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Identification
NameMetformin
Accession NumberDB00331  (APRD01099)
Typesmall molecule
Groupsapproved
Description

Metformin is a biguanide antihyperglycemic agent used for treating non-insulin-dependent diabetes mellitus (NIDDM). It improves glycemic control by decreasing hepatic glucose production, decreasing glucose absorption and increasing insulin-mediated glucose uptake. Metformin is the only oral antihyperglycemic agent that is not associated with weight gain. Metformin may induce weight loss and is the drug of choice for obese NIDDM patients. When used alone, metformin does not cause hypoglycemia; however, it may potentiate the hypoglycemic effects of sulfonylureas and insulin. Its main side effects are dyspepsia, nausea and diarrhea. Dose titration and/or use of smaller divided doses may decrease side effects. Metformin should be avoided in those with severely compromised renal function (creatinine clearance < 30 ml/min), acute/decompensated heart failure, severe liver disease and for 48 hours after the use of iodinated contrast dyes due to the risk of lactic acidosis. Lower doses should be used in the elderly and those with decreased renal function. Metformin decreases fasting plasma glucose, postprandial blood glucose and glycosolated hemoglobin (HbA1c) levels, which are reflective of the last 8-10 weeks of glucose control. Metformin may also have a positive effect on lipid levels. In 2012, a combination tablet of linagliptin plus metformin hydrochloride was marketed under the name Jentadueto for use in patients when treatment with both linagliptin and metformin is appropriate.

Structure
Thumb
Synonyms
SynonymLanguageCode
1,1-DimethylbiguanideNot AvailableNot Available
DimethylbiguanidNot AvailableIS
HaurymellinNot AvailableIS
MetforminNot AvailableUSAN, BAN
MetforminaNot AvailableDCIT
MetformineNot AvailableDCF
Metformine pamoateNot AvailableIS
MetforminumLatinINN
N,N-Dimethylimidodicarbonimidic diamideNot AvailableIUPAC
Salts
Name/CAS Structure Properties
Metformin Hydrochloride
Thumb
  • InChI Key: OETHQSJEHLVLGH-UHFFFAOYSA-N
  • Monoisotopic Mass: 165.078123116
  • Average Mass: 165.625
DBSALT000114
Brand names
NameCompany
Apo-MetforminApotex
FortametAndrx
Gen-MetforminGenpharm ULC
GlucophageSanofi-Aventis
Glucophage XRSanofi-Aventis
GlumetzaValeant
Mylan-MetforminMylan
Novo-MetforminNovopharm
Nu-MetforminNu-Pharm
PMS-MetforminPharmascience
Ran-MetforminRanbaxy
Ratio-MetforminRatiopharm
RiometRanbaxy
Sandoz MetforminSandox
Teva-MetforminTeva Canada
Brand mixtures
Brand NameIngredients
Actoplus MetPioglitazone and Metformin
AvandametRosiglitazone and Metformin
GlucovanceGlyburide and Metformin
JanumetSitagliptin and Metformin
JentaduetoLinagliptin and Metformin hydrochloride
KazanoAlogliptin and Metformin
KombiglyzeSaxagliptin and Metformin
MetaglipGlipizide and Metformin
PrandiMetRepaglinide and Metformin
Categories
CAS number657-24-9
WeightAverage: 129.1636
Monoisotopic: 129.101445377
Chemical FormulaC4H11N5
InChI KeyXZWYZXLIPXDOLR-UHFFFAOYSA-N
InChI
InChI=1S/C4H11N5/c1-9(2)4(7)8-3(5)6/h1-2H3,(H5,5,6,7,8)
IUPAC Name
1-carbamimidamido-N,N-dimethylmethanimidamide
SMILES
CN(C)C(=N)NC(N)=N
Mass SpecNot Available
Taxonomy
KingdomOrganic Compounds
SuperclassOrganonitrogen Compounds
ClassGuanidines
SubclassBiguanides
Direct parentBiguanides
Alternative parentsTertiary Amines; Polyamines; Amidines
Substituentstertiary amine; polyamine; amidine; amine
Classification descriptionThis compound belongs to the biguanides. These are organic compounds containing two N-linked guanidines.
Pharmacology
IndicationFor use as an adjunct to diet and exercise in adult patients (18 years and older) with NIDDM. May also be used for the management of metabolic and reproductive abnormalities associated with polycystic ovary syndrome (PCOS). Jentadueto is for the treatment of patients when both linagliptin and metformin is appropriate.
PharmacodynamicsMetformin is an oral antihyperglycemic agent that improves glucose tolerance in patients with NIDDM, lowering both basal and postprandial plasma glucose. Metformin is not chemically or pharmacologically related to any other class of oral antihyperglycemic agents. Unlike sulfonylureas, metformin does not produce hypoglycemia in either patients with NIDDM or healthy subjects and does not cause hyperinsulinemia. Metformin does not affect insulin secretion.
Mechanism of actionMetformin's mechanisms of action differ from other classes of oral antihyperglycemic agents. Metformin decreases blood glucose levels by decreasing hepatic glucose production, decreasing intestinal absorption of glucose, and improving insulin sensitivity by increasing peripheral glucose uptake and utilization. These effects are mediated by the initial activation by metformin of AMP-activated protein kinase (AMPK), a liver enzyme that plays an important role in insulin signaling, whole body energy balance, and the metabolism of glucose and fats. Activation of AMPK is required for metformin's inhibitory effect on the production of glucose by liver cells. Increased peripheral utilization of glucose may be due to improved insulin binding to insulin receptors. Metformin administration also increases AMPK activity in skeletal muscle. AMPK is known to cause GLUT4 deployment to the plasma membrane, resulting in insulin-independent glucose uptake. The rare side effect, lactic acidosis, is thought to be caused by decreased liver uptake of serum lactate, one of the substrates of gluconeogenesis. In those with healthy renal function, the slight excess is simply cleared. However, those with severe renal impairment may accumulate clinically significant serum lactic acid levels. Other conditions that may precipitate lactic acidosis include severe hepatic disease and acute/decompensated heart failure.
AbsorptionAbsorbed over 6 hours, bioavailability is 50 to 60% under fasting conditions. Administration with food decreases and delays absorption. Some evidence indicates that the level of absorption is not dose-related, suggesting that absorption occurs through a saturable process. Limited data from animal and human cell cultures indicate that absorption occurs through a passive, non-saturable process, possibly involving a paracellular route. Peak action occurs 3 hours after oral administration.
Volume of distribution

