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Identification
NameInsulin Detemir
Accession NumberDB01307
Typebiotech
Groupsapproved
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 structureNo structure small
Protein chemical formulaC267H402N64O76S6
Protein average weight5916.9 Daltons
Sequences
>Protein sequence for A chain
GIVEQCCTSICSLYQLENYCN
>Protein sequence for B chain 
FVNQHLCGSHLVEALYLVCGERGFFYTPK
Download FASTA Format
SynonymsNot Available
SaltsNot Available
Brand names
NameCompany
LevemirNovo Nordisk
Levemir FlexPen Novo Nordisk
Brand mixturesNot Available
CategoriesNot Available
CAS number169148-63-4
Taxonomy
KingdomOrganic Compounds
SuperclassOrganic Acids
ClassCarboxylic Acids and Derivatives
SubclassAmino Acids, Peptides, and Analogues
Direct parentPeptides
Alternative parentsNot Available
SubstituentsNot Available
Classification descriptionNot Available
Pharmacology
IndicationFor 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.
PharmacodynamicsInsulin 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. Interestingly, it has a lower affinity (30%) for the insulin receptor than human insulin.
Mechanism of actionInsulin 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.
AbsorptionMaximum serum concentrations are reached 6 to 8 hours following subcutaneous injection. When single dose of 0.5 units/kg of insulin detemir was given to adult type 1 diabetes patients, the maximum serum concentration (Cmax) was 4,641 ± 2,299 pmol/L. Absorption is also dependent on the site of injection. When injected into the thigh, the AUC was lower than when injected into the deltoid and abdominal regions. 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 eliminationNot Available
Half life5 - 7 hours depending on dose. The half life also differs between age groups (type 1 diabetes patients): Children (6-12 years) = 302 ± 100 minutes; Adolescents (13-17 years) = 301 ± 107 minutes; Adults (18-65 years) = 425 ± 78 minutes
Clearance

Apparent clearance (CL/F), type 1 diabetes adult patients = 3.41 ± 1.00 L/min·kg

ToxicityHypoglycemia 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
PathwaysNot Available
SNP Mediated EffectsNot Available
SNP Mediated Adverse Drug ReactionsNot Available
ADMET
Predicted ADMET features
Property Value Probability
Human Intestinal Absorption Not Available Not Available
Blood Brain Barrier Not Available Not Available
Caco-2 permeable Not Available Not Available
P-glycoprotein substrate Not Available Not Available
P-glycoprotein inhibitor I Not Available Not Available
P-glycoprotein inhibitor II Not Available Not Available
Renal organic cation transporter Not Available Not Available
CYP450 2C9 substrate Not Available Not Available
CYP450 2D6 substrate Not Available Not Available
CYP450 3A4 substrate Not Available Not Available
CYP450 1A2 substrate Not Available Not Available
CYP450 2C9 substrate Not Available Not Available
CYP450 2D6 substrate Not Available Not Available
CYP450 2C19 substrate Not Available Not Available
CYP450 3A4 substrate Not Available Not Available
CYP450 inhibitory promiscuity Not Available Not Available
Ames test Not Available Not Available
Carcinogenicity Not Available Not Available
Biodegradation Not Available Not Available
Rat acute toxicity Not Available Not applicable
hERG inhibition (predictor I) Not Available Not Available
hERG inhibition (predictor II) Not Available Not Available
Pharmacoeconomics
Manufacturers
  • Novo nordisk inc
Packagers
Dosage forms
FormRouteStrength
Injection, solutionSubcutaneous100 units/ml
Prices
Unit descriptionCostUnit
Levemir flexpen 100 unit/ml14.28USDml
DrugBank does not sell nor buy drugs. Pricing information is supplied for informational purposes only.
Patents
CountryPatent NumberApprovedExpires (estimated)
United States57504971999-05-162019-05-16
United States60110071994-02-022014-02-02
Canada21714242002-06-042014-09-16
Properties
Stateliquid
Experimental PropertiesNot Available
Spectra
SpectraNot Available
References
Synthesis ReferenceNot 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
  4. Danne T, Lupke K, Walte K, Von Schuetz W, Gall MA: Insulin detemir is characterized by a consistent pharmacokinetic profile across age-groups in children, adolescents, and adults with type 1 diabetes. Diabetes Care. 2003 Nov;26(11):3087-92. Pubmed
  5. Owens DR, Bolli GB: Beyond the era of NPH insulin—long-acting insulin analogs: chemistry, comparative pharmacology, and clinical application. Diabetes Technol Ther. 2008 Oct;10(5):333-49. doi: 10.1089/dia.2008.0023. Pubmed
External Links
ResourceLink
PharmGKBPA164746470
RxListhttp://www.rxlist.com/levemir-drug.htm
Drugs.comhttp://www.drugs.com/monograph/insulin-detemir.html
PDRhealthhttp://www.pdrhealth.com/drugs/rx/rx-mono.aspx?contentFileName=lev1746.html&contentName=Levemir&contentId=435
WikipediaInsulin_detemir
ATC CodesNot Available
AHFS Codes
  • 68:20.08
PDB EntriesNot Available
FDA labelshow(911 KB)
MSDSshow(504 KB)
Interactions
Drug Interactions
Drug
AcebutololThe beta-blocker, acebutolol, may decrease symptoms of hypoglycemia.
AtenololThe beta-blocker, atenolol, may decrease symptoms of hypoglycemia.
BisoprololThe beta-blocker, bisoprolol, may decrease symptoms of hypoglycemia.
CarvedilolThe beta-blocker, carvedilol, may decrease symptoms of hypoglycemia.
ClofibrateIncreases the effect of insulin
DexfenfluramineFenfluramine increases the effect of insulin
EsmololThe beta-blocker, esmolol, may decrease symptoms of hypoglycemia.
FenfluramineFenfluramine increases the effect of insulin
Somatropin recombinantSomatropin may antagonize the hypoglycemic effect of insulin detemir. Monitor for changes in fasting and postprandial blood sugars.
Food InteractionsNot Available

1. Insulin receptor

Kind: protein

Organism: Human

Pharmacological action: yes

Actions: agonist

Components

Name UniProt ID Details
Insulin receptor P06213 Details

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

1. Cytochrome P450 1A2

Kind: protein

Organism: Human

Pharmacological action: unknown

Actions: inducer

Components

Name UniProt ID Details
Cytochrome P450 1A2 P05177 Details

References:

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

1. Serum albumin

Kind: protein

Organism: Human

Pharmacological action: no

Actions: other/unknown

Components

Name UniProt ID Details
Serum albumin P02768 Details

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 June 27, 2013 17:10