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Pharmaceutical Research

, Volume 21, Issue 8, pp 1498–1504 | Cite as

The Mechanism of Protraction of Insulin Detemir, a Long-Acting, Acylated Analog of Human Insulin

  • Svend Havelund
  • Anne Plum
  • Ulla Ribel
  • Ib Jonassen
  • Aage Vølund
  • Jan Markussen
  • Peter Kurtzhals
Article

Abstract

Purpose. Insulin detemir has been found in clinical trials to be absorbed with very low variability. A series of experiments were performed to elucidate the underlying mechanisms.

Methods. The disappearance from an injected subcutaneous depot and elimination studies in plasma were carried out in pigs. Size-exclusion chromatography was used to assess the self-association and albumin binding states of insulin detemir and analogs.

Results. Disappearance T50% from the injection depot was 10.2 ± 1.2 h for insulin detemir and 2.0 ± 0.1 h for a monomeric acylated insulin analog. Self-association of acylated insulin analogs with same albumin affinity in saline correlated with disappearance rate and addition of albumin to saline showed a combination of insulin detemir self association and albumin binding. Intravenous kinetic studies showed that the clearance and volume of distribution decreased with increasing albumin binding affinity of different acylated insulin analogs.

Conclusions. The protracted action of detemir is primarily achieved through slow absorption into blood. Dihexamerization and albumin binding of hexameric and dimeric detemir prolongs residence time at the injection depot. Some further retention of detemir occurs in the circulation where albumin binding causes buffering of insulin concentration. Insulin detemir provides a novel principle of protraction, enabling increased predictability of basal insulin.

albumin binding insulin detemir insulin pharmacokinetics insulin self-association protracted action 

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Copyright information

© Plenum Publishing Corporation 2004

Authors and Affiliations

  • Svend Havelund
    • 1
  • Anne Plum
    • 1
  • Ulla Ribel
    • 1
  • Ib Jonassen
    • 1
  • Aage Vølund
    • 1
  • Jan Markussen
    • 1
  • Peter Kurtzhals
    • 1
  1. 1.Research and DevelopmentNovo Nordisk A/SBagsvaerdDenmark

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