654 L for metformin 850 mg administered as a single dose. The volume of distribution following IV administration is 63-276 L, likely due to less binding in the GI tract and/or different methods used to determine volume of distribution.

Protein bindingMetformin is negligibly bound to plasma proteins.
Metabolism

Metformin is not metabolized.

Route of eliminationIntravenous single-dose studies in normal subjects demonstrate that metformin is excreted unchanged in the urine and does not undergo hepatic metabolism (no metabolites have been identified in humans) nor biliary excretion. Approximately 90% of the drug is eliminated in 24 hours in those with healthy renal function. Renal clearance of metformin is approximately 3.5 times that of creatinine clearance, indicating the tubular secretion is the primary mode of metformin elimination.
Half life6.2 hours. Duration of action is 8-12 hours.
Clearance

718-1552 mL/minute following single oral dose of 0.5-1.5 g. Metformin is removed by hemodialysis at a rate of approximately 170 ml/min under good hemodynamic conditions.

ToxicityAcute oral toxicity (LD50): 350 mg/kg [Rabbit]. It would be expected that adverse reactions of a more intense character including epigastric discomfort, nausea, and vomiting followed by diarrhea, drowsiness, weakness, dizziness, malaise and headache might be seen.
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 + 0.9156
Blood Brain Barrier + 0.5868
Caco-2 permeable - 0.8958
P-glycoprotein substrate Non-substrate 0.6643
P-glycoprotein inhibitor I Non-inhibitor 0.9613
P-glycoprotein inhibitor II Non-inhibitor 0.8892
Renal organic cation transporter Non-inhibitor 0.7518
CYP450 2C9 substrate Non-substrate 0.7929
CYP450 2D6 substrate Non-substrate 0.7325
CYP450 3A4 substrate Non-substrate 0.6906
CYP450 1A2 substrate Non-inhibitor 0.9046
CYP450 2C9 substrate Non-inhibitor 0.9159
CYP450 2D6 substrate Non-inhibitor 0.9231
CYP450 2C19 substrate Non-inhibitor 0.913
CYP450 3A4 substrate Non-inhibitor 0.9506
CYP450 inhibitory promiscuity Low CYP Inhibitory Promiscuity 0.9763
Ames test Non AMES toxic 0.7367
Carcinogenicity Non-carcinogens 0.6691
Biodegradation Not ready biodegradable 0.938
Rat acute toxicity 1.7407 LD50, mol/kg Not applicable
hERG inhibition (predictor I) Weak inhibitor 0.9807
hERG inhibition (predictor II) Non-inhibitor 0.9274
Pharmacoeconomics
Manufacturers
  • Ranbaxy pharmaceuticals inc
  • Andrx labs llc
  • Bristol myers squibb co
  • Depomed inc
  • Actavis elizabeth llc
  • Amneal pharmaceuticals ny llc
  • Apotex inc etobicoke site
  • Barr laboratories inc
  • Impax laboratories inc
  • Ivax pharmaceuticals inc sub teva pharmaceuticals usa
  • Mutual pharmaceutical co inc
  • Mylan pharmaceuticals inc
  • Neurosci inc
  • Nostrum pharmaceuticals inc
  • Ranbaxy laboratories ltd
  • Sandoz inc
  • Sun pharmaceutical industries ltd
  • Teva pharmaceuticals usa inc
  • Torrent pharma inc
  • Torrent pharmaceuticals ltd
  • Watson laboratories inc
  • Watson laboratories inc florida
  • Zydus pharmaceuticals usa inc
  • Bristol myers squibb co pharmaceutical research institute
  • Alphapharm party ltd
  • Alvogen inc
  • Apotex inc
  • Aurobindo pharma ltd
  • Caraco pharmaceutical laboratories ltd
  • Dr reddys laboratories inc
  • Genpharm inc
