Identification

Name
Phenformin
Accession Number
DB00914  (APRD00511)
Type
Small Molecule
Groups
Approved, Investigational, Withdrawn
Description

A biguanide hypoglycemic agent with actions and uses similar to those of metformin. Although it is generally considered to be associated with an unacceptably high incidence of lactic acidosis, often fatal, it is still available in some countries. (From Martindale, The Extra Pharmacopoeia, 30th ed, p290)

Structure
Thumb
Synonyms
  • DBI
  • Fenformin
  • Fenformina
  • Phenformine
  • Phenforminum
  • β-Phenethybiguanide
Product Ingredients
IngredientUNIICASInChI Key
Phenformin Hydrochloride91XC93EU03834-28-6YSUCWSWKRIOILX-UHFFFAOYSA-N
International/Other Brands
DBI (Ciba-Geigy)
Categories
UNII
DD5K7529CE
CAS number
114-86-3
Weight
Average: 205.2596
Monoisotopic: 205.132745505
Chemical Formula
C10H15N5
InChI Key
ICFJFFQQTFMIBG-UHFFFAOYSA-N
InChI
InChI=1S/C10H15N5/c11-9(12)15-10(13)14-7-6-8-4-2-1-3-5-8/h1-5H,6-7H2,(H6,11,12,13,14,15)
IUPAC Name
1-carbamimidamido-N-(2-phenylethyl)methanimidamide
SMILES
NC(=N)NC(=N)NCCC1=CC=CC=C1

Pharmacology

Indication

For the reatment of type II diabetes mellitus.

Pharmacodynamics

Used to treat diabetes, phenformin is a biguanide (contains 2 guanidino groups) hypoglycemic agent with actions and uses similar to those of metformin (Glucophage). Both drugs work by (1) decreasing the absorption of glucose by the intestines, (2) decreasing the production of glucose in the liver, and by (3) increasing the body's ability to use insulin more effectively. More specifically, phenformin improves glycemic control by improving insulin sensitivity. Phenformin is generally considered to be associated with an unacceptably high incidence of actic acidosis. In general biguanides should be used only in stable type II diabetics who are free of liver, kidney and cardiovascular problems and who cannot be controlled with diet.

Mechanism of action

Phenformin binds to the AMP-activated protein kinase (AMPK). AMPK is an ultra-sensitive cellular energy sensor that monitors energy consumption and down-regulates ATP-consuming processes when activated. The biguanide phenformin has been shown to independently decrease ion transport processes, influence cellular metabolism and activate AMPK. Phenformin's hypoglycemic activity is related the effect it has in activating AMPK and fooling insulin sensitive cells into thinking that insulin levels are low and causing the body to use glucose as if in a state of low caloric consumption. This drug also seems to inhibit several varients of ATP-sensitive potassium channels (namely the receptor subtype Kir6.1).

TargetActionsOrganism
A5'-AMP-activated protein kinase catalytic subunit alpha-1
activator
Human
UATP-sensitive inward rectifier potassium channel 8
inhibitor
Human
Absorption
Not Available
Volume of distribution
Not Available
Protein binding
Not Available
Metabolism
Not Available
Route of elimination
Not Available
Half life
Not Available
Clearance
Not Available
Toxicity
Not Available
Affected organisms
  • Humans and other mammals
Pathways
Not Available
Pharmacogenomic Effects/ADRs
Not Available

Interactions

Drug Interactions
DrugInteraction
AbirateroneThe serum concentration of Phenformin can be increased when it is combined with Abiraterone.
AcetazolamideThe therapeutic efficacy of Phenformin can be increased when used in combination with Acetazolamide.
Acetylsalicylic acidAcetylsalicylic acid may increase the hypoglycemic activities of Phenformin.
AgmatineThe serum concentration of Agmatine can be increased when it is combined with Phenformin.
AmcinonideThe therapeutic efficacy of Phenformin can be decreased when used in combination with Amcinonide.
Aminosalicylic AcidAminosalicylic Acid may increase the hypoglycemic activities of Phenformin.
AmitriptylineAmitriptyline may decrease the hypoglycemic activities of Phenformin.
AmoxapineAmoxapine may decrease the hypoglycemic activities of Phenformin.
AripiprazoleThe therapeutic efficacy of Phenformin can be decreased when used in combination with Aripiprazole.
Arsenic trioxideThe therapeutic efficacy of Phenformin can be decreased when used in combination with Arsenic trioxide.
Food Interactions
Not Available

