969:Insulin-Like Growth Factor Binding Proteins; D007334:Insulin-Like Growth Factor I / Q000008:administration & dosage / Q000378:metabolism / Q000493:pharmacokinetics*; D007668:Kidney / Q000378:metabolism*; D008247:Lysosomes / Q000378:metabolism; D008871:Microvilli / Q000378:metabolism; D008970:Molecular Weight; D051381:Rats; D011994:Recombinant Proteins / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics; D014018:Tissue Distribution
D001798:Blood Proteins; D002352:Carrier Proteins; D018969:Insulin-Like Growth Factor Binding Proteins; D011994:Recombinant Proteins; D007334:Insulin-Like Growth Factor I