  • Glenmark generics ltd
  • Granules india ltd
  • Indicus pharma llc
  • Ipca laboratories ltd
  • Mutual pharmacal co
  • Provident pharmaceutical inc
  • Watson laboratories
Packagers
Dosage forms
FormRouteStrength
TabletOral2.5MG; 1GM (LINAGLIPTIN; METFORMIN HYDROCHLORIDE)
TabletOral2.5MG; 500MG (LINAGLIPTIN; METFORMIN HYDROCHLORIDE)
TabletOral2.5MG; 850MG (LINAGLIPTIN; METFORMIN HYDROCHLORIDE)
TabletOral500 mg
TabletOral850 mg
Tablet, extended releaseOral
Prices
Unit descriptionCostUnit
Fortamet er 1000 mg tablet6.93USDtablet
Fortamet 1000 mg 24 Hour tablet6.01USDtablet
Fortamet 500 mg 24 Hour tablet2.55USDtablet
Fortamet er 500 mg tablet2.48USDtablet
Glucophage 1000 mg tablet2.33USDtablet
Metformin hcl crystals2.14USDg
Glucophage 850 mg tablet1.94USDtablet
Glucophage XR 750 mg 24 Hour tablet1.8USDtablet
Glucophage xr 750 mg tablet1.71USDtablet
Metformin hcl 1000 mg tablet1.48USDtablet
MetFORMIN HCl 750 mg 24 Hour tablet1.25USDtablet
Metformin hcl 850 mg tablet1.22USDtablet
Glucophage XR 500 mg 24 Hour tablet1.17USDtablet
Glucophage 500 mg tablet1.14USDtablet
Glucophage xr 500 mg tablet1.14USDtablet
Glucophage xr 500 mg tablet sa1.11USDtablet
MetFORMIN HCl 500 mg 24 Hour tablet0.75USDtablet
Metformin hcl 500 mg tablet0.72USDtablet
Glucophage 850 mg Tablet0.38USDtablet
Glucophage 500 mg Tablet0.3USDtablet
Riomet 500 mg/5 ml solution0.27USDml
Riomet 500 mg/5ml Solution0.27USDml
Apo-Metformin 850 mg Tablet0.21USDtablet
Co Metformin 850 mg Tablet0.21USDtablet
Mylan-Metformin 850 mg Tablet0.21USDtablet
Novo-Metformin 850 mg Tablet0.21USDtablet
Nu-Metformin 850 mg Tablet0.21USDtablet
Pms-Metformin 850 mg Tablet0.21USDtablet
Ratio-Metformin Hydrochloride 850 mg Tablet0.21USDtablet
Sandoz Metformin Fc 850 mg Tablet0.21USDtablet
Pms-Metformin 500 mg Tablet0.13USDtablet
Ran-Metformin 500 mg Tablet0.13USDtablet
Ratio-Metformin Hydrochloride 500 mg Tablet0.13USDtablet
Sandoz Metformin Fc 500 mg Tablet0.13USDtablet
Zym-Metformin 500 mg Tablet0.13USDtablet
Apo-Metformin 500 mg Tablet0.13USDtablet
Co Metformin 500 mg Tablet0.13USDtablet
Mylan-Metformin 500 mg Tablet0.13USDtablet
Novo-Metformin 500 mg Tablet0.13USDtablet
Nu-Metformin 500 mg Tablet0.13USDtablet
DrugBank does not sell nor buy drugs. Pricing information is supplied for informational purposes only.
Patents
CountryPatent NumberApprovedExpires (estimated)
United States68909572003-09-142023-09-14
United States63404751996-09-192016-09-19
Canada24764962009-12-152023-02-21
Canada24126712006-10-032021-02-26
Properties
Statesolid
Experimental Properties
PropertyValueSource
melting point223-226 °CNot Available
water solubilityFreely soluble as HCl saltNot Available
logP-0.5Not Available
pKa12.4Not Available
Predicted Properties
PropertyValueSource
water solubility1.38e+00 g/lALOGPS
logP-1.8ALOGPS
logP-0.92ChemAxon
logS-2ALOGPS
pKa (strongest basic)12.33ChemAxon
physiological charge2ChemAxon
hydrogen acceptor count5ChemAxon
hydrogen donor count4ChemAxon
polar surface area88.99ChemAxon
rotatable bond count0ChemAxon
refractivity56.64ChemAxon
polarizability13.43ChemAxon
number of rings0ChemAxon
bioavailability1ChemAxon
rule of fiveYesChemAxon
Ghose filterNoChemAxon
Veber's ruleNoChemAxon
MDDR-like ruleNoChemAxon
Spectra
SpectraMS/MSLC-MS1D NMR2D NMR
References
Synthesis Reference

