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Identification
Name Insulin Detemir
Accession Number DB01307
Type biotech
Groups approved
Description

Insulin detemir is a long-acting human insulin analogue used to maintain basal levels of insulin in diabetic individuals. It is produced using recombinant DNA technology in yeast cells. This insulin analogue has a 14-C fatty acid, myristic acid, bound to the lysine amino acid at position B29. The myristoyl side chain increases self-association and albumin binding. This along with slow systemic absorption from the injection site prolongs distribution of the hormone into tissues and results in a long duration of action. Novo Nordisk markets insulin detemir under the trade name Levemir.
Protein structure No_structure_small
Protein chemical formula C267H402N64O76S6
Protein average weight Not Available
Sequences
Synonyms
29B-[N6-(Oxo-tetradecy)-l-lysine]-(1A-21A),(1B-29B)-insulin (human)
Salts Not Available
Brand names
Name Company
Levemir Novo Nordisk
Brand mixtures Not Available
Categories
  • Hypoglycemic Agents
  • Antidiabetic
CAS number 169148-63-4
Taxonomy
Kingdom Not Available
Classes Not Available
Substructures Not Available
Pharmacology
Indication For the treatment of type 1 or 2 diabetes mellitus. May be used in combination with oral anti-diabetic agents in type 2 diabetic patients who are not in adequate metabolic control with oral anti-diabetic agents alone.
Pharmacodynamics Insulin is a natural hormone produced by beta cells of the pancreas. In non-diabetic individuals, a basal level of insulin is supplemented with insulin spikes following meals. Increased insulin secretion following meals is responsible for the metabolic changes that occur as the body transitions from a postabsorptive to absorptive state. Insulin promotes cellular uptake of glucose, particularly in muscle and adipose tissues, promotes energy storage via glycogenesis, opposes catabolism of energy stores, increases DNA replication and protein synthesis by stimulating amino acid uptake by liver, muscle and adipose tissue, and modifies the activity of numerous enzymes involved in glycogen synthesis and glycolysis. Insulin also promotes growth and is required for the actions of growth hormone (e.g. protein synthesis, cell division, DNA synthesis). Insulin detemir is a long-acting insulin analogue with a flat and predictable action profile. It is used to mimic the basal levels of insulin in diabetic individuals. The onset of action of insulin detemir is 1 to 2 hours and its duration of action is up to 24 hours.
Mechanism of action Insulin detemir binds to the insulin receptor (IR), a heterotetrameric protein consisting of two extracellular alpha units and two transmembrane beta units. The binding of insulin to the alpha subunit of IR stimulates the tyrosine kinase activity intrinsic to the beta subunit of the receptor. The bound receptor autophosphorylates and phosphorylates numerous intracellular substrates such as insulin receptor substrates (IRS) proteins, Cbl, APS, Shc and Gab 1. Activation of these proteins leads to the activation of downstream signaling molecules including PI3 kinase and Akt. Akt regulates the activity of glucose transporter 4 (GLUT4) and protein kinase C (PKC), both of which play critical roles in metabolism and catabolism. Insulin detemir’s long duration of action appears to be a result of slow systemic absorption from the injection site and delayed distribution to target tissues. The myristic acid side chain on insulin detemir increases self-association and gives it a high binding affinity to serum albumin. These features slows its distribution into target tissues and prolongs its duration of action.
Absorption Maximum serum concentrations are reached 6 to 8 hours following subcutaneous injection. Bioavailability is approximately 60%.
Volume of distribution
  • 0.1 L/kg
Protein binding > 98% bound to albumin
Metabolism As with natural insulin, all metabolites formed are inactive.
Route of elimination Not Available
Half life 5 - 7 hours depending on dose
Clearance Not Available
Toxicity Hypoglycemia may occur with inappropriately high doses. Neurogenic (autonomic) signs and symptoms of hypoglycemia include trembling, palpitations, sweating, anxiety, hunger, nausea and tingling. Neuroglycopenic signs and symptoms of hypoglycemia include difficulty concentrating, lethargy/weakness, confusion, drowsiness, vision changes, difficulty speaking, headache, and dizziness. Mild hypoglycemia is characterized by the presence of autonomic symptoms. Moderate hypoglycemia is characterized by the presence of autonomic and neuroglycopenic symptoms. Individuals may become unconscious in severe cases of hypoglycemia. Injection site reactions may also occur. Symptoms include: redness, inflammation, bruising, swelling and itching at the injection site.
Affected organisms
  • Humans and other mammals
Pathways Not Available
Pharmacoeconomics
Manufacturers
  • Novo nordisk inc
Packagers
Dosage forms
Form Route Strength
Injection, solution Subcutaneous 100 units/ml
Prices
Unit description Cost Unit
Levemir flexpen 100 unit/ml 14.28 USD ml
DrugBank does not sell nor buy drugs. Pricing information is supplied for informational purposes only.
Patents
Country Patent Number Approved Expires (estimated)
United States 5750497 1999-05-16 2019-05-16
United States 6011007 1994-02-02 2014-02-02
Canada 2171424 2002-06-04 2014-09-16
Properties
State liquid
Experimental Properties Not Available
References
Synthesis Reference Not Available
General Reference
  1. Kurtzhals P: Pharmacology of insulin detemir. Endocrinol Metab Clin North Am. 2007 Aug;36 Suppl 1:14-20. Pubmed
  2. Morales J: Defining the role of insulin detemir in Basal insulin therapy. Drugs. 2007;67(17):2557-84. Pubmed
  3. Tibaldi J: Actions of insulin beyond glycemic control: a perspective on insulin detemir. Adv Ther. 2007 Jul-Aug;24(4):868-82. Pubmed
External Links
Resource Link
PharmGKB PA164746470 Link_out
RxList http://www.rxlist.com/levemir-drug.htm Link_out
PDRhealth http://www.pdrhealth.com/drugs/rx/rx-mono.aspx?contentFileName=lev1746.html&contentName=Levemir&contentId=435 Link_out
Wikipedia http://en.wikipedia.org/wiki/Insulin_detemir Link_out
ATC Codes
  • A10AE05
AHFS Codes
  • 68:20.08
PDB Entries Not Available
FDA label Not Available
MSDS show (504 KB)
Interactions
Drug Interactions
Drug Interaction
Acebutolol The beta-blocker, acebutolol, may decrease symptoms of hypoglycemia.
Atenolol The beta-blocker, atenolol, may decrease symptoms of hypoglycemia.
Bisoprolol The beta-blocker, bisoprolol, may decrease symptoms of hypoglycemia.
Carvedilol The beta-blocker, carvedilol, may decrease symptoms of hypoglycemia.
Clofibrate Increases the effect of insulin
Dexfenfluramine Fenfluramine increases the effect of insulin
Esmolol The beta-blocker, esmolol, may decrease symptoms of hypoglycemia.
Fenfluramine Fenfluramine increases the effect of insulin
Somatropin recombinant Somatropin may antagonize the hypoglycemic effect of insulin detemir. Monitor for changes in fasting and postprandial blood sugars.
Food Interactions Not Available
Targets