References

General References
  1. Enia G, Garozzo M, Zoccali C: Lactic acidosis induced by phenformin is still a public health problem in Italy. BMJ. 1997 Nov 29;315(7120):1466-7. [PubMed:9418116]
  2. Rosand J, Friedberg JW, Yang JM: Fatal phenformin-associated lactic acidosis. Ann Intern Med. 1997 Jul 15;127(2):170. [PubMed:9230023]
External Links
Human Metabolome Database
HMDB0015050
KEGG Compound
C07673
PubChem Compound
8249
PubChem Substance
46505230
ChemSpider
7953
BindingDB
50240908
ChEBI
8064
ChEMBL
CHEMBL170988
Therapeutic Targets Database
DAP000206
PharmGKB
PA1000
HET
8CV
Wikipedia
Phenformin
ATC Codes
A10BA01 — PhenforminA10BD01 — Phenformin and sulfonylureas
PDB Entries
5uih

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
1RecruitingTreatmentMelanoma1
Not AvailableCompletedNot AvailableType 2 Diabetes Mellitus3

Pharmacoeconomics

Manufacturers
Not Available
Packagers
Not Available
Dosage forms
Not Available
Prices
Not Available
Patents
Not Available

Properties

State
Solid
Experimental Properties
PropertyValueSource
melting point (°C)176.5 °CPhysProp
water solubility210 mg/mLNot Available
logP-0.83HANSCH,C ET AL. (1995)
Predicted Properties
PropertyValueSource
Water Solubility0.232 mg/mLALOGPS
logP-0.72ALOGPS
logP0.83ChemAxon
logS-3ALOGPS
pKa (Strongest Basic)11.97ChemAxon
Physiological Charge2ChemAxon
Hydrogen Acceptor Count5ChemAxon
Hydrogen Donor Count5ChemAxon
Polar Surface Area97.78 Å2ChemAxon
Rotatable Bond Count3ChemAxon
Refractivity80.72 m3·mol-1ChemAxon
Polarizability22.14 Å3ChemAxon
Number of Rings1ChemAxon
Bioavailability1ChemAxon
Rule of FiveYesChemAxon
Ghose FilterYesChemAxon
Veber's RuleNoChemAxon
MDDR-like RuleNoChemAxon
Predicted ADMET features
PropertyValueProbability
Human Intestinal Absorption+0.9604
Blood Brain Barrier+0.6967
Caco-2 permeable-0.5144
P-glycoprotein substrateNon-substrate0.5078
P-glycoprotein inhibitor INon-inhibitor0.9322
P-glycoprotein inhibitor IINon-inhibitor0.6863
Renal organic cation transporterInhibitor0.6874
CYP450 2C9 substrateNon-substrate0.7776
CYP450 2D6 substrateSubstrate0.8415
CYP450 3A4 substrateNon-substrate0.7896
CYP450 1A2 substrateNon-inhibitor0.9045
CYP450 2C9 inhibitorNon-inhibitor0.9163
CYP450 2D6 inhibitorInhibitor0.8875
CYP450 2C19 inhibitorNon-inhibitor0.9025
CYP450 3A4 inhibitorNon-inhibitor0.881
CYP450 inhibitory promiscuityLow CYP Inhibitory Promiscuity0.9116
Ames testNon AMES toxic0.9133
CarcinogenicityNon-carcinogens0.928
BiodegradationNot ready biodegradable0.692
Rat acute toxicity2.5305 LD50, mol/kg Not applicable
hERG inhibition (predictor I)Weak inhibitor0.9162
hERG inhibition (predictor II)Non-inhibitor0.901
ADMET data is predicted using admetSAR, a free tool for evaluating chemical ADMET properties. (23092397)

Spectra

Mass Spec (NIST)
Not Available
Spectra
SpectrumSpectrum TypeSplash Key
Predicted GC-MS Spectrum - GC-MSPredicted GC-MSNot Available
Predicted MS/MS Spectrum - 10V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 20V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 40V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 10V, Negative (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 20V, Negative (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 40V, Negative (Annotated)Predicted LC-MS/MSNot Available

Taxonomy

Description
This compound belongs to the class of organic compounds known as biguanides. These are organic compounds containing two N-linked guanidines.
Kingdom
Organic compounds
Super Class
Organic nitrogen compounds
Class
Organonitrogen compounds
Sub Class
Guanidines
Direct Parent
Biguanides
Alternative Parents
Benzene and substituted derivatives / Carboximidamides / Organopnictogen compounds / Imines / Hydrocarbon derivatives
Substituents
Biguanide / Benzenoid / Monocyclic benzene moiety / Carboximidamide / Organopnictogen compound / Hydrocarbon derivative / Imine / Aromatic homomonocyclic compound
Molecular Framework
Aromatic homomonocyclic compounds
External Descriptors
biguanides (CHEBI:8064)

