ЭксенатидOh no, theres been an error

References

Synthesis Reference

Matthieu Giraud, Anne-Sophie Droz, Stephane Varray, El Djouhar Rekai, Marie-Helene Brichard, Daniel Latassa, Christine Devijver, Pascal Gilles, Jeanne-Marie Cauvin, Fernando Albericio, Marta Paradis Bas, «PROCESS FOR THE PRODUCTION OF EXENATIDE AND OF AN EXENATIDE ANALOGUE.» U.S. Patent US20110046349, issued February 24, 2011.

General References
  1. Gao W, Jusko WJ: Target-mediated pharmacokinetic and pharmacodynamic model of exendin-4 in rats, monkeys, and humans. Drug Metab Dispos. 2012 May;40(5):990-7. doi: 10.1124/dmd.111.042291. Epub 2012 Feb 15.
  2. Copley K, McCowen K, Hiles R, Nielsen LL, Young A, Parkes DG: Investigation of exenatide elimination and its in vivo and in vitro degradation. Curr Drug Metab. 2006 May;7(4):367-74.
  3. Liao S, Liang Y, Zhang Z, Li J, Wang J, Wang X, Dou G, Zhang Z, Liu K: In vitro metabolic stability of exendin-4: pharmacokinetics and identification of cleavage products. PLoS One. 2015 Feb 27;10(2):e0116805. doi: 10.1371/journal.pone.0116805. eCollection 2015.
  4. FDA Drug Approval Package: Exenatide
  5. FDA Pharmacology Review: Exenatide
External Links
KEGG Drug
D04121
PubChem Substance
ChEMBL
CHEMBL414357
Therapeutic Targets Database
DAP001038
PharmGKB
PA164749238
RxList
RxList Drug Page
Drugs.com
Drugs.com Drug Page
Wikipedia
Exenatide
ATC Codes
A10BJ01 — Exenatide

  • A10BJ — Glucagon-like peptide-1 (GLP-1) analogues
  • A10B — BLOOD GLUCOSE LOWERING DRUGS, EXCL. INSULINS
  • A10 — DRUGS USED IN DIABETES
  • A — ALIMENTARY TRACT AND METABOLISM
AHFS Codes
FDA label
Download (1.34 MB)
MSDS
Download (22.2 KB)

Pharmacoeconomics

Manufacturers
Not Available
Packagers
  • Amylin Pharmaceuticals
  • Baxter International Inc.
  • CP Pharmaceuticals Ltd.
  • Eli Lilly & Co.
  • Physicians Total Care Inc.
Dosage forms
Form Route Strength
Injection, powder, for suspension, extended release Subcutaneous 2 mg
Injection, powder, for suspension, extended release; kit Subcutaneous 2 mg
Injection, suspension, extended release Subcutaneous 2 mg/0.65mL
Kit Subcutaneous 2 mg/0.65mL
Injection, suspension, extended release Subcutaneous 2 mg/0.85mL
Suspension, extended release Subcutaneous 2 mg
Injection Subcutaneous 250 ug/1mL
Injection, solution Subcutaneous 10 micrograms
Injection, solution Subcutaneous 5 micrograms
Solution Subcutaneous 10 mcg
Solution Subcutaneous 5 mcg
Prices
Unit description Cost Unit
Byetta 10 MCG Pen 10 mcg/0.04ml Solution 2.4ml Pen 324.23USD pen
Byetta 5 mcg dose pen inj 316.76USD ml
Byetta 5 MCG Pen 5 mcg/0.02ml Solution 1.2ml Pen 276.57USD pen

DrugBank does not sell nor buy drugs. Pricing information is supplied for informational purposes only.

