title: The mechanism of protraction of insulin detemir, a long-acting, acylated analog of human insulin.
abstract: OBJECTIVE
  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.
authors.affiliation: Research and Development, Novo Nordisk A/S, Bagsvaerd, Denmark. svh@novonordisk.com
authors.forename: Svend
authors.initials: S
authors.lastname: Havelund
authors.forename: Anne
authors.initials: A
authors.lastname: Plum
authors.forename: Ulla
authors.initials: U
authors.lastname: Ribel
authors.forename: Ib
authors.initials: I
authors.lastname: Jonassen
authors.forename: Aage
authors.initials: A
authors.lastname: Vølund
authors.forename: Jan
authors.initials: J
authors.lastname: Markussen
authors.forename: Peter
authors.initials: P
authors.lastname: Kurtzhals
mesh_terms: D000215:Acylation; D000818:Animals; D002850:Chromatography, Gel; D003692:Delayed-Action Preparations; D005260:Female; D006207:Half-Life; D007275:Injections, Intravenous; D007279:Injections, Subcutaneous; D007328:Insulin / Q000819:agonists* / Q000031:analogs & derivatives* / Q000097:blood / Q000493:pharmacokinetics*; D000069057:Insulin Detemir; D049528:Insulin, Long-Acting; D008657:Metabolic Clearance Rate; D011485:Protein Binding; D012709:Serum Albumin / Q000378:metabolism*; D013552:Swine
chemical_list: D003692:Delayed-Action Preparations; D007328:Insulin; D049528:Insulin, Long-Acting; D012709:Serum Albumin; D000069057:Insulin Detemir