Jorn Moeckel, Rolf-Dieter Gabel, Heinrich Woog, “Pharmaceutical preparation containing metformin and a process for producing it.” U.S. Patent US5955106, issued October, 1991.

US5955106
General Reference
  1. Witters LA: The blooming of the French lilac. J Clin Invest. 2001 Oct;108(8):1105-7. Pubmed
  2. UNGAR G, FREEDMAN L, SHAPIRO SL: Pharmacological studies of a new oral hypoglycemic drug. Proc Soc Exp Biol Med. 1957 May;95(1):190-2. Pubmed
  3. Lord JM, Flight IH, Norman RJ: Metformin in polycystic ovary syndrome: systematic review and meta-analysis. BMJ. 2003 Oct 25;327(7421):951-3. Pubmed
  4. Marchesini G, Brizi M, Bianchi G, Tomassetti S, Zoli M, Melchionda N: Metformin in non-alcoholic steatohepatitis. Lancet. 2001 Sep 15;358(9285):893-4. Pubmed
  5. Nair S, Diehl AM, Wiseman M, Farr GH Jr, Perrillo RP: Metformin in the treatment of non-alcoholic steatohepatitis: a pilot open label trial. Aliment Pharmacol Ther. 2004 Jul 1;20(1):23-8. Pubmed
External Links
ResourceLink
KEGG DrugD04966
KEGG CompoundC07151
PubChem Compound4091
PubChem Substance46507752
ChemSpider3949
ChEBI6801
ChEMBLCHEMBL1431
Therapeutic Targets DatabaseDAP000205
PharmGKBPA450395
Drug Product Database2265583
RxListhttp://www.rxlist.com/cgi/generic4/glumetza.htm
Drugs.comhttp://www.drugs.com/metformin.html
WikipediaMetformin
ATC CodesA10BD11A10BA02
AHFS Codes
  • 68:20.04
PDB EntriesNot Available
FDA labelshow(239 KB)
MSDSshow(73.8 KB)
Interactions
Drug Interactions
Drug
CimetidineCimetidine may increase the therapeutic and adverse effects of metformin by increasing its serum concentration. Consider alternate therapy.
GlucosaminePossible hyperglycemia
Somatropin recombinantSomatropin may antagonize the hypoglycemic effect of metformin. Monitor for changes in fasting and postprandial blood sugars.
Food Interactions
  • Avoid alcohol.
  • Take with food to reduce gastric irritation.

