METFORMIN

Details

Stereochemistry	ACHIRAL
Molecular Formula	C4H11N5
Molecular Weight	129.1636
Optical Activity	NONE
Defined Stereocenters	0 / 0
E/Z Centers	0
Charge	0

SHOW SMILES / InChI

Structure Search

SMILES

CN(C)C(=N)NC(N)=N

InChI

InChIKey=XZWYZXLIPXDOLR-UHFFFAOYSA-N

InChI=1S/C4H11N5/c1-9(2)4(7)8-3(5)6/h1-2H3,(H5,5,6,7,8)

HIDE SMILES / InChI

Description
Sources: https://packageinserts.bms.com/pi/pi_glucophage.pdf
Curator's Comment: Description was created based on several sources, including https://www.ncbi.nlm.nih.gov/pubmed/25333032 | http://www.rsc.org/images/eic_nov2011_metformin_tcm18-210010.pdf | https://www.ncbi.nlm.nih.gov/pubmed/22117616

Metformin is the most widely used drug to treat type 2 diabetes, and is one of only two oral antidiabetic drugs on the World Health Organization (WHO) list of essential medicines. Metformin is an antihyperglycemic agent which improves glucose tolerance in patients with type 2 diabetes, lowering both basal and postprandial plasma glucose. Metformin decreases hepatic glucose production, decreases intestinal absorption of glucose, and improves insulin sensitivity by increasing peripheral glucose uptake and utilization. However, we still do not completely understand its mechanisms of action. The main effect of this drug from the biguanide family is to acutely decrease hepatic glucose production, mostly through a mild and transient inhibition of the mitochondrial respiratory chain complex I. In addition, the resulting decrease in hepatic energy status activates AMPK (AMP-activated protein kinase), a cellular metabolic sensor, providing a generally accepted mechanism for the action of metformin on hepatic gluconeogenesis. The use of metformin, the most commonly prescribed drug for type 2 diabetes, was repeatedly associated with the decreased risk of the occurrence of various types of cancers, especially of pancreas and colon and hepatocellular carcinoma.

CNS Activity

Originator

Approval Year

Targets

Primary Target	Pharmacology	Condition	Potency
gluconeogenesis 4 Target ID: GO:0006094 Sources: https://www.ncbi.nlm.nih.gov/pubmed/22117616 \| https://www.ncbi.nlm.nih.gov/pubmed/20577053	Inhibitor 8146
Mitochondrial complex I (NADH dehydrogenase) 11 Target ID: CHEMBL2363065 Sources: https://www.ncbi.nlm.nih.gov/pubmed/22117616	Inhibitor 8146
AMP-activated protein kinase, AMPK 17 Target ID: CHEMBL2096907 Sources: https://www.ncbi.nlm.nih.gov/pubmed/22117616	Activator 1404

Conditions

Condition	Modality	Targets	Highest Phase	Product
Type 2 diabetes mellitus 255 Sources: https://packageinserts.bms.com/pi/pi_glucophage.pdf	Primary		Approved 8307	GLUCOPHAGE Approved Use Metformin hydrochloride tablets, USP is indicated as an adjunct to diet and exercise to improve glycemic control in adults and children with type 2 diabetes mellitus. Metformin hydrochloride extended-release tablets, USP is indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus. Launch Date 7.9418878E11
Cancer 581 Sources: https://www.ncbi.nlm.nih.gov/pubmed/22117616 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4200668/	Primary		Phase III 651	Unknown Approved Use Unknown

C_max

Value	Dose	Co-administered	Analyte	Population
815.39 ng/mL DRUG LABEL https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/212595s000lbl.pdf	750 mg single, oral dose: 750 mg route of administration: Oral experiment type: SINGLE co-administered:		METFORMIN plasma	Homo sapiens population: HEALTHY age: ADULT sex: MALE food status: HIGH-FAT

AUC

Value	Dose	Co-administered	Analyte	Population
7694.78 ng × h/mL DRUG LABEL https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/212595s000lbl.pdf	750 mg single, oral dose: 750 mg route of administration: Oral experiment type: SINGLE co-administered:		METFORMIN plasma	Homo sapiens population: HEALTHY age: ADULT sex: MALE food status: HIGH-FAT

T_1/2

Value	Dose	Co-administered	Analyte	Population
4.19 h DRUG LABEL https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/212595s000lbl.pdf	750 mg single, oral dose: 750 mg route of administration: Oral experiment type: SINGLE co-administered:		METFORMIN plasma	Homo sapiens population: HEALTHY age: ADULT sex: MALE food status: HIGH-FAT

