Phenformin

Pharmaceutical

Pharmaceuticals -> Listed in ZINC15

log Kow= -0.83

0.1

Crystals from isopropanol; pH (0.1 Molar aq soln): 6.7; MP 175-178 °C; Sol in water /Hydrochloride/

2.32e-01 g/L

145.7 Ų [M+H]+ [CCS Type: DT; Buffer gas: N2; Ionization: APCI+; Dataset: TOXCAST; Source Identifier: DTXSID0021121]

146.7 Ų [M+Na]+ [CCS Type: TW; Method: calibrated with polyalanine and drug standards]

Drug products withdrawn or removed from the market for reasons of safety or effectiveness. Phenformin hydrochloride: All drug products containing phenformin hydrochloride. /Phenformin hydrochloride/

Manufacturers, packers, and distributors of drug and drug products for human use are responsible for complying with the labeling, certification, and usage requirements as prescribed by the Federal Food, Drug, and Cosmetic Act, as amended (secs 201-902, 52 Stat. 1040 et seq., as amended; 21 U.S.C. 321-392).

SRP: At the time of review, criteria for land treatment or burial (sanitary landfill) disposal practices are subject to significant revision. Prior to implementing land disposal of waste residue (including waste sludge), consult with environmental regulatory agencies for guidance on acceptable disposal practices.

PHENFORMIN HAS BEEN REPORTED...TO ENHANCE ACTIVITY OF WARFARIN. PROPOSED MECHANISM IS INCR FIBRINOLYTIC EFFECT CAUSED BY PHENFORMIN SEEN DURING FIRST FEW MO OF TREATMENT.

USE OF PROPRANOLOL IN DIABETIC PT...CAN RESULT IN DISTURBANCE OF CARBOHYDRATE METABOLISM & SHOULD BE AVOIDED. IF INSULIN & PROPRANOLOL...GIVEN CONCURRENTLY, PERIODIC SERUM GLUCOSE LEVELS SHOULD BE DETERMINED. ...SIMILAR PRECAUTIONS...APPLICABLE TO CONCURRENT USE OF...PHENFORMIN.

DIABETIC PT TREATED WITH PHENFORMIN SHOULD AVOID INGESTION OF ALCOHOLIC BEVERAGES BECAUSE CONCURRENT USE MAY CAUSE HYPOGLYCEMIC REACTIONS OR LEAD TO LIFE-THREATENING LACTIC ACIDOSIS WITH SHOCK.

DIPHENYLHYDANTOIN GIVEN IP TO RATS DECR LIVER LEVELS OF THIAMIN, RIBOFLAVIN, NIACIN, & PANTOTHENIC ACID. HEPATIC THIAMIN CONTENT WAS NORMALIZED BY SIMULTANEOUS ADMIN OF EITHER ACETOHEXAMINE OR PHENFORMIN.

For more Interactions (Complete) data for PHENFORMIN (6 total), please visit the HSDB record page.

The following link will take the user to the National Toxicology Program (NTP) Test Agent Search Results page, which tabulates all of the "Standard Toxicology & Carcinogenesis Studies", "Developmental Studies", and "Genetic Toxicity Studies" performed with this chemical. Clicking on the "Testing Status" link will take the user to the status (i.e., in review, in progress, in preparation, on test, completed, etc.) and results of all the studies that the NTP has done on this chemical. /Phenformin hydrochloride/ [http://ntp-apps.niehs.nih.gov/ntp_tox/index.cfm?fuseaction=ntpsearch.searchresults&searchterm=834-28-6]

Drug-Induced Liver Injury Severity and Toxicity (DILIst)