Patents
Patent Number Pediatric Extension Approved Expires (estimated)
Unlock Additional Data
US8216180 No 2012-07-10 2028-01-12 US
US8439864 No 2013-05-14 2028-03-25 US
US6667061 Yes 2003-12-23 2020-11-25 US
US6495164 No 2002-12-17 2020-05-25 US
US5424286 No 1995-06-13 2016-12-01 US
US6858576 No 2005-02-22 2017-01-06 US
US6872700 No 2005-03-29 2020-01-14 US
US6956026 No 2005-10-18 2018-01-07 US
US7741269 No 2010-06-22 2018-01-07 US
US7297761 No 2007-11-20 2017-10-15 US
US7521423 No 2009-04-21 2017-10-15 US
US6902744 No 2005-06-07 2020-01-14 US
US9238076 No 2016-01-19 2024-04-15 US
US8906851 No 2014-12-09 2026-08-18 US
US7612176 No 2009-11-03 2025-04-13 US
US8431685 No 2013-04-30 2025-04-13 US
US8461105 No 2013-06-11 2025-04-13 US
US8329648 No 2012-12-11 2026-08-18 US
US7456254 No 2008-11-25 2025-06-30 US
US7563871 No 2009-07-21 2024-04-15 US
US6824822 No 2004-11-30 2022-10-09 US
US6479065 No 2002-11-12 2020-08-10 US
US7223440 No 2007-05-29 2021-08-31 US
US8685934 No 2014-04-01 2030-05-26 US
US8501698 No 2013-08-06 2027-06-20 US
US6414126 No 2002-07-02 2020-10-04 US
US6515117 No 2003-02-04 2020-10-04 US
US6936590 No 2005-08-30 2020-10-04 US
US9198925 No 2015-12-01 2020-10-04 US
US7919598 No 2011-04-05 2029-12-16 US
US8361972 No 2013-01-29 2028-03-21 US
US8716251 No 2014-05-06 2028-03-21 US
US7851502 No 2010-12-14 2028-08-19 US
US8221786 No 2012-07-17 2028-03-21 US
US9320853 No 2016-04-26 2028-03-25 US
US8827963 No 2014-09-09 2029-02-04 US
US8712615 No 2014-04-29 2030-01-18 US
US8998876 No 2015-04-07 2030-01-07 US
US8758292 No 2014-06-24 2027-11-12 US
US8690837 No 2014-04-08 2029-05-19 US
US8895033 No 2014-11-25 2030-10-04 US
US8721615 No 2014-05-13 2030-01-18 US
US9884092 No 2018-02-06 2026-08-18 US

Additional Data Available

Filed On

Filed On
The date on which a patent was filed with the relevant government.
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Identification

Name
Exenatide
Accession Number
DB01276
Type
Biotech
Groups
Approved, Investigational
Biologic Classification
Protein Based TherapiesHormones
Description

Exenatide is a glucagon-like peptide-1 (GLP-1) analog. It functions to activate the GLP-1 receptor and increases insulin secretion, decrease glucagon secretion, and slow gastric emptying to improve glycemic control. Exenatide was given FDA approval on April 28, 2005.

Protein structure
Protein chemical formula
C184H282N50O60S
Protein average weight
4186.6 Da
Sequences
>Exenatide
HGEGTFTSDLSKQMEEEAVRLFIEWLKNGGPSSGAPPPS

Download FASTA Format

Synonyms
  • Exenatida
  • Exenatide
  • Exenatide synthetic
  • Exendin 4
  • Exendin-4
  • Synthetic exendin-4
External IDs
AC 2993AC-002993AC-2993AC-2993AAC-2993LARAC002993AC2993AC2993ADA-3091ITCA-650LY-2148568LY2148568
Prescription Products

Additional Data Available

  • Application Number

    Application Number

    A unique ID assigned by the FDA when a product is submitted for approval by the labeller.

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  • Product Code

    Product Code

    A governmentally-recognized ID which uniquely identifies the product within its regulatory market.

