Banner
targets (1) transporters (3)
for drugs
Identification
Name Metformin
Accession Number DB00331 (APRD01099)
Type small molecule
Groups approved
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
Download: MOL | SDF | SMILES | InChI
Display: 2D Structure | 3D Structure
Synonyms Not Available
Salts
  • metformin hydrochloride
Brand names
Name Company
Apo-Metformin Apotex
Fortamet
Gen-Metformin
Glucophage Sanofi-Aventis
Glucophage XR Sanofi-Aventis
Glumetza Valeant
Glycon
Mylan-Metformin Mylan
Novo-Metformin Novopharm
Nu-Metformin Nu-Pharm
PMS-Metformin Pharmascience
Ran-Metformin Ranbaxy
Ratio-Metformin Ratiopharm
Riomet
Sandoz Metformin Sandox
Teva-Metformin Teva Canada
First Prev Next Last
Brand mixtures
Brand Name Ingredients
Jentadueto linagliptin plus metformin hydrochloride
Categories
  • Antidiabetic
CAS number 657-24-9
Weight Average: 129.1636
Monoisotopic: 129.101445377
Chemical Formula C4H11N5
InChI Key InChIKey=XZWYZXLIPXDOLR-UHFFFAOYSA-N
InChI
InChI=1S/C4H11N5/c1-9(2)4(7)8-3(5)6/h1-2H3,(H5,5,6,7,8)
Plain Text
IUPAC Name
1-carbamimidamido-N,N-dimethylmethanimidamide
SMILES
CN(C)C(=N)NC(N)=N
Plain Text
Mass Spec Not Available
Taxonomy
Kingdom Organic
Classes
  • Biguanides
Substructures
  • Biguanides
  • Guanidines
  • Carboxamidines
Pharmacology
Indication For 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.
Pharmacodynamics Metformin 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 action Metformin'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.
Absorption Absorbed 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 binding Metformin is negligibly bound to plasma proteins.
Metabolism Metformin is not metabolized.
Route of elimination Intravenous 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 life 6.2 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.
Toxicity Acute 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
Pathways Not Available
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
Form Route Strength
Tablet Oral 2.5MG; 1GM (LINAGLIPTIN; METFORMIN HYDROCHLORIDE)
Tablet Oral 2.5MG; 500MG (LINAGLIPTIN; METFORMIN HYDROCHLORIDE)
Tablet Oral 2.5MG; 850MG (LINAGLIPTIN; METFORMIN HYDROCHLORIDE)
Tablet Oral 500 mg
Tablet Oral 850 mg
Tablet, extended release Oral
Prices
Unit description Cost Unit
Fortamet er 1000 mg tablet 6.93 USD tablet
Fortamet 1000 mg 24 Hour tablet 6.01 USD tablet
Fortamet 500 mg 24 Hour tablet 2.55 USD tablet
Fortamet er 500 mg tablet 2.48 USD tablet
Glucophage 1000 mg tablet 2.33 USD tablet
Metformin hcl crystals 2.14 USD g
Glucophage 850 mg tablet 1.94 USD tablet
Glucophage XR 750 mg 24 Hour tablet 1.8 USD tablet
Glucophage xr 750 mg tablet 1.71 USD tablet
Metformin hcl 1000 mg tablet 1.48 USD tablet
MetFORMIN HCl 750 mg 24 Hour tablet 1.25 USD tablet
Metformin hcl 850 mg tablet 1.22 USD tablet
Glucophage XR 500 mg 24 Hour tablet 1.17 USD tablet
Glucophage 500 mg tablet 1.14 USD tablet
Glucophage xr 500 mg tablet 1.14 USD tablet
Glucophage xr 500 mg tablet sa 1.11 USD tablet
MetFORMIN HCl 500 mg 24 Hour tablet 0.75 USD tablet
Metformin hcl 500 mg tablet 0.72 USD tablet
Glucophage 850 mg Tablet 0.38 USD tablet
Glucophage 500 mg Tablet 0.3 USD tablet
Riomet 500 mg/5 ml solution 0.27 USD ml
Riomet 500 mg/5ml Solution 0.27 USD ml
Apo-Metformin 850 mg Tablet 0.21 USD tablet
Co Metformin 850 mg Tablet 0.21 USD tablet
Mylan-Metformin 850 mg Tablet 0.21 USD tablet
Novo-Metformin 850 mg Tablet 0.21 USD tablet
Nu-Metformin 850 mg Tablet 0.21 USD tablet
Pms-Metformin 850 mg Tablet 0.21 USD tablet
Ratio-Metformin Hydrochloride 850 mg Tablet 0.21 USD tablet
Sandoz Metformin Fc 850 mg Tablet 0.21 USD tablet
Pms-Metformin 500 mg Tablet 0.13 USD tablet
Ran-Metformin 500 mg Tablet 0.13 USD tablet
Ratio-Metformin Hydrochloride 500 mg Tablet 0.13 USD tablet
Sandoz Metformin Fc 500 mg Tablet 0.13 USD tablet
Zym-Metformin 500 mg Tablet 0.13 USD tablet
Apo-Metformin 500 mg Tablet 0.13 USD tablet
Co Metformin 500 mg Tablet 0.13 USD tablet
Mylan-Metformin 500 mg Tablet 0.13 USD tablet
Novo-Metformin 500 mg Tablet 0.13 USD tablet
Nu-Metformin 500 mg Tablet 0.13 USD tablet
First Prev Next Last
DrugBank does not sell nor buy drugs. Pricing information is supplied for informational purposes only.
Patents
Country Patent Number Approved Expires (estimated)
United States 6890957 2003-09-14 2023-09-14
United States 6340475 1996-09-19 2016-09-19
Canada 2476496 2009-12-15 2023-02-21
Canada 2412671 2006-10-03 2021-02-26
Properties
State solid
Experimental Properties
Property Value Source
melting point 223-226 °C Not Available
water solubility Freely soluble as HCl salt Not Available
logP -0.5 Not Available
pKa 12.4 Not Available
Predicted Properties
Property Value Source
water solubility 1.38e+00 g/l ALOGPS
logP -1.8 ALOGPS
logP -0.92 ChemAxon
logS -2 ALOGPS
pKa (strongest basic) 12.33 ChemAxon
physiological charge 2 ChemAxon
hydrogen acceptor count 5 ChemAxon
hydrogen donor count 4 ChemAxon
polar surface area 88.99 ChemAxon
rotatable bond count 0 ChemAxon
refractivity 56.64 ChemAxon
polarizability 13.43 ChemAxon
References
Synthesis Reference Not Available
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
Resource Link
KEGG Drug D04966 Link_out
KEGG Compound C07151 Link_out
PubChem Compound 4091 Link_out
PubChem Substance 46507752 Link_out
ChemSpider 3949 Link_out
ChEBI 6801 Link_out
ChEMBL 6801 Link_out
Therapeutic Targets Database DAP000205 Link_out
PharmGKB PA450395 Link_out
Drug Product Database 2265583 Link_out
RxList http://www.rxlist.com/cgi/generic4/glumetza.htm Link_out
Drugs.com http://www.drugs.com/metformin.html Link_out
Wikipedia http://en.wikipedia.org/wiki/Metformin Link_out
ATC Codes
  • A10BA02
  • A10BD11
AHFS Codes
  • 68:20.04
PDB Entries Not Available
FDA label show (239 KB)
MSDS show (73.8 KB)
Interactions
Drug Interactions
Drug Interaction
Cimetidine Cimetidine may increase the therapeutic and adverse effects of metformin by increasing its serum concentration. Consider alternate therapy.
Glucosamine Possible hyperglycemia
Somatropin recombinant Somatropin 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