Doses

Dose	Population	Adverse events
2550 mg 1 times / day steady, oral Recommended Dose: 2550 mg, 1 times / day Route: oral Route: steady Dose: 2550 mg, 1 times / day Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/020357s034,021202s018lbl.pdf	unhealthy, adult n = 141 Health Status: unhealthy Condition: type 2 diabetes mellitus Age Group: adult Population Size: 141 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/020357s034,021202s018lbl.pdf	Disc. AE: Diarrhea... AEs leading to discontinuation/dose reduction: Diarrhea (6%) Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/020357s034,021202s018lbl.pdf
850 mg 1 times / day steady, oral Recommended Dose: 850 mg, 1 times / day Route: oral Route: steady Dose: 850 mg, 1 times / day Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/020357s034,021202s018lbl.pdf	unhealthy, adult Health Status: unhealthy Age Group: adult Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/020357s034,021202s018lbl.pdf	Disc. AE: Lactic acidosis... AEs leading to discontinuation/dose reduction: Lactic acidosis (grade 5) Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/020357s034,021202s018lbl.pdf

AEs

AE	Significance	Dose	Population
Diarrhea	6% Disc. AE	2550 mg 1 times / day steady, oral Recommended Dose: 2550 mg, 1 times / day Route: oral Route: steady Dose: 2550 mg, 1 times / day Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/020357s034,021202s018lbl.pdf	unhealthy, adult n = 141 Health Status: unhealthy Condition: type 2 diabetes mellitus Age Group: adult Population Size: 141 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/020357s034,021202s018lbl.pdf
Lactic acidosis	grade 5 Disc. AE	850 mg 1 times / day steady, oral Recommended Dose: 850 mg, 1 times / day Route: oral Route: steady Dose: 850 mg, 1 times / day Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/020357s034,021202s018lbl.pdf	unhealthy, adult Health Status: unhealthy Age Group: adult Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/020357s034,021202s018lbl.pdf

Overview

CYP3A4	CYP2C9	CYP2D6	hERG
substrate 1670

OverviewOther

Other Inhibitor	Other Substrate	Other Inducer
	OCT1 317 OCT2 336 MATE1 131 OCTN1 47

Drug as perpetrator

Target	Modality	Activity	Metabolite	Clinical evidence
PXR 45	supressor 149 Sources: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3205227/ Page: -	yes

Drug as victim

Target	Modality	Activity	Clinical evidence
CYP3A4 1670	substrate 3264 Sources: https://bpspubs.onlinelibrary.wiley.com/doi/full/10.1111/j.1476-5381.2010.00913.x Page: -	yes
MATE1 131	substrate 3264 Sources: https://www.sciencedirect.com/science/article/pii/S0928098716300938#bb0050 Page: -	yes
OCT1 317	substrate 3264 Sources: https://link.springer.com/article/10.1007/s12272-014-0510-6 Page: -	yes
OCTN1 47	substrate 3264 Sources: https://www.sciencedirect.com/science/article/pii/S002235491530945X Page: -	yes
OCT2 336	substrate 3264 Sources: https://link.springer.com/article/10.1007/s12272-014-0510-6 Page: -	yes	yes (co-administration study) Comment: Co-administration of cimetidine, pyrimethamine, trimethoprim, lansoprazole, dolutegravir and vandetanib with metformin has been shown to increase its AUC by 1.2 to 1.7-fold Sources: https://link.springer.com/article/10.1007/s12272-014-0510-6 Page: -

Sourcing

Vendor/Aggregator	ID	URL
ChEBI	CHEBI:6801	https://www.ebi.ac.uk/chebi/searchId.do?chebiId=CHEBI:6801
ChemicalBook	CB0506294	https://www.chemicalbook.com/ChemicalProductProperty_EN_CB0506294
MolPort	MolPort-002-929-560	https://www.molport.com/shop/molecule-link/MolPort-002-929-560
MolPort	MolPort-005-767-418	https://www.molport.com/shop/molecule-link/MolPort-005-767-418
ZINC	ZINC000012859773	http://zinc15.docking.org/substances/ZINC000012859773
eMolecules	10320221	https://www.emolecules.com/cgi-bin/more?vid=10320221
eMolecules	26219491	https://www.emolecules.com/cgi-bin/more?vid=26219491
eMolecules	661910	https://www.emolecules.com/cgi-bin/more?vid=661910