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Categories
  • Alimentary Tract and Metabolism
  • Amino Acids, Peptides, and Proteins
  • Anti-Obesity Agents
  • Biological Factors
  • Blood Glucose Lowering Agents
  • Bodily Secretions
  • Drugs Used in Diabetes
  • Fluids and Secretions
  • GLP-1 Agonists
  • Glucagon-Like Peptide 1
  • Glucagon-like Peptide-1 (GLP-1) Agonists
  • Glucagon-like peptide-1 (GLP-1) analogues
  • Hormones
  • Hormones, Hormone Substitutes, and Hormone Antagonists
  • Hypoglycemia-Associated Agents
  • Incretin Mimetics
  • Incretins
  • Peptides
  • Toxins, Biological
  • Venoms
UNII
9P1872D4OL
CAS number
141758-74-9

Pharmacology

Indication

Exenatide is indicated for improving glycemic control in adults with type 2 diabetes mellitus along with diet and exercise.

Associated Conditions
Pharmacodynamics

When patients take exenatide the body’s natural response to glucose is modulated. More insulin and less glucagon are released in response to glucose, though in cases of hypoglycemia a normal amount of glucagon is released. Exenatide also slows gastric emptying, leading to a slower and prolonged release of glucose into the systemic circulation. Together these effects prevent hyper and hypoglycemia.

Mechanism of action

Exenatide is a human glucacon-like peptide-1(GLP-1) receptor agonist. By activating this receptor, insulin secretion is increased and glucagon secretion is decreased in a glucose dependant manner. Exenatide also slows gastric emptying and decreases food intake. These effects work synergistically to improve glycemic control by reducing the likelihood of hyper and hypoglycemia.

Target Actions Organism
A agonist Humans

Comprehensive structured data on known drug adverse effects with statistical prevalence. MedDRA and ICD10 ids are provided for adverse effect conditions and symptoms.

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Additional Data Available

Contraindications

Structured data covering drug contraindications. Each contraindication describes a scenario in which the drug is not to be used. Includes restrictions on co-administration, contraindicated populations, and more.

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Additional Data Available

Blackbox Warnings

Structured data representing warnings from the black box section of drug labels. These warnings cover important and dangerous risks, contraindications, or adverse effects.

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Absorption

Exenatide reaches a peak plasma concentration in 2.1 hours. Because exenatide is administerd subcutaneously, the bioavailability is 1.

Volume of distribution

28.3L.

Protein binding

Protein binding of exenatide has not been determined.

Metabolism

Exenatide is filtered through the glomerulus before being degraded to smaller peptides and amino acids by dipeptidyl peptidase-4, metalloproteases, endopeptidase 24-11, amino proteases, and serine proteases,. It is currently believed that the metalloproteases are responsible for most of the degradation of exenatide. Exenatide is metabolised to small peptides .

Route of elimination

Exenatide is mainly eliminated by glomerular filtration followed by proteolysis before finally being eliminated in the urine,.

Half life

2.4 hours

Clearance

9.1 L/hour.

Toxicity

In animal studies, exenatide was associated with fetal deformities of ribs and vertebrae as well as slowed growth. In humans, uncontrolled hyperglycemia can be associated with an up to 25% risk of miscarriage. No human studies in pregnancy have been performed with exenatide and so exenatide should only be prescribed in pregnancy if the benefit to the mother and fetus outweigh the risks. In mice, exenatide is excreted in the milk at a concentration 2.5% of the plasma concentration though this data may not be applicable to humans. The effect of exenatide on breastfed infants is also unknown and so the risk and benefit of breastfeeding while taking exenatide must be weighed. There is no data for the use of exenatide in pediatric patients. Geriatric patients do not have different results for safety and efficacy of exenatide though caution should still be used in this group as they are at higher risk of renal impairment or other comorbidities that may affect the liklihood of adverse effects. No dosage adjustments are necessary for patients with creatinine clearance ≥50mL/min, though prescribing to patients with creatinine clearance 30-50mL/min should be done cautiously. Exenatide is not recommended for patients with creatinine clearance . Hepatic impairment is not expected to affect clearance of exenatide though no studies have been performed to confirm this.