Targets

Kind
Protein
Organism
Human
Pharmacological action
Yes
Actions
Activator
General Function
Tau-protein kinase activity
Specific Function
Catalytic subunit of AMP-activated protein kinase (AMPK), an energy sensor protein kinase that plays a key role in regulating cellular energy metabolism. In response to reduction of intracellular A...
Gene Name
PRKAA1
Uniprot ID
Q13131
Uniprot Name
5'-AMP-activated protein kinase catalytic subunit alpha-1
Molecular Weight
64008.64 Da
References
  1. Woollhead AM, Sivagnanasundaram J, Kalsi KK, Pucovsky V, Pellatt LJ, Scott JW, Mustard KJ, Hardie DG, Baines DL: Pharmacological activators of AMP-activated protein kinase have different effects on Na+ transport processes across human lung epithelial cells. Br J Pharmacol. 2007 Aug;151(8):1204-15. Epub 2007 Jul 2. [PubMed:17603555]
  2. Chen S, Murphy J, Toth R, Campbell DG, Morrice NA, Mackintosh C: Complementary regulation of TBC1D1 and AS160 by growth factors, insulin and AMPK activators. Biochem J. 2008 Jan 15;409(2):449-59. [PubMed:17995453]
  3. Zhang L, He H, Balschi JA: Metformin and phenformin activate AMP-activated protein kinase in the heart by increasing cytosolic AMP concentration. Am J Physiol Heart Circ Physiol. 2007 Jul;293(1):H457-66. Epub 2007 Mar 16. [PubMed:17369473]
Kind
Protein
Organism
Human
Pharmacological action
Unknown
Actions
Inhibitor
General Function
Inward rectifier potassium channel activity
Specific Function
This potassium channel is controlled by G proteins. Inward rectifier potassium channels are characterized by a greater tendency to allow potassium to flow into the cell rather than out of it. Their...
Gene Name
KCNJ8
Uniprot ID
Q15842
Uniprot Name
ATP-sensitive inward rectifier potassium channel 8
Molecular Weight
47967.455 Da
References
  1. Aziz Q, Thomas A, Khambra T, Tinker A: Phenformin has a direct inhibitory effect on the ATP-sensitive potassium channel. Eur J Pharmacol. 2010 May 25;634(1-3):26-32. doi: 10.1016/j.ejphar.2010.02.023. Epub 2010 Feb 25. [PubMed:20188727]

Enzymes

Details
1. Cytochrome P450 2D6
Kind
Protein
Organism
Human
Pharmacological action
Unknown
Actions
Substrate
General Function
Steroid hydroxylase activity
Specific Function
Responsible for the metabolism of many drugs and environmental chemicals that it oxidizes. It is involved in the metabolism of drugs such as antiarrhythmics, adrenoceptor antagonists, and tricyclic...
Gene Name
CYP2D6
Uniprot ID
P10635
Uniprot Name
Cytochrome P450 2D6
Molecular Weight
55768.94 Da
References
  1. Preissner S, Kroll K, Dunkel M, Senger C, Goldsobel G, Kuzman D, Guenther S, Winnenburg R, Schroeder M, Preissner R: SuperCYP: a comprehensive database on Cytochrome P450 enzymes including a tool for analysis of CYP-drug interactions. Nucleic Acids Res. 2010 Jan;38(Database issue):D237-43. doi: 10.1093/nar/gkp970. Epub 2009 Nov 24. [PubMed:19934256]
  2. Drug Interactions: Cytochrome P450 Drug Interaction Table [Link]

Transporters

Kind
Protein
Organism
Human
Pharmacological action
Unknown
Actions
Inhibitor
General Function
Quaternary ammonium group transmembrane transporter activity
Specific Function
Mediates tubular uptake of organic compounds from circulation. Mediates the influx of agmatine, dopamine, noradrenaline (norepinephrine), serotonin, choline, famotidine, ranitidine, histamin, creat...
Gene Name
SLC22A2
Uniprot ID
O15244
Uniprot Name
Solute carrier family 22 member 2
Molecular Weight
62579.99 Da
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:12240953]
Kind
Protein
Organism
Human
Pharmacological action
Unknown
Actions
Substrate
Inhibitor
General Function
Secondary active organic cation transmembrane transporter activity
Specific Function
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-methylnico...
Gene Name
SLC22A1
Uniprot ID
O15245
Uniprot Name
Solute carrier family 22 member 1
Molecular Weight
61153.345 Da
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:12240953]
  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:12130709]

Drug created on June 13, 2005 07:24 / Updated on October 10, 2018 21:48