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

Molecular Formula	C4H11N5
Molecular Weight	129.1636
Charge	0
Count

Stereochemistry	ACHIRAL
Additional Stereochemistry	No
Defined Stereocenters	0 / 0
E/Z Centers	0
Optical Activity	NONE

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 8297
Mitochondrial complex I (NADH dehydrogenase) 11 Target ID: CHEMBL2363065 Sources: https://www.ncbi.nlm.nih.gov/pubmed/22117616	Inhibitor 8297
AMP-activated protein kinase, AMPK 17 Target ID: CHEMBL2096907 Sources: https://www.ncbi.nlm.nih.gov/pubmed/22117616	Activator 1430

Conditions

Condition	Modality	Targets	Highest Phase	Product
Type 2 diabetes mellitus 259 Sources: https://packageinserts.bms.com/pi/pi_glucophage.pdf	Primary		Approved 8429	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 1995
Cancer 592 Sources: https://www.ncbi.nlm.nih.gov/pubmed/22117616 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4200668/	Primary		Phase III 656	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 1737

OverviewOther

Other Inhibitor	Other Substrate	Other Inducer
	OCT1 327 OCT2 355 MATE1 135 OCTN1 47

Drug as perpetrator

Target	Modality	Activity	Metabolite	Clinical evidence
PXR 46	supressor 155 Sources: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3205227/ Page: -	yes

Drug as victim

Target	Modality	Activity	Clinical evidence
CYP3A4 1737	substrate 3367 Sources: https://bpspubs.onlinelibrary.wiley.com/doi/full/10.1111/j.1476-5381.2010.00913.x Page: -	yes
MATE1 135	substrate 3367 Sources: https://www.sciencedirect.com/science/article/pii/S0928098716300938#bb0050 Page: -	yes
OCT1 327	substrate 3367 Sources: https://link.springer.com/article/10.1007/s12272-014-0510-6 Page: -	yes
OCTN1 47	substrate 3367 Sources: https://www.sciencedirect.com/science/article/pii/S002235491530945X Page: -	yes
OCT2 355	substrate 3367 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
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
Effect of altered gastric emptying and gastrointestinal motility on metformin absorption.	2000 Oct	11012555
[Marked creatine-phosphokinase elevation in myopathy after treatment with bezafibrate].	2000 Sep	11062950
[Prevention of lactic acidosis due to metformin intoxication in contrast media nephropathy].	2000 Sep 30	11045136
Nuclear magnetic resonance studies of hepatic glucose metabolism in humans.	2001	11237214
[Type 2 diabetes mellitus: Which place for thiazolidinediones in the therapeutic strategy?].	2001 Apr	11452223
[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
Mechanism of fat-induced hepatic gluconeogenesis: effect of metformin.	2001 Aug	11440903
Myositis, microvesicular hepatitis, and progression to cirrhosis from troglitazone added to simvastatin.	2001 Feb	11281188
Metformin retention independent of renal failure in intestinal occlusion.	2001 Feb	11240442
[Intensified conventional insulin therapy in patients with type 2 diabetes mellitus. Positive long-term effects of insulin lispro on metabolic control and microalbuminuria].	2001 Jan 11	11217677
Combination therapy in type 2 diabetes: the role of repaglinide.	2001 Jan 25	11235608
Case of the month. Hepatic and renal failure in a patient taking troglitazone and metformin.	2001 Jul	11452755
Digestive hemorrhage caused by a Meckel's diverticulum in a metformin-treated patient: is there any connection?	2001 Jun	11468878
Lactic acidosis in metformin therapy: searching for a link with metformin in reports of 'metformin-associated lactic acidosis'.	2001 Jun	11412284
The effects of long-term metformin treatment on adrenal and ovarian steroidogenesis in women with polycystic ovary syndrome.	2001 Jun	11375796
Metformin and intervention in polycystic ovary syndrome. Endocrine Society of Australia, the Australian Diabetes Society and the Australian Paediatric Endocrine Group.	2001 Jun 4	11453331
Comparison of the metabolic effects of metformin and troglitazone on fructose-induced insulin resistance in male Sprague-Dawley rats.	2001 Mar	11393112
Rosiglitazone.	2001 Mar	11336599
Cost-effectiveness analysis of intensive blood-glucose control with metformin in overweight patients with type II diabetes (UKPDS No. 51).	2001 Mar	11317659
Polycystic ovary syndrome and ovulation induction.	2001 Mar	11293001
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
[Role and modalities of insulin treatment in type 2 diabetics].	2001 Mar	11270269
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
Preparation and characterisation of rose Bengal-loaded surface-modified albumin nanoparticles.	2001 Mar 12	11245913
Preclinical evaluation of pharmacokinetic-pharmacodynamic rationale for oral CR metformin formulation.	2001 Mar 12	11245912
Cardiomyocyte dysfunction in sucrose-fed rats is associated with insulin resistance.	2001 May	11334425
Insulin, leptin, IGF-I and insulin-dependent protein concentrations after insulin-sensitizing therapy in obese women with polycystic ovary syndrome.	2001 May	11331217
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
Thiazolidinediones but not metformin directly inhibit the steroidogenic enzymes P450c17 and 3beta -hydroxysteroid dehydrogenase.	2001 May 18	11278997
[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.

Substance Class	Chemical Created by `admin` on `Fri Dec 15 15:16:21 GMT 2023` Edited by `admin` on `Fri Dec 15 15:16:21 GMT 2023`
Record UNII	9100L32L2N
Record Status	`Validated (UNII)`
Record Version

Download

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