Affected organisms

Pathways
Not Available
Pharmacogenomic Effects/ADRs

Not Available

Mechanism of action

Exenatide binds to the intact human Glucagon-like peptide-1 receptor (GLP-1R) in a similar way to the human peptide glucagon-like peptide-1 (GLP-1); exenatide bears a 50% amino acid homology to GLP-1 and it has a longer half-life in vivo.

Exenatide is believed to facilitate glucose control in at least five ways:

  1. Exenatide augments pancreas response (i.e. increases insulin secretion) in response to eating meals; the result is the release of a higher, more appropriate amount of insulin that helps lower the rise in blood sugar from eating. Once blood sugar levels decrease closer to normal values, the pancreas response to produce insulin is reduced; other drugs (like injectable insulin) are effective at lowering blood sugar, but can «overshoot» their target and cause blood sugar to become too low, resulting in the dangerous condition of hypoglycemia.
  2. Exenatide also suppresses pancreatic release of glucagon in response to eating, which helps stop the liver from overproducing sugar when it is unneeded, which prevents hyperglycemia (high blood sugar levels).
  3. Exenatide helps slow down gastric emptying and thus decreases the rate at which meal-derived glucose appears in the bloodstream.
  4. Exenatide has a subtle yet prolonged effect to reduce appetite, promote satiety via hypothalamic receptors (different receptors than for amylin). Most people using exenatide slowly lose weight, and generally the greatest weight loss is achieved by people who are the most overweight at the beginning of exenatide therapy. Clinical trials have demonstrated the weight reducing effect continues at the same rate through 2.25 years of continued use. When separated into weight loss quartiles, the highest 25% experience substantial weight loss, and the lowest 25% experience no loss or small weight gain.
  5. Exenatide reduces liver fat content. Fat accumulation in the liver or nonalcoholic fatty liver disease (NAFLD) is strongly related with several metabolic disorders, in particular low HDL cholesterol and high triglycerides, present in patients with type 2 diabetes. It became apparent that exenatide reduced liver fat in mice, rat and more recently in man.

In 2016 work published showing that it can reverse impaired calcium signalling in steatotic liver cells, which, in turn, might be associated with proper glucose control.

Interactions

Drug Interactions

This information should not be interpreted without the help of a healthcare provider. If you believe you are experiencing an interaction, contact a healthcare provider immediately. The absence of an interaction does not necessarily mean no interactions exist.

Drug Interaction
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(R)-warfarin Exenatide can cause an increase in the absorption of (R)-warfarin resulting in an increased serum concentration and potentially a worsening of adverse effects.
(S)-Warfarin Exenatide can cause an increase in the absorption of (S)-Warfarin resulting in an increased serum concentration and potentially a worsening of adverse effects.
2,4-thiazolidinedione The risk or severity of hypoglycemia can be increased when Exenatide is combined with 2,4-thiazolidinedione.
4-hydroxycoumarin Exenatide can cause an increase in the absorption of 4-hydroxycoumarin resulting in an increased serum concentration and potentially a worsening of adverse effects.
5-(2-methylpiperazine-1-sulfonyl)isoquinoline The therapeutic efficacy of Exenatide can be increased when used in combination with 5-(2-methylpiperazine-1-sulfonyl)isoquinoline.
7,8-Dichloro-1,2,3,4-tetrahydroisoquinoline 7,8-Dichloro-1,2,3,4-tetrahydroisoquinoline may increase the hypoglycemic activities of Exenatide.
Acarbose The risk or severity of hypoglycemia can be increased when Acarbose is combined with Exenatide.
Acebutolol The therapeutic efficacy of Exenatide can be increased when used in combination with Acebutolol.
Acenocoumarol Exenatide can cause an increase in the absorption of Acenocoumarol resulting in an increased serum concentration and potentially a worsening of adverse effects.
Acetazolamide The therapeutic efficacy of Exenatide can be increased when used in combination with Acetazolamide.