Phenformin

DILI Positive

DOI:10.1016/j.drudis.2019.09.022

A bioassay of the carcinogenicity of phenformin hydrochloride was conducted using Fischer 344 rats and B6C3F1 mice. The cmpd was admin in the diet for 78 wk to groups of 35 animals of each species and sex, using concn of 15,000 and 30,000 ppm for rats and concn of 1,200 and 2,500 ppm for mice. Treatment was followed by a period of observation of 26 wk. Control groups consisted of 15 untreated animals of each species and sex. Average weights attained by treated groups of rats and mice were consistently lower than those of control groups in all tests except that male for male rats, in which case the weights shown by treated and control animals were indistinguishable. Survival was apparently unaffected in both species by treatment with phenformin, but was poor in mice due to intercurrent disease. Tumors appearing in treated rats and mice were similar in type and number to those in controls, and no pathologic or statistical evidence of induction of tumors in these species by phenformin was found. Levels of Evidence of Carcinogenicity: Male Rats: Negative; Female Rats: Negative; Male Mice: Negative; Female Mice: Negative. /Phenformin hydrochloride/

Drug products withdrawn or removed from the market for reasons of safety or effectiveness. Phenformin hydrochloride: All drug products containing phenformin hydrochloride. /Phenformin hydrochloride/

Manufacturers, packers, and distributors of drug and drug products for human use are responsible for complying with the labeling, certification, and usage requirements as prescribed by the Federal Food, Drug, and Cosmetic Act, as amended (secs 201-902, 52 Stat. 1040 et seq., as amended; 21 U.S.C. 321-392).

A - Alimentary tract and metabolism

QA - Alimentary tract and metabolism

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.

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).

IN VITRO, PHENFORMIN, IN RELATIVELY LARGE DOSES, INCR GLUCOSE UTILIZATION BY ENHANCING ANAEROBIC GLYCOLYSIS. THIS IS THOUGHT TO OCCUR AS RESULT OF, OR COINCIDENT WITH, INHIBITION OF CELLULAR RESPIRATION. ...ADENOSINE TRIPHOSPHATE (ATP) CONCN FALL & THOSE OF LACTATE INCR. SECOND ACTION OF DRUG IS TO DECR GLUCONEOGENESIS.

...MOST RECENTLY RECOGNIZED IS INHIBITION OF INTESTINAL ABSORPTION OF GLUCOSE & PROBABLY CERTAIN OTHER SUBSTANCES AS WELL; FOR EXAMPLE, DECR ABSORPTION OF VITAMIN B12 HAS BEEN OBSERVED. ...DOES NOT ACT IN NORMAL SUBJECT...PRESUMABLY BECAUSE INCR IN PERIPHERAL GLUCOSE UTILIZATION IS COMPENSATED FOR BY INCR HEPATIC GLUCOSE...

BIGUANIDES APPARENTLY LOWER BLOOD SUGAR INDIRECTLY BY INHIBITING GLUCONEOGENESIS & INCR INSULIN SENSITIVITY. /ORAL HYPOGLYCEMICS/

They induce and increase in peripheral glucose utilization, a decrease in hepatic gluconeogenesis, and a decrease in intestinal absorption of glucose, vitamin B, and bile acids. /Biguanides/

Phenformin generally lowers the blood sugar only in the diabetic patient; it also depresses the blood sugar level in a nutritionally starved individual but not in one who is well fed. In its usual dose administered to a healthy individual, phenformin does not induce lactic acidosis. Phenformin requires insulin for its action, but does not induce and elevation in plasma insulin levels.

IN RATS & GUINEA PIGS, MAJOR METABOLITE OF PHENFORMIN, N(1)-BETA-PHENETHYLBIGUANIDE, IS N(1)-P-HYDROXY-BETA-PHENETHYLBIGUANIDE, & CORRESPONDING O-ETHER GLUCURONIDE HAS ALSO BEEN DETECTED.

METAB IN RATS & GUINEA PIGS. RATS EXCRETED LARGE AMT OF 4-HYDROXYPHENFORMIN (FREE & GLUCURONIC ACID CONJUGATED) & SOME UNCHANGED PHENFORMIN. METAB VARIED WITH DOSE & ROUTE OF ADMIN. GUINEA PIGS EXCRETED SMALL AMT OF 4-HYDROXYPHENFORMIN AFTER IP ADMIN & NONE AFTER ORAL ADMIN.