Pharmacological action: yes
Actions: inducer

AMPK is responsible for the regulation of fatty acid synthesis by phosphorylation of acetyl-CoA carboxylase. Also regulates cholesterol synthesis via phosphorylation and inactivation of hydroxymethylglutaryl-CoA reductase and hormone- sensitive lipase. This is a regulatory subunit, may be a positive regulator of AMPK activity. It may also serve as an adaptor molecule for the catalytic alpha-subunit

Organism class: human
UniProt ID: Q9Y478 Link_out
Gene: PRKAB1 Link_out
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

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
Enzymes
Searched, but no enzymes found.
Transporters

1. Solute carrier family 22 member 2

Actions: substrate, inhibitor

Mediates tubular uptake of organic compounds from circulation. Mediates the influx of agmatine, dopamine, noradrenaline (norepinephrine), serotonin, choline, famotidine, ranitidine, histamin, creatinine, amantadine, memantine, acriflavine, 4-[4-(dimethylamino)-styryl]-N-methylpyridinium ASP, amiloride, metformin, N-1-methylnicotinamide (NMN), tetraethylammonium (TEA), 1-methyl-4-phenylpyridinium (MPP), cimetidine, cisplatin and oxaliplatin. Cisplatin may develop a nephrotoxic action. Transport of creatinine is inhibited by fluoroquinolones such as DX-619 and LVFX. This transporter is a major determinant of the anticancer activity of oxaliplatin and may contribute to antitumor specificity

UniProt ID: O15244 Link_out
Gene: SLC22A2 Link_out
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

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

2. Solute carrier family 22 member 1

Actions: substrate, inhibitor

Translocates a broad array of organic cations with various structures and molecular weights including the model compounds 1-methyl-4-phenylpyridinium (MPP), tetraethylammonium (TEA), N-1-methylnicotinamide (NMN), 4-(4-(dimethylamino)styryl)- N-methylpyridinium (ASP), the endogenous compounds choline, guanidine, histamine, epinephrine, adrenaline, noradrenaline and dopamine, and the drugs quinine, and metformin. The transport of organic cations is inhibited by a broad array of compounds like tetramethylammonium (TMA), cocaine, lidocaine, NMDA receptor antagonists, atropine, prazosin, cimetidine, TEA and NMN, guanidine, cimetidine, choline, procainamide, quinine, tetrabutylammonium, and tetrapentylammonium. Translocates organic cations in an electrogenic and pH-independent manner. Translocates organic cations across the plasma membrane in both directions. Transports the polyamines spermine and spermidine. Transports pramipexole across the basolateral membrane of the proximal tubular epithelial cells. The choline transport is activated by MMTS. Regulated by various intracellular signaling pathways including inhibition by protein kinase A activation, and endogenously activation by the calmodulin complex, the calmodulin- dependent kinase II and LCK tyrosine kinase

UniProt ID: O15245 Link_out
Gene: SLC22A1 Link_out
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

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

3. Multidrug and toxin extrusion protein 1

Actions: inhibitor

Solute transporter for tetraethylammonium (TEA), 1- methyl-4-phenylpyridinium (MPP), cimetidine, N-methylnicotinamide (NMN), metformin, creatinine, guanidine, procainamide, topotecan, estrone sulfate, acyclovir, ganciclovir and also the zwitterionic cephalosporin, cephalexin and cephradin. Seems to also play a role in the uptake of oxaliplatin (a new platinum anticancer agent). Able to transport paraquat (PQ or N,N-dimethyl-4-4'-bipiridinium); a widely used herbicid. Responsible for the secretion of cationic drugs across the brush border membranes

UniProt ID: Q96FL8 Link_out
Gene: SLC47A1 Link_out
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

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
Carriers
Searched, but no carriers found.
Comments
Drug created on June 13, 2005 07:24 / Updated on May 13, 2013 22:24