Additional Data Available

  • Extended Description

    Extended Description

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  • Severity

    Severity

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  • Evidence Level

    Evidence Level

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Food Interactions
Not Available

Side effects

The main side effects of exenatide use are gastrointestinal in nature, including acid or sour stomach, belching, diarrhea, heartburn, indigestion, nausea, and vomiting; exenatide is therefore not meant for people with severe gastrointestinal disease. Other side effects include dizziness, headache, and feeling jittery. Drug interactions listed on the package insert include delayed or reduced concentrations of lovastatin, paracetamol (acetaminophen), and digoxin, although this has not been proven to alter the effectiveness of these other medications.

In response to postmarketing reports of acute pancreatitis in patients using exenatide, the FDA added a warning to the labeling of Byetta in 2007. In August 2008, four additional deaths from pancreatitis in users of exenatide were reported to the FDA; while no definite relationship had been established, the FDA was reportedly considering additional changes to the drug’s labeling. Examination of the medical records of the millions of patients part of the United Healthcare Insurance plans did not show any greater rate of pancreatitis among Byetta users than among diabetic patients on other medications. However, diabetics do have a slightly greater incidence of pancreatitis than do non-diabetics.

It also may increase risk of mild sulfonylurea-induced hypoglycemia.

Additionally, the FDA has raised concerns over the lack of data to determine if the long-acting once-weekly version of exenatide (but not the twice-daily form of exenatide) may increase thyroid cancer risk. This concern comes out of observing a very small but nevertheless increased risk of thyroid cancer in rodents that was observed for another drug (liraglutide) that is in the same class as exenatide. The data available for exenatide showed less of a risk towards thyroid cancer than liraglutide, but to better quantify the risk the FDA has required Amylin to conduct additional rodent studies to better identify the thyroid issue. The approved form of the once weekly exenatide has a black box warning discussing the thyroid issue. Eli Lilly has reported they have not seen a link in humans, but that it cannot be ruled out. Eli Lilly has stated the drug causes an increase in thyroid problems in rats given high doses.

In March 2013, the FDA issued a Drug Safety Communication announcing investigations into incretin mimetics due to findings by academic researchers. A few weeks later, the European Medicines Agency launched a similar investigation into GLP-1 agonists and DPP-4 inhibitors.

Taxonomy

Description
Not Available
Kingdom
Organic Compounds
Super Class
Organic Acids
Class
Carboxylic Acids and Derivatives
Sub Class
Amino Acids, Peptides, and Analogues
Direct Parent
Peptides
Alternative Parents
Not Available
Substituents
Not Available
Molecular Framework
Not Available
External Descriptors
Not Available

