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Developmental changes in pharmacokinetics of recombinant human insulin-like growth factor-I in rats
K Higaki1, Y Matsumoto, R Fujimoto
1Department of Pharmaceutics, Faculty of Pharmaceutical Sciences, Okayama University, Japan.
Insights
Young rats eliminate recombinant human insulin-like growth factor-I (rhIGF-I) faster than adult rats due to lower IGF-binding protein levels. This impacts rhIGF-I pharmacokinetics, showing developmental differences in drug metabolism.
Area of Science:
- Pharmacology
- Endocrinology
- Developmental Biology
Background:
- Recombinant human insulin-like growth factor-I (rhIGF-I) is used therapeutically.
- Understanding its pharmacokinetic profile across different developmental stages is crucial for effective dosing.
- Rats at 4 weeks (young growing) and 7 weeks (adult) represent distinct developmental phases.
Purpose of the Study:
- To investigate the developmental changes in the pharmacokinetics of rhIGF-I after intravenous administration in rats.
- To compare the elimination rates and clearance of rhIGF-I in young versus adult rats.
- To explore the relationship between IGF-binding protein levels and rhIGF-I pharmacokinetics.
Main Methods:
- Intravenous administration of rhIGF-I to rats aged 4 and 7 weeks.
- Multi-exponential analysis of plasma rhIGF-I decline over time.
- Calculation of pharmacokinetic parameters including total body clearance (CL[total]) and mean residence time (MRT).
- Assessment of IGF-binding proteins (IGFBPs), specifically the 150 kDa complex involving IGFBP-3.
Main Results:
- rhIGF-I plasma concentrations were generally lower in 4-week-old rats compared to 7-week-old rats.
- rhIGF-I exhibited faster elimination in 4-week-old rats (lower CL[total], shorter MRT) than in 7-week-old rats.
- Dose-dependent pharmacokinetics were observed in 7-week-old rats but not in 4-week-old rats.
- Younger rats had lower levels of the 150 kDa IGF-binding protein complex.
Conclusions:
- Pharmacokinetics of rhIGF-I differ significantly between young growing and adult rats.
- Faster elimination of rhIGF-I in younger rats is likely attributed to lower plasma levels of IGFBP-3.
- These findings highlight the importance of age-related factors in rhIGF-I pharmacokinetics and therapeutic application.
Abstract:
Developmental changes in pharmacokinetics of recombinant human insulin-like growth factor-I (rhIGF-I) were investigated after i.v. administration to rats aged 4 and 7 weeks, as young growing rats and adult rats, respectively. rhIGF-I in the plasma declined multi-exponentially in both groups of rats. Plasma concentrations of rhIGF-I were lower at almost all the time points examined in 4 weeks old rats than 7 weeks old rats. The values of total body clearance (CL[total]) and mean residence time (MRT) indicated that rhIGF-I disappeared more rapidly in 4 weeks old rats than 7 weeks old rats at any dosage. Dose-dependent pharmacokinetics was observed in 7 weeks old rats: the higher the dosage was, the larger the value of CL(total) came to be, but not in 4 weeks old rats. The amounts of IGF-binding proteins (IGFBPs) in the plasma were assessed by determining the endogenous IGF-I, and the levels of the 150 kDa complex, a ternary complex of IGF-I with IGFPB-3 and an acid labile-subunit, were found to be lower in 4 weeks old rats than in 7 weeks old rats. In rats at 4 weeks of age, the elimination of rhIGF-I was significantly faster than for the 7 week old rats, which would be due to the lower plasma levels of IGFBP-3 in young growing rats.