Buformin
Encyclopedia
Buformin is an oral anti-diabetic drug
of the biguanide
class, chemically related to metformin
and phenformin
. Buformin was marketed by German pharmaceutical company Grünenthal
as Silubin.
subcutaneous 18mg/kg; mouse LD50
intraperitoneal 140mg/kg and 300mg/kg oral. Partition coefficient
: log P (octanol-water) -1.20E+00; Water Solubility 7.46E+05 mg/L at 25°. Vapor pressure
1.64E-04 mm Hg at 25° (EST); Henry's Law
Constant 8.14E-16 atm-m3/mole at 25° (EST). Atmospheric OH Rate Constant 1.60E-10 cm3/molecule-sec at 25°
, but is still available and prescribed in Hungary, Taiwan, and Japan. The lactic acidosis
occurred only in patients with a buformin plasma level of greater than 0.60 µg/ml and was rare in patients with normal renal function.
In one report the toxic oral dose was 329 ± 30mg/day in 24 patients who developed lactic acidosis on buformin. Another group of 24 patients on 258 ± 25mg/day did not develop lactic acidosis on 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.
Anti-diabetic drug
Anti-diabetic medications treat diabetes mellitus by lowering glucose levels in the blood. With the exceptions of insulin, exenatide, and pramlintide, all are administered orally and are thus also called oral hypoglycemic agents or oral antihyperglycemic agents...
of the biguanide
Biguanide
Biguanide can refer to a molecule, or to a class of drugs based upon this molecule. Biguanides can function as oral antihyperglycemic drugs used for diabetes mellitus or prediabetes treatment...
class, chemically related to metformin
Metformin
Metformin is an oral antidiabetic drug in the biguanide class. It is the first-line drug of choice for the treatment of type 2 diabetes, in particular, in overweight and obese people and those with normal kidney function. Its use in gestational diabetes has been limited by safety concerns...
and phenformin
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 It was marketed as DBI by Ciba-Geigy but was withdrawn from most markets in the late 1970s due to a high risk of lactic acidosis, which was fatal in 50% of cases....
. Buformin was marketed by German pharmaceutical company Grünenthal
Grünenthal
Grünenthal GmbH is a German pharmaceutical company in Stolberg near Aachen, which holds the patent to Ultram , and its much stronger derivative Nucynta , both used as analgesics with Norepinephrine Reuptake Inhibition...
as Silubin.
Chemistry and Animal Toxicology
Buformin hydrochloride is a fine white to slightly yellow crystalline powder, odorless, with a weakly acidic bitter taste, melting point 174° to 177°, strong base, freely soluble in water, methanol and ethanol, insoluble in chloroform and ether. Toxicity: guinea pig LD50LD50
In toxicology, the median lethal dose, LD50 , LC50 or LCt50 of a toxin, radiation, or pathogen is the dose required to kill half the members of a tested population after a specified test duration...
subcutaneous 18mg/kg; mouse LD50
LD50
In toxicology, the median lethal dose, LD50 , LC50 or LCt50 of a toxin, radiation, or pathogen is the dose required to kill half the members of a tested population after a specified test duration...
intraperitoneal 140mg/kg and 300mg/kg oral. Partition coefficient
Partition coefficient
In chemistry and the pharmaceutical sciences, a partition- or distribution coefficient is the ratio of concentrations of a compound in the two phases of a mixture of two immiscible solvents at equilibrium. The terms "gas/liquid partition coefficient" and "air/water partition coefficient" are...
: log P (octanol-water) -1.20E+00; Water Solubility 7.46E+05 mg/L at 25°. Vapor pressure
Vapor pressure
Vapor pressure or equilibrium vapor pressure is the pressure of a vapor in thermodynamic equilibrium with its condensed phases in a closed system. All liquids have a tendency to evaporate, and some solids can sublimate into a gaseous form...
1.64E-04 mm Hg at 25° (EST); Henry's Law
Henry's law
In physics, Henry's law is one of the gas laws formulated by William Henry in 1803. It states that:An equivalent way of stating the law is that the solubility of a gas in a liquid at a particular temperature is proportional to the pressure of that gas above the liquid...
Constant 8.14E-16 atm-m3/mole at 25° (EST). Atmospheric OH Rate Constant 1.60E-10 cm3/molecule-sec at 25°
Mechanism of Action
Buformin delays absorption of glucose from the gastrointestinal tract, increases insulin sensitivity and glucose uptake into cells and inhibits synthesis of glucose by the liver. Buformin and the other biguanides are not hypoglycemic, but rather anti-hyperglycemic agents. They do not produce hypoglycemia; instead, they reduce basal and postprandial hyperglycemia in diabetics.Pharmacokinetics
After oral administration of 50 mg of buformin to volunteers, almost 90% of the applied quantity was recovered in the urine; the rate constant of elimination was found to be 0.38 hr-1. Buformin is a strong base (pKA = 11.3) and not absorbed in the stomach. After i.v. injection of about 1 mg/kg buformin-14-C, the initial serum concentration is 0.2-0.4 µg/ml. Serum level and urinary elimination rate are linearly correlated. In man, after oral administration of 50 mg 14-C-buformin, the maximum serum concentration was 0.26-0.41 µg/ml. The buformin was eliminated with an average half-life of 2 h. 84% of the dose administered was found excreted unchanged in the urine. Buformin is not metabolized in man.Dosage
The daily dose of buformin is 150-300 mg by mouth. Buformin has also been available in a sustained release preparation.Contraindications
Diabetic coma; ketoacidosis; severe infection; trauma; other severe infections where buformin is unlikely to control the hyperglycemia; renal or hepatic impairment; heart failure; recent myocardial infarct; dehydration; alcoholism; conditions likely to predispose to lactic acidosis.Toxicity
Buformin was withdrawn from the market in most countries due to an elevated risk of causing lactic acidosisLactic acidosis
Lactic acidosis is a physiological condition characterized by low pH in body tissues and blood accompanied by the buildup of lactate especially D-lactate, and is considered a distinct form of metabolic acidosis. The condition typically occurs when cells receive too little oxygen , for example...
, but is still available and prescribed in Hungary, Taiwan, and Japan. The lactic acidosis
Lactic acidosis
Lactic acidosis is a physiological condition characterized by low pH in body tissues and blood accompanied by the buildup of lactate especially D-lactate, and is considered a distinct form of metabolic acidosis. The condition typically occurs when cells receive too little oxygen , for example...
occurred only in patients with a buformin plasma level of greater than 0.60 µg/ml and was rare in patients with normal renal function.
In one report the toxic oral dose was 329 ± 30mg/day in 24 patients who developed lactic acidosis on buformin. Another group of 24 patients on 258 ± 25mg/day did not develop lactic acidosis on buformin.
Anti-Cancer Properties
Buformin, along with PhenforminPhenformin
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....
and Metformin
Metformin
Metformin is an oral antidiabetic drug in the biguanide class. It is the first-line drug of choice for the treatment of type 2 diabetes, in particular, in overweight and obese people and those with normal kidney function. Its use in gestational diabetes has been limited by safety concerns...
, 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.