Targets

Details1. Glucagon-like peptide 1 receptor

Kind
Protein
Organism
Humans
Pharmacological action
Yes
Actions
Agonist
General Function
Transmembrane signaling receptor activity
Specific Function
This is a receptor for glucagon-like peptide 1. The activity of this receptor is mediated by G proteins which activate adenylyl cyclase.
Gene Name
GLP1R
Uniprot ID
P43220
Uniprot Name
Glucagon-like peptide 1 receptor
Molecular Weight
53025.22 Da
References
  1. Briones M, Bajaj M: Exenatide: a GLP-1 receptor agonist as novel therapy for Type 2 diabetes mellitus. Expert Opin Pharmacother. 2006 Jun;7(8):1055-64.
  2. Hargrove DM, Kendall ES, Reynolds JM, Lwin AN, Herich JP, Smith PA, Gedulin BR, Flanagan SD, Jodka CM, Hoyt JA, McCowen KM, Parkes DG, Anderson CM: Biological activity of AC3174, a peptide analog of exendin-4. Regul Pept. 2007 Jun 7;141(1-3):113-9. Epub 2007 Jan 11.
  3. Wajchenberg BL: beta-cell failure in diabetes and preservation by clinical treatment. Endocr Rev. 2007 Apr;28(2):187-218. Epub 2007 Mar 12.
  4. Mack CM, Moore CX, Jodka CM, Bhavsar S, Wilson JK, Hoyt JA, Roan JL, Vu C, Laugero KD, Parkes DG, Young AA: Antiobesity action of peripheral exenatide (exendin-4) in rodents: effects on food intake, body weight, metabolic status and side-effect measures. Int J Obes (Lond). 2006 Sep;30(9):1332-40. Epub 2006 Mar 14.
  5. Geelhoed-Duijvestijn PH: Incretins: a new treatment option for type 2 diabetes? Neth J Med. 2007 Feb;65(2):60-4.
  6. Mann RJ, Nasr NE, Sinfield JK, Paci E, Donnelly D: The major determinant of exendin-4/glucagon-like peptide 1 differential affinity at the rat glucagon-like peptide 1 receptor N-terminal domain is a hydrogen bond from SER-32 of exendin-4. Br J Pharmacol. 2010 Aug;160(8):1973-84. doi: 10.1111/j.1476-5381.2010.00834.x.
  7. Degn KB, Brock B, Juhl CB, Djurhuus CB, Grubert J, Kim D, Han J, Taylor K, Fineman M, Schmitz O: Effect of intravenous infusion of exenatide (synthetic exendin-4) on glucose-dependent insulin secretion and counterregulation during hypoglycemia. Diabetes. 2004 Sep;53(9):2397-403.
  8. Diamant M, Bunck MC, Heine RJ: . Ned Tijdschr Geneeskd. 2004 Sep 25;148(39):1912-7.
  9. Kolterman OG, Kim DD, Shen L, Ruggles JA, Nielsen LL, Fineman MS, Baron AD: Pharmacokinetics, pharmacodynamics, and safety of exenatide in patients with type 2 diabetes mellitus. Am J Health Syst Pharm. 2005 Jan 15;62(2):173-81.
  10. Barnett AH: Exenatide. Drugs Today (Barc). 2005 Sep;41(9):563-78.
  11. Lebovitz HE: Therapeutic options in development for management of diabetes: pharmacologic agents and new technologies. Endocr Pract. 2006 Jan-Feb;12 Suppl 1:142-7.
  12. Chen X, Ji ZL, Chen YZ: TTD: Therapeutic Target Database. Nucleic Acids Res. 2002 Jan 1;30(1):412-5.

Enzymes

Details1. Dipeptidyl peptidase 4

Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Substrate
General Function
Virus receptor activity
Specific Function
Cell surface glycoprotein receptor involved in the costimulatory signal essential for T-cell receptor (TCR)-mediated T-cell activation. Acts as a positive regulator of T-cell coactivation, by bindi…
Gene Name
DPP4
Uniprot ID
P27487
Uniprot Name
Dipeptidyl peptidase 4
Molecular Weight
88277.935 Da
References
  1. Liao S, Liang Y, Zhang Z, Li J, Wang J, Wang X, Dou G, Zhang Z, Liu K: In vitro metabolic stability of exendin-4: pharmacokinetics and identification of cleavage products. PLoS One. 2015 Feb 27;10(2):e0116805. doi: 10.1371/journal.pone.0116805. eCollection 2015.

Carriers

Details1. Serum albumin

Kind
Protein
Organism
Humans
Pharmacological action
Unknown
General Function
Toxic substance binding
Specific Function
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 colloid…
Gene Name
ALB
Uniprot ID
P02768
Uniprot Name
Serum albumin
Molecular Weight
69365.94 Da
References
  1. Chae SY, Jin CH, Shin JH, Son S, Kim TH, Lee S, Youn YS, Byun Y, Lee MS, Lee KC: Biochemical, pharmaceutical and therapeutic properties of long-acting lithocholic acid derivatized exendin-4 analogs. J Control Release. 2010 Mar 3;142(2):206-13. doi: 10.1016/j.jconrel.2009.10.025. Epub 2009 Nov 10.

Drug created on May 16, 2007 14:43 / Updated on November 19, 2019 16:38