The mechanism of protraction of insulin detemir, a long-acting, acylated analog of human insulin.
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.
Havelund
Svend
S
Research and Development, Novo Nordisk A/S, Bagsvaerd, Denmark. svh@novonordisk.com
Plum
Anne
A
Ribel
Ulla
U
Jonassen
Ib
I
Vølund
Aage
A
Markussen
Jan
J
Kurtzhals
Peter
P
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
D003692:Delayed-Action Preparations; D007328:Insulin; D049528:Insulin, Long-Acting; D012709:Serum Albumin; D000069057:Insulin Detemir