Phenformin

Phenformin is an anti-diabetic 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 It was marketed as DBI by Ciba-Geigy but was withdrawn from most markets in the late 1970s due to a high risk of lactic acidosis, which was fatal in 50% of cases.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 discovered in 1957 by Ungar, Freedman and Seymour Shapiro, working for the US Vitamin Corporation. Clinical trials began in 1958 which showed it to be effective but with gastrointestinal side effects.

Toxicity
Phenformin sales began to decline in the US from 1973 due to negative trial studies and reports of lactic acidosis. By October 1976, the FDA Endocrinology and Metabolism Advisory Committee recommended phenformin be removed from the market. The FDA began formal proceedings in May 1977 leading to its eventual withdrawal on November 15, 1978.

In 1977, 385,000 patients with early-stage diabetes were taking phenformin in the US. Ralph Nader's Health Research Group put the US government under pressure to ban the drug. Ciba-Geigy Corp resisted, claiming there was no satisfactory alternative for many patients. However, 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). As of 2008, phenformin was still legally available in Italy, Brazil, Uruguay, China, Poland, Greece and Portugal. Cases of phenformin-induced lactic acidosis continue to be reported worldwide. In Hong Kong, where phenformin is banned, cases of phenformin-induced lactic acidosis have occurred after taking Chinese proprietary medicines, claiming to be herbal, which were adulterated with phenformin. In the US, the FDA has recalled Chinese "herbal products" containing phenformin.

The related drug metformin is considerably safer than phenformin, with 3 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.

Cimetidine may reduce renal clearance of phenformin and increase lactic acidosis risk. There is also increased risk of lactic acidosis with alcohol, nephrotoxic drugs.

Chemistry and Pharmacokinetics
Phenformin hydrochloride is a white crystalline powder, Mp 175° to 178°, soluble 1 in 8 parts of water and 1 in 15 of ethanol; practically insoluble in chloroform and ether, dissociation Constant pKa 2.7, 11.8 (32°), Partition Coefficient Log P(octanol/water) = –0.8. 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 8 subjects, peak plasma concentrations of 0.08 to 0.18 mg/L (mean 0.13) were attained in about 3 h; plasma concentrations were higher in 4 subjects who were poor metabolisers of debrisoquine in comparison with the 4 extensive metabolisers. Following daily oral doses of 50 mg three times a day to 8 subjects, plasma concentrations of 0.10 to 0.24 mg/L (mean 0.18) were reported 2 h after a dose. Plasma half–life of phenformin is 10 to 15 h. Phenformin protein binding in plasma, is about 12 to 20%.

Dosage
Oral, Type II diabetes mellitus: Adult: 200-400 mg twice daily.

Anti-Cancer Properties
Phenformin, along with Buformin and Metformin, inhibits the growth and development of cancer. The anti-cancer property of these drugs is due to their ability to disrupt the Warburg effect and revert the cytosolic glycolysis characteristic of cancer cells to normal oxidation of pyruvate by the mitochondria. Metformin reduces liver glucose production in diabetics and disrupts the Warburg effect in cancer by AMPK activation and inhibition of the mTor pathway.