Absorption, Distribution and Excretion
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.

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Metabolism / Metabolites
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.

Interactions
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.

[1]. Phenformin as an Anticancer Agent: Challenges and Prospects. Int J Mol Sci. 2019 Jul 5;20(13):3316.

[2]. A review of phenformin, metformin, and imeglimin. Drug Dev Res. 2020 Jun;81(4):390-401.

Phenformin is a member of the class of biguanides that is biguanide in which one of the terminal nitrogen atoms is substituted by a 2-phenylethyl group. It was used as an anti-diabetic drug but was later withdrawn from the market due to potential risk of lactic acidosis. It has a role as an antineoplastic agent, a geroprotector and a hypoglycemic agent. It is functionally related to a biguanide.
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)
Phenformin is an agent belonging to the biguanide class of antidiabetics with antihyperglycemic activity. Phenformin is not used clinically due to the high risk of lactic acidosis that is associated with its use.
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)

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Drug Indication
For the reatment of type II diabetes mellitus.

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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).
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.

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Therapeutic Uses
Hypoglycemic Agents
EXPTL USE: PHENFORMIN (2 MG) ADMIN 5 DAYS/WK TO C3H/SN MICE FROM AGE 3.5 MO UNTIL DEATH DECR THE NUMBER OF SPONTANEOUS TUMORS 4.0 FOLD & AVG SURVIVAL OF ANIMALS BY 100 DAYS.
IF PT REQUIRES MORE THAN 40 UNITS OF INSULIN/DAY, HE IS UNLIKELY TO RESPOND TO PHENFORMIN. ...PHENFORMIN PLUS ESTROGENS HAVE BEEN USED WITH SUCCESS IN REDUCING MORTALITY IN SURVIVORS OF MYOCARDIAL INFARCTION.
PHENFORMIN IS USED IN TREATMENT OF MATURITY-ONSET DIABETES...
For more Therapeutic Uses (Complete) data for PHENFORMIN (8 total), please visit the HSDB record page.

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Drug Warnings
IN PRESENCE OF RENAL GLYCOSURIA, FATAL HYPOGLYCEMIA CAN OCCUR.
IRREVERSIBLE LACTIC ACIDOSIS OCCURRED IN TWO PATIENTS UNDERGOING PHENFORMIN THERAPY FOR DIABETES.
PHENFORMIN...ANTIDIABETIC AGENT TAKEN ORALLY, IS REPORTED TO HAVE CAUSED TRANSITORY MYOPIA IN 53-YR-OLD DIABETIC PATIENTS.
DIABETIC SUBJECTS WITH SEVERE HEPATIC OR RENAL INSUFFICIENCY OR CONGESTIVE HEART FAILURE ARE NOT SUITABLE CANDIDATES FOR ORAL HYPOGLYCEMIC THERAPY. ...ITS ADMIN DURING PREGNANCY IS CURRENTLY NOT RECOMMENDED.
For more Drug Warnings (Complete) data for PHENFORMIN (11 total), please visit the HSDB record page.

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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.

C10H15N5

205.27

205.132

114-86-3

Phenformin hydrochloride;834-28-6

8249

White to off-white solid powder

1.2±0.1 g/cm3

332.2±35.0 °C at 760 mmHg

280-282°C

154.7±25.9 °C

0.0±0.7 mmHg at 25°C

1.620

-0.6

3

1

4

15

236

0

ICFJFFQQTFMIBG-UHFFFAOYSA-N

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)

1-(diaminomethylidene)-2-(2-phenylethyl)guanidine

BRN 1977317 Azucaps DebeonePhenformin Insoral

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

May dissolve in DMSO (in most cases), if not, try other solvents such as H2O, Ethanol, or DMF with a minute amount of products to avoid loss of samples

Note: Listed below are some common formulations that may be used to formulate products with low water solubility (e.g. < 1 mg/mL), you may test these formulations using a minute amount of products to avoid loss of samples.

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Injection Formulation 1: DMSO : Tween 80： Saline = 10 : 5 : 85 (i.e. 100 μL DMSO stock solution → 50 μL Tween 80 → 850 μL Saline)
*Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH ₂ O to obtain a clear solution.
Injection Formulation 2: DMSO : PEG300 ：Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL DMSO → 400 μLPEG300 → 50 μL Tween 80 → 450 μL Saline)
Injection Formulation 3: DMSO : Corn oil = 10 : 90 (i.e. 100 μL DMSO → 900 μL Corn oil)
Example: Take the Injection Formulation 3 (DMSO : Corn oil = 10 : 90) as an example, if 1 mL of 2.5 mg/mL working solution is to be prepared, you can take 100 μL 25 mg/mL DMSO stock solution and add to 900 μL corn oil, mix well to obtain a clear or suspension solution (2.5 mg/mL, ready for use in animals).

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Injection Formulation 4: DMSO : 20% SBE-β-CD in saline = 10 : 90 [i.e. 100 μL DMSO → 900 μL (20% SBE-β-CD in saline)]
*Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution.
Injection Formulation 5: 2-Hydroxypropyl-β-cyclodextrin : Saline = 50 : 50 (i.e. 500 μL 2-Hydroxypropyl-β-cyclodextrin → 500 μL Saline)
Injection Formulation 6: DMSO : PEG300 : castor oil : Saline = 5 : 10 : 20 : 65 (i.e. 50 μL DMSO → 100 μLPEG300 → 200 μL castor oil → 650 μL Saline)
Injection Formulation 7: Ethanol : Cremophor : Saline = 10： 10 : 80 (i.e. 100 μL Ethanol → 100 μL Cremophor → 800 μL Saline)
Injection Formulation 8: Dissolve in Cremophor/Ethanol (50 : 50), then diluted by Saline
Injection Formulation 9: EtOH : Corn oil = 10 : 90 (i.e. 100 μL EtOH → 900 μL Corn oil)
Injection Formulation 10: EtOH : PEG300：Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL EtOH → 400 μLPEG300 → 50 μL Tween 80 → 450 μL Saline)

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Oral Formulation 1: Suspend in 0.5% CMC Na (carboxymethylcellulose sodium)
Oral Formulation 2: Suspend in 0.5% Carboxymethyl cellulose
Example: Take the Oral Formulation 1 (Suspend in 0.5% CMC Na) as an example, if 100 mL of 2.5 mg/mL working solution is to be prepared, you can first prepare 0.5% CMC Na solution by measuring 0.5 g CMC Na and dissolve it in 100 mL ddH2O to obtain a clear solution; then add 250 mg of the product to 100 mL 0.5% CMC Na solution, to make the suspension solution (2.5 mg/mL, ready for use in animals).

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Oral Formulation 3: Dissolved in PEG400
Oral Formulation 4: Suspend in 0.2% Carboxymethyl cellulose
Oral Formulation 5: Dissolve in 0.25% Tween 80 and 0.5% Carboxymethyl cellulose
Oral Formulation 6: Mixing with food powders

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Note: Please be aware that the above formulations are for reference only. InvivoChem strongly recommends customers to read literature methods/protocols carefully before determining which formulation you should use for in vivo studies, as different compounds have different solubility properties and have to be formulated differently.

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 (Please use freshly prepared in vivo formulations for optimal results.)