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Phenformin
Clinical data
AHFS/Drugs.com	International Drug Names
Routes of; administration	Oral
ATC code	A10BA01 (WHO) ;
Identifiers
	IUPAC name 2-(N-phenethylcarbamimidoyl)guanidine;
CAS Number	114-86-3 ;
PubChem CID	8249;
DrugBank	DB00914 ;
ChemSpider	7953 ;
UNII	DD5K7529CE;
KEGG	D08351 ;
ChEBI	CHEBI:8064 ;
ChEMBL	ChEMBL170988 ;
CompTox Dashboard (EPA)	DTXSID1023449 ;
ECHA InfoCard	100.003.689
Chemical and physical data
Formula	C10H15N5
Molar mass	205.265 g·mol−1
3D model (JSmol)	Interactive image;
Melting point	175 to 178 °C (347 to 352 °F)
	SMILES N(=C(/N=C(\N)N)N)\CCc1ccccc1;
	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) ; Key:ICFJFFQQTFMIBG-UHFFFAOYSA-N ;
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Phenformin is an antidiabetic drug from the biguanide class. It was marketed as DBI by Ciba-Geigy, but was withdrawn from most markets in the late 1970s due to a high risk of lactic acidosis, which was fatal in 50% of cases.

Phenformin was developed in 1957 by Ungar, Freedman and Seymour Shapiro, working for the U.S. Vitamin Corporation. Clinical trials begun in 1958 showed it to be effective, but with gastrointestinal side effects.^[1]

Toxicity

Phenformin sales began to decline in the U.S. from 1973 due to negative trial studies and reports of lactic acidosis. By October 1976, the U.S. Food and Drug Administration (FDA) Endocrinology and Metabolism Advisory Committee recommended phenformin be removed from the market. The FDA began formal proceedings in May 1977, leading to Phenformin's eventual withdrawal on November 15, 1978.^[2]

In 1977, 385,000 patients with early-stage diabetes were taking phenformin in the U.S.. Ralph Nader's Health Research Group put the U.S. government under pressure to ban the drug. Ciba-Geigy Corp resisted, claiming there was no satisfactory alternative for many patients. But in July the FDA declared the drug an "imminent hazard to the public health" and gave doctors 90 days to switch to an alternative treatment (such as insulin, dietary restrictions or other drugs).^[3] As of 2008, phenformin was still legally available in Italy, Brazil, Uruguay, China, Poland, Greece and Portugal and cases of phenformin-induced lactic acidosis continued to be reported worldwide.^[4] In Hong Kong, where phenformin is banned, cases of phenformin-induced lactic acidosis occurred after taking Chinese proprietary medicines, claiming to be herbal, which were adulterated with phenformin.^[5] In the U.S., in 2001 the FDA recalled Chinese "herbal products" containing phenformin.^[6]

The related drug metformin is considerably safer than phenformin, with three cases of lactic acidosis per 100,000 patient-years compared to 64 cases per 100,000 patient-years, and those are mostly confined to patients with impaired renal function.^[7]

Chemistry and pharmacokinetics

Phenformin hydrochloride is a white crystalline powder, with a melting point of 175–178 °C; it is soluble at 1 in 8 parts of water and 1 in 15 of ethanol, and practically insoluble in chloroform and ether.^{[citation needed]} Phenformin is less polar and more lipid soluble and exhibits a higher affinity for mitochondrial membranes than metformin.^[8] Its dissociation constant (pKa) is 2.7, 11.8 (at 32 °C), and log P = –0.8.^{[citation needed]}

Phenformin is well absorbed after oral administration. The major metabolic reaction is aromatic hydroxylation to form 4-hydroxyphenformin, which is then conjugated with glucuronic acid. Up to about 50% of a dose is excreted in the urine in 24 h, about two–thirds in the form of unchanged drug and one–third as the hydroxy metabolite. Following a single oral dose of 50 mg to eight subjects, peak plasma concentrations of 0.08–0.18 mg/L (mean 0.13) were attained in about 3 h; plasma concentrations were higher in four subjects who were poor metabolisers of debrisoquine in comparison with the four extensive metabolisers. Following daily oral doses of 50 mg three times a day to eight subjects, plasma concentrations of 0.10–0.24 mg/L (mean 0.18) were reported 2 h after a dose. Plasma half-life of phenformin is 10–15 h. Phenformin protein binding in plasma is about 12–20%.^{[citation needed]}

Research

Vladimir Dilman first proposed in 1971 that biguanides like metformin and phenformin may have potential to treat cancer, prevent cancer, and to extend life, an idea that was subsequently supported by in vitro and animal studies, as well as an apparent reduction in the incidence of cancer in people taking metformin for diabetes.^[9]

Laboratory studies attribute these apparent effects to inhibition of mTOR, inhibition of complex I, with phenformin being a more potent inhibitor than metformin,^[8]^[9] It appears that inhibition of complex I may cause diminished TCA cycle intermediate production and decreased mitochondrial ATP production thus resulting in AMPK activation and lower mTOR activity.^[8]

References

^ McKendry JB, Kuwayti K, Rado PP (May 1959). "Clinical experience with DBI (phenformin) in the management of diabetes". Canadian Medical Association Journal. 80 (10): 773–778. PMC 1831029. PMID 13652024.
^ Tonascia S, Meinert CL (1986). Clinical trials: design, conduct, and analysis. Oxford [Oxfordshire]: Oxford University Press. pp. 53–54, 59. ISBN 978-0-19-503568-1.
^ "Diabetic drug linked to deaths banned". Boca Raton News. UPI. July 26, 1977.
^ Fimognari FL, Corsonello A, Pastorelli R, Antonelli Incalzi R (December 2008). "Older age and phenformin therapy: a dangerous association". Internal and Emergency Medicine. 3 (4): 401–403. doi:10.1007/s11739-008-0154-y. PMID 18415028. S2CID 33747462.
^ Ching CK, Lai CK, Poon WT, Wong EN, Yan WW, Chan AY, Mak TW (February 2008). "Hazards posed by a banned drug--phenformin is still hanging around" (PDF). Hong Kong Medical Journal = Xianggang Yi Xue Za Zhi. 14 (1): 50–54. PMID 18239244.
^ Speth PA, Linssen PC, Termond EF, Boezeman JB, Wessels HM, Haanen C (July 2001). "In vivo and in vitro pharmacokinetic differences between four structurally closely related anthracyclines in hematopoietic cell subtypes in humans". Drug Metabolism and Disposition. 17 (1): 98–105. PMID 2566478.
^ Crofford OB (August 1995). "Metformin". The New England Journal of Medicine. 333 (9): 588–589. doi:10.1056/NEJM199508313330910. PMID 7623910.
^ ^a ^b ^c Weinberg SE, Chandel NS (January 2015). "Targeting mitochondria metabolism for cancer therapy". Nature Chemical Biology. 11 (1): 9–15. doi:10.1038/nchembio.1712. PMC 4340667. PMID 25517383.
^ ^a ^b Pryor R, Cabreiro F (November 2015). "Repurposing metformin: an old drug with new tricks in its binding pockets". The Biochemical Journal. 471 (3): 307–322. doi:10.1042/BJ20150497. PMC 4613459. PMID 26475449.