Disposition of recombinant human insulin-like growth factor-I in normal and hypophysectomized rats

T. Kimura, Y. Kanzaki, Y. Matsumoto, M. Mandai, Yuji Kurosaki, T. Nakayama

Research output: Contribution to journalArticle

12 Citations (Scopus)

Abstract

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 β-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 (CL(total)) 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 CL(total), 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. However, since unbound rhIGF-I and the 50 kDa complex were eliminated rapidly through the kidney, most of the rhIGF-I in the plasma was present as the 150 kDa complex later on. The lack of 150 kDa complex in the plasma of Hypox rats might be the reason why the CL(total) of rhIGF-I is greater in Hypox rats than in normal rats.

Original languageEnglish
Pages (from-to)310-315
Number of pages6
JournalBiological and Pharmaceutical Bulletin
Volume17
Issue number2
Publication statusPublished - 1994

Fingerprint

Insulin-Like Growth Factor I
Kidney
Microvilli
Ligation
olifen
Pharmacokinetics

ASJC Scopus subject areas

  • Molecular Medicine
  • Pharmacology, Toxicology and Pharmaceutics(all)

Cite this

Disposition of recombinant human insulin-like growth factor-I in normal and hypophysectomized rats. / Kimura, T.; Kanzaki, Y.; Matsumoto, Y.; Mandai, M.; Kurosaki, Yuji; Nakayama, T.

In: Biological and Pharmaceutical Bulletin, Vol. 17, No. 2, 1994, p. 310-315.

Research output: Contribution to journalArticle

Kimura, T, Kanzaki, Y, Matsumoto, Y, Mandai, M, Kurosaki, Y & Nakayama, T 1994, 'Disposition of recombinant human insulin-like growth factor-I in normal and hypophysectomized rats', Biological and Pharmaceutical Bulletin, vol. 17, no. 2, pp. 310-315.
Kimura, T. ; Kanzaki, Y. ; Matsumoto, Y. ; Mandai, M. ; Kurosaki, Yuji ; Nakayama, T. / Disposition of recombinant human insulin-like growth factor-I in normal and hypophysectomized rats. In: Biological and Pharmaceutical Bulletin. 1994 ; Vol. 17, No. 2. pp. 310-315.
@article{91f0c5a9e2f841bbb250c9610220ab31,
title = "Disposition of recombinant human insulin-like growth factor-I in normal and hypophysectomized rats",
abstract = "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 β-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 (CL(total)) 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 CL(total), 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. However, since unbound rhIGF-I and the 50 kDa complex were eliminated rapidly through the kidney, most of the rhIGF-I in the plasma was present as the 150 kDa complex later on. The lack of 150 kDa complex in the plasma of Hypox rats might be the reason why the CL(total) of rhIGF-I is greater in Hypox rats than in normal rats.",
author = "T. Kimura and Y. Kanzaki and Y. Matsumoto and M. Mandai and Yuji Kurosaki and T. Nakayama",
year = "1994",
language = "English",
volume = "17",
pages = "310--315",
journal = "Biological and Pharmaceutical Bulletin",
issn = "0918-6158",
publisher = "Pharmaceutical Society of Japan",
number = "2",

}

TY - JOUR

T1 - Disposition of recombinant human insulin-like growth factor-I in normal and hypophysectomized rats

AU - Kimura, T.

AU - Kanzaki, Y.

AU - Matsumoto, Y.

AU - Mandai, M.

AU - Kurosaki, Yuji

AU - Nakayama, T.

PY - 1994

Y1 - 1994

N2 - 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 β-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 (CL(total)) 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 CL(total), 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. However, since unbound rhIGF-I and the 50 kDa complex were eliminated rapidly through the kidney, most of the rhIGF-I in the plasma was present as the 150 kDa complex later on. The lack of 150 kDa complex in the plasma of Hypox rats might be the reason why the CL(total) of rhIGF-I is greater in Hypox rats than in normal rats.

AB - 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 β-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 (CL(total)) 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 CL(total), 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. However, since unbound rhIGF-I and the 50 kDa complex were eliminated rapidly through the kidney, most of the rhIGF-I in the plasma was present as the 150 kDa complex later on. The lack of 150 kDa complex in the plasma of Hypox rats might be the reason why the CL(total) of rhIGF-I is greater in Hypox rats than in normal rats.

UR - http://www.scopus.com/inward/record.url?scp=0028214779&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=0028214779&partnerID=8YFLogxK

M3 - Article

VL - 17

SP - 310

EP - 315

JO - Biological and Pharmaceutical Bulletin

JF - Biological and Pharmaceutical Bulletin

SN - 0918-6158

IS - 2

ER -