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Summary
General Info

PubChem

PubChem Compound 14219

Name:	Metformin
PubChem Compound ID:	14219
Description:	A biguanide hypoglycemic agent used in the treatment of non-insulin-dependent diabetes mellitus not responding to dietary modification. Metformin improves glycemic control by improving insulin sensitivity and decreasing intestinal absorption of glucose. (From Martindale, The Extra Pharmacopoeia, 30th ed, p289)
Molecular formula:	C₄H₁₂ClN₅
Molecular weight:	165.624 g/mol
Synonyms:	Glucophage (TN); Diabesin; Metformin hydrochloride [USAN]; Glucomet; 56258-19-6; Biocos; Novo-Metformin; Metformin hydrochloride (JP15/USP); Diamin; Riomet. show more » Glucophage (TN); Diabesin; Metformin hydrochloride [USAN]; Glucomet; 56258-19-6; Biocos; Novo-Metformin; Metformin hydrochloride (JP15/USP); Diamin; Riomet; Metomin; Siamformet; N,N-Dimethylbiguanide hydrochloride; Dextin; BIGUANIDE, 1,1-DIMETHYL-, HYDROCHLORIDE; Imidodicarbonimidic diamide, N,N-dimethyl-, monohydrochloride (9CI); Metformin monohydrochloride; Metiguanide monohydrochloride; Diabefagos; Thiabet; Walaphage; Benofomin; Diformin Retard; Mescorit; 1,1-DIMETHYLBIGUANIDE HYDROCHLORIDE; Glycoran; MLS000028493; D.B.I.; Glucophage-Mite; Metforal; AI3-51264; Miformin; Glucoform; Glibomet; Glucofago; Dabex; Glupermin; Diaphage; Apo-Metformin; Glucophage Retard; Diabetmin; Dimethylbiguanide hydrochloride; Geamet; Glucomine; D 15095; Glucoliz; Diaberit; Risidon; Denkaform; Metolmin; Metformin hydrochloride; N1,N1-Dimethylbiguanide hydrochloride; Haurymellin hydrochloride; Diformin; Orabet; Glyformin; DMGG hydrochloride; SMR000058277; EINECS 214-230-6; Prestwick_519; Diaformin; 1115-70-4; 144377-16-2; Islotin retard; NSC 91485; LA 6023; LS-43900; Gluformin; HSDB 7080; Diabetex; D00944; Glyciphage; Meglucon; Glucophage 850; 15537-72-1; Metbay; Meguan; Gluconil; Metaglip; Biguanide, 1,1-dimethyl-, monohydrochloride (8CI); Glucophage Forte; Fornidd; Glucophage show less «

DrugBank

Identification

Name:	Metformin
Name (isomeric):	DB00331
Drug Type:	small molecule
Description:	A biguanide hypoglycemic agent used in the treatment of non-insulin-dependent diabetes mellitus not responding to dietary modification. Metformin improves glycemic control by improving insulin sensitivity and decreasing intestinal absorption of glucose. (From Martindale, The Extra Pharmacopoeia, 30th ed, p289)
Synonyms:	Metformin HCL; metformin hydrochloride
Brand:	Riomet, Nu-Metformin, Ran-Metformin, Ratio-Metformin, Gen-Metformin, Glucophage, Fortamet, Glumetza, Mylan-Metformin, Apo-Metformin, Glycon, Sandoz Metformin, Novo-Metformin, Teva-Metformin, Glucophage XR, PMS-Metformin
Category:	Antidiabetic
CAS number:	657-24-9

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).
Pharmacology:	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 ... show more » 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. show less «
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 init... show more » 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. show less «
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.
Protein binding:	Metformin is negligibly bound to plasma proteins.
Biotransformation:	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

Interactions

Food interaction:

Avoid alcohol.

Take with food to reduce gastric irritation.

Drug interaction:

Glucosamine	Possible hyperglycemia
Somatropin recombinant	Somatropin may antagonize the hypoglycemic effect of metformin. Monitor for changes in fasting and postprandial blood sugars.
Cimetidine	Cimetidine may increase the therapeutic and adverse effects of metformin by increasing its serum concentration. Consider alternate therapy.

Targets

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

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

UniProt ID:

Q9Y478

Gene:

PRKAB1

Actions:

inducer

References:

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.
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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.
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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.
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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.
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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.
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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.
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Towler MC, Hardie DG: AMP-activated protein kinase in metabolic control and insulin signaling. Circ Res. 2007 Feb 16;100(3):328-41.
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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.
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Transporters

Solute carrier family 22 member 2

Solute carrier family 22 member 1

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

Gene:

SLC22A1

Actions:

substrate, inhibitor

References:

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.
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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.
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Zolk O: Current understanding of the pharmacogenomics of metformin. Clin Pharmacol Ther. 2009 Dec;86(6):595-8.
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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.
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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.
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Multidrug and toxin extrusion protein 1