PubMed

Title	Date	PubMed
Folate administration reduces circulating homocysteine levels in NIDDM patients on long-term metformin treatment.	1998 Aug	10095804
[Hepatotoxic reaction associated with metformin and chlorpropamide treatment].	1999 Feb	10216414
Pioglitazone hydrochloride in combination with metformin in the treatment of type 2 diabetes mellitus: a randomized, placebo-controlled study. The Pioglitazone 027 Study Group.	2000 Dec	11192132
The effect of metformin on glycemic control, serum lipids and lipoproteins in diet alone and sulfonylurea-treated type 2 diabetic patients with sub-optimal metabolic control.	2000 Nov	11126815
[Marked creatine-phosphokinase elevation in myopathy after treatment with bezafibrate].	2000 Sep	11062950
Endocrine and metabolic effects of metformin versus ethinyl estradiol-cyproterone acetate in obese women with polycystic ovary syndrome: a randomized study.	2000 Sep	10999803
Increased intake of calcium reverses vitamin B12 malabsorption induced by metformin.	2000 Sep	10977010
Metformin, the rebirth of a biguanide: mechanism of action and place in the prevention and treatment of insulin resistance.	2001	11460576
[Thiazolidinediones: clinical data and perspectives].	2001 Apr	11452222
Acute postoperative metabolic complications of diabetes.	2001 Apr	11376521
The effects of metformin on body mass index and glucose tolerance in obese adolescents with fasting hyperinsulinemia and a family history of type 2 diabetes.	2001 Apr	11335776
Sulfonylurea treatment of type 2 diabetic patients does not reduce the vasodilator response to ischemia.	2001 Apr	11315840
ION-pair liquid chromatography technique for the estimation of metformin in its multicomponent dosage forms.	2001 Apr	11274860
Metformin-associated lactic acidosis.	2001 Apr	11267815
[Metformin and intravascular contrast media. National guidelines 2001-03-16].	2001 Apr 18	11370412
Nateglinide for type 2 diabetes.	2001 Apr 2	11283474
[Effects of metformin on insulin resistance and on ovarian steroidogenesis in women with polycystic ovary syndrome].	2001 Aug	11431640
Myositis, microvesicular hepatitis, and progression to cirrhosis from troglitazone added to simvastatin.	2001 Feb	11281188
Diabetes in elderly adults.	2001 Jan	11193234
Do interventions to reduce coronary heart disease reduce the incidence of type 2 diabetes? A possible role for inflammatory factors.	2001 Jan 23	11157682
Cholestatic jaundice associated with the use of metformin.	2001 Jul	11467664
Relationship between ethnicity and glycemic control, lipid profiles, and blood pressure during the first 9 years of type 2 diabetes: U.K. Prospective Diabetes Study (UKPDS 55).	2001 Jul	11423497
Gonadotropins at menopause: the influence of obesity, insulin resistance, and estrogens.	2001 Jul	11322964
Nateglinide.	2001 Jul 1	11449877
Digestive hemorrhage caused by a Meckel's diverticulum in a metformin-treated patient: is there any connection?	2001 Jun	11468878
Thiazolidinediones and liver toxicity.	2001 Jun	11431595
Management of type 2 diabetes. Evolving strategies for treatment.	2001 Jun	11430184
Lactic acidosis in metformin therapy: searching for a link with metformin in reports of 'metformin-associated lactic acidosis'.	2001 Jun	11412284
Pharmacokinetics of metformin gastric-retentive tablets in healthy volunteers.	2001 Jun	11402634
Use of urea containing dialysate to avoid disequilibrium syndrome, enabling intensive dialysis treatment of a diabetic patient with renal failure and severe metformin induced lactic acidosis.	2001 Jun	11390747
The effects of long-term metformin treatment on adrenal and ovarian steroidogenesis in women with polycystic ovary syndrome.	2001 Jun	11375796
The synergistic effect of miglitol plus metformin combination therapy in the treatment of type 2 diabetes.	2001 Jun	11375358
[Metformin and contrast media--increased risk of lactic acidosis?].	2001 Jun 10	11464691
Comparison of the metabolic effects of metformin and troglitazone on fructose-induced insulin resistance in male Sprague-Dawley rats.	2001 Mar	11393112
Improvement of glycemic control by 1 year of insulin therapy leads to a sustained decrease in sE-selectin concentrations in type 2 diabetes.	2001 Mar	11289483
Effect of metformin on glucagon-like peptide 1 (GLP-1) and leptin levels in obese nondiabetic subjects.	2001 Mar	11289473
Insulin reduction with metformin increases luteal phase serum glycodelin and insulin-like growth factor-binding protein 1 concentrations and enhances uterine vascularity and blood flow in the polycystic ovary syndrome.	2001 Mar	11238496
Accumulation of triglyceride-rich lipoprotein in subjects with abdominal obesity: the biguanides and the prevention of the risk of obesity (BIGPRO) 1 study.	2001 Mar	11231921
Preclinical evaluation of pharmacokinetic-pharmacodynamic rationale for oral CR metformin formulation.	2001 Mar 12	11245912
Direct-to-consumer advertisements for Glucophage XR.	2001 Mar 19	11257717
[Current and future aspects of oral antidiabetic agents in type 2 diabetes].	2001 May	11395869
The oral insulin sensitizer, thiazolidinedione, increases plasma vascular endothelial growth factor in type 2 diabetic patients.	2001 May	11347762
Use of the ligand immunofunctional assay for human insulin-like growth factor ((IGF) binding protein-3 (IGFBP-3) to analyze IGFBP-3 proteolysis and igf-i bioavailability in healthy adults, GH-deficient and acromegalic patients, and diabetics.	2001 May	11344189
The effect of a thiazolidinedione drug, troglitazone, on glycemia in patients with type 2 diabetes mellitus poorly controlled with sulfonylurea and metformin. A multicenter, randomized, double-blind, placebo-controlled trial.	2001 May 1	11329231
[Metformin and anesthesia--how great is the risk of lactic acidosis].	2001 May 18	11402930
[Insulin therapy in the type 2 obese diabetic patient. Supplementing the deficit].	2001 May 24	11420829
[Metformin in the treatment of type 1 diabetics--a placebo controlled study].	2001 May 24	11411059
Effect of a series of novel sulphonylthioureas on glucose tolerance in the obese fa/fa Zucker rat.	2001 May-Jun	11380511