1. Insulin receptor

Pharmacological action: yes
Actions: agonist

This receptor binds insulin and has a tyrosine-protein kinase activity. Isoform Short has a higher affinity for insulin. Mediates the metabolic functions of insulin. Binding to insulin stimulates association of the receptor with downstream mediators including IRS1 and phosphatidylinositol 3'-kinase (PI3K). Can activate PI3K either directly by binding to the p85 regulatory subunit, or indirectly via IRS1

Organism class: human
UniProt ID: P06213 Link_out
Gene: INSR Link_out
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

References:
  1. Hennige AM, Sartorius T, Tschritter O, Preissl H, Fritsche A, Ruth P, Haring HU: Tissue selectivity of insulin detemir action in vivo. Diabetologia. 2006 Jun;49(6):1274-82. Epub 2006 Mar 29. Pubmed
  2. Kurtzhals P, Schaffer L, Sorensen A, Kristensen C, Jonassen I, Schmid C, Trub T: Correlations of receptor binding and metabolic and mitogenic potencies of insulin analogs designed for clinical use. Diabetes. 2000 Jun;49(6):999-1005. Pubmed
  3. Sorensen AR, Stidsen CE, Ribel U, Nishimura E, Sturis J, Jonassen I, Bouman SD, Kurtzhals P, Brand CL: Insulin detemir is a fully efficacious, low affinity agonist at the insulin receptor. Diabetes Obes Metab. 2010 Aug;12(8):665-73. Pubmed
  4. Wada T, Azegami M, Sugiyama M, Tsuneki H, Sasaoka T: Characteristics of signalling properties mediated by long-acting insulin analogue glargine and detemir in target cells of insulin. Diabetes Res Clin Pract. 2008 Sep;81(3):269-77. Epub 2008 Jun 27. Pubmed
  5. Chen X, Ji ZL, Chen YZ: TTD: Therapeutic Target Database. Nucleic Acids Res. 2002 Jan 1;30(1):412-5. Pubmed
Enzymes

1. Cytochrome P450 1A2

Actions: inducer

Cytochromes P450 are a group of heme-thiolate monooxygenases. In liver microsomes, this enzyme is involved in an NADPH-dependent electron transport pathway. It oxidizes a variety of structurally unrelated compounds, including steroids, fatty acids, and xenobiotics. Most active in catalyzing 2-hydroxylation. Caffeine is metabolized primarily by cytochrome CYP1A2 in the liver through an initial N3-demethylation. Also acts in the metabolism of aflatoxin B1 and acetaminophen

UniProt ID: P05177 Link_out
Gene: CYP1A2
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

References:
  1. Flockhart DA. Drug Interactions: Cytochrome P450 Drug Interaction Table. Indiana University School of Medicine (2007). Accessed May 28, 2010.
Carriers

1. Serum albumin

Actions: other/unknown

Serum albumin, the main protein of plasma, has a good binding capacity for water, Ca(2+), Na(+), K(+), fatty acids, hormones, bilirubin and drugs. Its main function is the regulation of the colloidal osmotic pressure of blood

UniProt ID: P02768 Link_out
Gene: ALB Link_out
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

References:
  1. Klein O, Lynge J, Endahl L, Damholt B, Nosek L, Heise T: Albumin-bound basal insulin analogues (insulin detemir and NN344): comparable time-action profiles but less variability than insulin glargine in type 2 diabetes. Diabetes Obes Metab. 2007 May;9(3):290-9. Pubmed
  2. Kurtzhals P: Pharmacology of insulin detemir. Endocrinol Metab Clin North Am. 2007 Aug;36 Suppl 1:14-20. Pubmed
Comments
Drug created on June 30, 2007 08:45 / Updated on September 29, 2010 14:35