LABELED COMPD WAS ADMIN. AN UNIDENTIFIED METAB & ITS GLUCURONIDE, WHICH MAY RESULT FROM ALIPHATIC C- OR N-HYDROXYLATION, ACCOUNTED FOR 47% OF 24-HR URINARY RADIOACTIVITY (17% OF DOSE) FOLLOWING ORAL ADMIN TO GUINEA PIGS.

26 HR FOLLOWING ADMIN OF SINGLE DOSE OF PHENFORMIN, 50 MG/KG ORALLY, P-HYDROXYPHENFORMIN WAS MAJOR URINARY METAB IN PHENOTYPICALLY EXTENSIVE METABOLIZERS, BUT WAS NOT OBSERVED IN PHENOTYPICALLY POOR METABOLIZERS.

METAB IN 8 DIABETIC PT WITH RENAL IMPAIRMENT. EXCRETION OF THE METAB P-HYDROXYPHENETHYLBIGUANIDE WAS VARIABLE (BETWEEN 4.9% & 27% OF TOTAL URINARY DOSE LOSS) PROBABLY DUE TO GENETIC POLYMORPHISM OF HEPATIC MECHANISMS FOR HYDROXYLATION.

Phenformin has known human metabolites that include p-Hydroxyphenylethylbiguanide.

PHENFORMIN IS ADEQUATELY ABSORBED FROM GI TRACT. DRUG HAS SHORT T/2 (3 HR) & CORRESPONDINGLY BRIEF DURATION OF ACTION. HYPOGLYCEMIC EFFECT MAY BE PROLONGED TO BETWEEN 6 & 14 HR WITH USE OF TIMED-DISINTEGRATION CAPSULES.

(14)C-LABELED PHENFORMIN ADMIN TO RATS (100 MG/KG ORALLY OR IP) & GUINEA PIGS (25 MG/KG ORALLY & 12.5 IP). EXCRETION OF RADIOACTIVITY & METAB WAS SLOWER IN GUINEA PIGS WHICH MAY PARTLY EXPLAIN THE INCR PHARMACOLOGICAL RESPONSE OF GUINEA PIGS TO PHENFORMIN.

RATS ELIMINATED 26% OF AN INTRADUODENAL DOSE OF LABELED PHENFORMIN (20 MG/KG) IN BILE IN 6 HR COMPARED TO 6% IN GUINEA PIG.

IN 8 DIABETIC PT HALF-LIFE OF PHENFORMIN WAS UNRELATED TO DEGREE OF RENAL IMPAIRMENT, WHEREAS REDUCED RENAL CLEARANCES OF INSULIN & CREATININE WERE SIGNIFICANTLY CORRELATED WITH PROLONGED HALF-LIFE OF ITS METABOLITE P-HYDROXYPHENETHYLBIGUANIDE.

Therap cat: Antidiabetic

An oral hypoglycemic drug; used as the hydrochloride salt.

EQUIMOLAR QUANTITIES OF PHENETHYLAMINE & DICYANODIAMIDE (CYANOGUANIDINE) ARE MIXED & NEUTRALIZED WITH AQ HCL. WATER IS DISTILLED OFF UNTIL MIXT BOILS (@ ABOUT 129 DEG) AFTER REFLUX IS ALLOWED TO CONTINUE FOR 3 HR. CRUDE PRODUCT MAY BE CRYSTALLIZED FROM ISOPROPANOL. US PATENT 2,961,377. /HYDROCHLORIDE/

PREPN FROM BETA-PHENETHYLAMINE HYDROCHLORIDE & DICYANDIAMIDE

Shapiro, Freedman, US pats 2,961,377 and 3,057,780 (1960 and 1962, both to USV).