Patents

Sample Use Guides

In Vivo Use Guide

Recommended Dosing Schedule Adults The usual starting dose of GLUCOPHAGE Tablets is 500 mg twice a day or 850 mg once a day, given with meals. In general, clinically significant responses are not seen at doses below 1500 mg per day. Dosage increases should be made in increments of 500 mg weekly or 850 mg every 2 weeks, up to a total of 2000 mg per day, given in divided doses. The dosage of GLUCOPHAGE must be individualized on the basis of both effectiveness and tolerability. Patients can also be titrated from 500 mg twice a day to 850 mg twice a day after 2 weeks. For those patients requiring additional glycemic control, GLUCOPHAGE may be given to a maximum daily dose of 2550 mg per day. Doses above 2000 mg may be better tolerated given 3 times a day with meals. The usual starting dose of GLUCOPHAGE XR (metformin hydrochloride) Extended-Release Tablets is 500 mg once daily with the evening meal. In general, clinically significant responses are not seen at doses below 1500 mg per day. Dosage increases should be made in increments of 500 mg weekly, up to a maximum of 2000 mg once daily with the evening meal. The dosage of GLUCOPHAGE XR must be individualized on the basis of both effectiveness and tolerability. If glycemic control is not achieved on GLUCOPHAGE XR 2000 mg once daily, a trial of GLUCOPHAGE XR 1000 mg twice daily should be considered. If higher doses of metformin are required, GLUCOPHAGE should be used at total daily doses up to 2550 mg administered in divided daily doses, as described above. (See CLINICAL PHARMACOLOGY: Clinical Studies.) Patients receiving GLUCOPHAGE treatment may be safely switched to GLUCOPHAGE XR once daily at the same total daily dose, up to 2000 mg once daily. Following a switch from GLUCOPHAGE to GLUCOPHAGE XR, glycemic control should be closely monitored and dosage adjustments made accordingly (see CLINICAL PHARMACOLOGY: Clinical Studies). Pediatrics The usual starting dose of GLUCOPHAGE is 500 mg twice a day, given with meals. Dosage increases should be made in increments of 500 mg weekly up to a maximum of 2000 mg per day, given in divided doses. The dosage of GLUCOPHAGE must be individualized on the basis of both effectiveness and tolerability. Safety and effectiveness of GLUCOPHAGE XR in pediatric patients have not been established.

Route of Administration: Oral

In Vitro Use Guide

Herein, our aim was to examine whether micromolar concentrations of metformin alone could bring about cancer cell death and whether micromolar metformin could increase the cytotoxic effect of commonly used chemotherapies in A2780 and SKOV3 cell lines and primary cultured cancer cells isolated from the peritoneal fluid of patients with advanced ovarian cancer. Our results in cell lines demonstrate that no significant loss of viability or change in cell cycle was observed with micromolar metformin alone; however, we observed cytotoxicity with micromolar metformin in combination with chemotherapy at concentrations where the chemotherapy alone produced no loss in viability.

Name

Type

Language

METFORMIN

Official Name

English

METFORMIN [VANDF]

Common Name

English

METFORMIN [MI]

Common Name

English

METFORMIN [USAN]

Common Name

English

1,1-Dimethylbiguanide

Systematic Name

English

METFORMIN EXTENDED RELEASE

Common Name

English

Metformin [WHO-DD]

Common Name

English

IMIDODICARBONIMIDIC DIAMIDE, N,N-DIMETHYL-

Systematic Name

English

metformin [INN]

Common Name

English

Classification Tree Code System Code

WHO-VATC

QA10BD15