Targets

1. 5'-AMP-activated protein kinase subunit beta-1

Kind: protein

Organism: Human

Pharmacological action: yes

Actions: inducer

Components

Name UniProt ID Details
5'-AMP-activated protein kinase subunit beta-1 Q9Y478 Details

References:

  1. Kovacic S, Soltys CL, Barr AJ, Shiojima I, Walsh K, Dyck JR: Akt activity negatively regulates phosphorylation of AMP-activated protein kinase in the heart. J Biol Chem. 2003 Oct 10;278(41):39422-7. Epub 2003 Jul 29. Pubmed
  2. Hardie DG: Minireview: the AMP-activated protein kinase cascade: the key sensor of cellular energy status. Endocrinology. 2003 Dec;144(12):5179-83. Epub 2003 Sep 4. Pubmed
  3. Ruderman NB, Saha AK, Kraegen EW: Minireview: malonyl CoA, AMP-activated protein kinase, and adiposity. Endocrinology. 2003 Dec;144(12):5166-71. Epub 2003 Sep 18. Pubmed
  4. Leverve XM, Guigas B, Detaille D, Batandier C, Koceir EA, Chauvin C, Fontaine E, Wiernsperger NF: Mitochondrial metabolism and type-2 diabetes: a specific target of metformin. Diabetes Metab. 2003 Sep;29(4 Pt 2):6S88-94. Pubmed
  5. Leclerc I, Woltersdorf WW, da Silva Xavier G, Rowe RL, Cross SE, Korbutt GS, Rajotte RV, Smith R, Rutter GA: Metformin, but not leptin, regulates AMP-activated protein kinase in pancreatic islets: impact on glucose-stimulated insulin secretion. Am J Physiol Endocrinol Metab. 2004 Jun;286(6):E1023-31. Epub 2004 Feb 10. Pubmed
  6. Vucicevic L, Misirkic M, Janjetovic K, Harhaji-Trajkovic L, Prica M, Stevanovic D, Isenovic E, Sudar E, Sumarac-Dumanovic M, Micic D, Trajkovic V: AMP-activated protein kinase-dependent and -independent mechanisms underlying in vitro antiglioma action of compound C. Biochem Pharmacol. 2009 Jun 1;77(11):1684-93. Epub 2009 Mar 14. Pubmed
  7. Towler MC, Hardie DG: AMP-activated protein kinase in metabolic control and insulin signaling. Circ Res. 2007 Feb 16;100(3):328-41. Pubmed
  8. Musi N, Hirshman MF, Nygren J, Svanfeldt M, Bavenholm P, Rooyackers O, Zhou G, Williamson JM, Ljunqvist O, Efendic S, Moller DE, Thorell A, Goodyear LJ: Metformin increases AMP-activated protein kinase activity in skeletal muscle of subjects with type 2 diabetes. Diabetes. 2002 Jul;51(7):2074-81. Pubmed

Transporters

1. Solute carrier family 22 member 1

Kind: protein

Organism: Human

Pharmacological action: unknown

Actions: substrate inhibitor

Components

Name UniProt ID Details
Solute carrier family 22 member 1 O15245 Details

References:

  1. Dresser MJ, Xiao G, Leabman MK, Gray AT, Giacomini KM: Interactions of n-tetraalkylammonium compounds and biguanides with a human renal organic cation transporter (hOCT2). Pharm Res. 2002 Aug;19(8):1244-7. Pubmed
  2. Wang DS, Jonker JW, Kato Y, Kusuhara H, Schinkel AH, Sugiyama Y: Involvement of organic cation transporter 1 in hepatic and intestinal distribution of metformin. J Pharmacol Exp Ther. 2002 Aug;302(2):510-5. Pubmed
  3. Zolk O: Current understanding of the pharmacogenomics of metformin. Clin Pharmacol Ther. 2009 Dec;86(6):595-8. Pubmed
  4. Tzvetkov MV, Vormfelde SV, Balen D, Meineke I, Schmidt T, Sehrt D, Sabolic I, Koepsell H, Brockmoller J: The effects of genetic polymorphisms in the organic cation transporters OCT1, OCT2, and OCT3 on the renal clearance of metformin. Clin Pharmacol Ther. 2009 Sep;86(3):299-306. Epub 2009 Jun 17. Pubmed
  5. Ahlin G, Karlsson J, Pedersen JM, Gustavsson L, Larsson R, Matsson P, Norinder U, Bergstrom CA, Artursson P: Structural requirements for drug inhibition of the liver specific human organic cation transport protein 1. J Med Chem. 2008 Oct 9;51(19):5932-42. Epub 2008 Sep 13. Pubmed

2. Solute carrier family 22 member 2

Kind: protein

Organism: Human

Pharmacological action: unknown

Actions: substrate inhibitor

Components

Name UniProt ID Details
Solute carrier family 22 member 2 O15244 Details

References:

  1. Dresser MJ, Xiao G, Leabman MK, Gray AT, Giacomini KM: Interactions of n-tetraalkylammonium compounds and biguanides with a human renal organic cation transporter (hOCT2). Pharm Res. 2002 Aug;19(8):1244-7. Pubmed
  2. Zolk O: Current understanding of the pharmacogenomics of metformin. Clin Pharmacol Ther. 2009 Dec;86(6):595-8. Pubmed
  3. Berman HM, Westbrook J, Feng Z, Gilliland G, Bhat TN, Weissig H, Shindyalov IN, Bourne PE: The Protein Data Bank. Nucleic Acids Res. 2000 Jan 1;28(1):235-42. Pubmed
  4. Kimura N, Masuda S, Tanihara Y, Ueo H, Okuda M, Katsura T, Inui K: Metformin is a superior substrate for renal organic cation transporter OCT2 rather than hepatic OCT1. Drug Metab Pharmacokinet. 2005 Oct;20(5):379-86. Pubmed

3. Solute carrier family 22 member 3

Kind: protein

Organism: Human

Pharmacological action: unknown

Actions: substrate

Components

Name UniProt ID Details
Solute carrier family 22 member 3 O75751 Details

References:

  1. Muller J, Lips KS, Metzner L, Neubert RH, Koepsell H, Brandsch M: Drug specificity and intestinal membrane localization of human organic cation transporters (OCT). Biochem Pharmacol. 2005 Dec 5;70(12):1851-60. Epub 2005 Nov 2. Pubmed

4. Multidrug and toxin extrusion protein 1

Kind: protein

Organism: Human

Pharmacological action: unknown

Actions: inhibitor

Components

Name UniProt ID Details
Multidrug and toxin extrusion protein 1 Q96FL8 Details

References:

  1. Meyer zu Schwabedissen HE, Verstuyft C, Kroemer HK, Becquemont L, Kim RB: Human multidrug and toxin extrusion 1 (MATE1/SLC47A1) transporter: functional characterization, interaction with OCT2 (SLC22A2), and single nucleotide polymorphisms. Am J Physiol Renal Physiol. 2010 Apr;298(4):F997-F1005. Epub 2010 Jan 6. Pubmed

5. Equilibrative nucleoside transporter 4

Kind: protein

Organism: Human

Pharmacological action: unknown

Actions: substrate

Components

Name UniProt ID Details
Equilibrative nucleoside transporter 4 Q7RTT9 Details

References:

  1. Zhou M, Xia L, Wang J: Metformin transport by a newly cloned proton-stimulated organic cation transporter (plasma membrane monoamine transporter) expressed in human intestine. Drug Metab Dispos. 2007 Oct;35(10):1956-62. Epub 2007 Jun 28. Pubmed

Comments
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Drug created on June 13, 2005 07:24 / Updated on September 16, 2013 17:09