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

97.78

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

注意: 如下所列的是一些常用的体内动物实验溶解配方，主要用于溶解难溶或不溶于水的产品（水溶度<1 mg/mL）。 建议您先取少量样品进行尝试，如该配方可行，再根据实验需求增加样品量。

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注射用配方1: DMSO : Tween 80： Saline = 10 : 5 : 85 (如： 100 μL DMSO → 50 μL Tween 80 → 850 μL Saline)
*生理盐水/Saline的制备：将0.9g氯化钠/NaCl溶解在100 mL ddH ₂ O中，得到澄清溶液。
注射用配方 2: DMSO : PEG300 ：Tween 80 : Saline = 10 : 40 : 5 : 45 (如： 100 μL DMSO → 400 μL PEG300 → 50 μL Tween 80 → 450 μL Saline)
注射用配方 3: DMSO : Corn oil = 10 : 90 (如： 100 μL DMSO → 900 μL Corn oil)
示例: 以注射用配方 3 (DMSO : Corn oil = 10 : 90) 为例说明, 如果要配制 1 mL 2.5 mg/mL的工作液, 您可以取 100 μL 25 mg/mL 澄清的 DMSO 储备液，加到 900 μL Corn oil/玉米油中, 混合均匀。

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注射用配方 4: DMSO : 20% SBE-β-CD in Saline = 10 : 90 [如：100 μL DMSO → 900 μL (20% SBE-β-CD in Saline)]
*20% SBE-β-CD in Saline的制备（4°C，储存1周）：将2g SBE-β-CD (磺丁基-β-环糊精) 溶解于10mL生理盐水中，得到澄清溶液。
注射用配方 5: 2-Hydroxypropyl-β-cyclodextrin : Saline = 50 : 50 (如： 500 μL 2-Hydroxypropyl-β-cyclodextrin (羟丙基环胡精)→ 500 μL Saline)
注射用配方 6: DMSO : PEG300 : Castor oil : Saline = 5 : 10 : 20 : 65 (如： 50 μL DMSO → 100 μL PEG300 → 200 μL Castor oil → 650 μL Saline)
注射用配方 7: Ethanol : Cremophor : Saline = 10： 10 : 80 (如： 100 μL Ethanol → 100 μL Cremophor → 800 μL Saline)
注射用配方 8: 溶解于Cremophor/Ethanol (50 : 50), 然后用生理盐水稀释。
注射用配方 9: EtOH : Corn oil = 10 : 90 (如： 100 μL EtOH → 900 μL Corn oil)
注射用配方 10: EtOH : PEG300：Tween 80 : Saline = 10 : 40 : 5 : 45 (如： 100 μL EtOH → 400 μL PEG300 → 50 μL Tween 80 → 450 μL Saline)

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口服配方 1: 悬浮于0.5% CMC Na (羧甲基纤维素钠)
口服配方 2: 悬浮于0.5% Carboxymethyl cellulose (羧甲基纤维素)
示例: 以口服配方 1 (悬浮于 0.5% CMC Na)为例说明, 如果要配制 100 mL 2.5 mg/mL 的工作液, 您可以先取0.5g CMC Na并将其溶解于100mL ddH2O中，得到0.5%CMC-Na澄清溶液；然后将250 mg待测化合物加到100 mL前述 0.5%CMC Na溶液中，得到悬浮液。

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口服配方 3: 溶解于 PEG400 (聚乙二醇400)
口服配方 4: 悬浮于0.2% Carboxymethyl cellulose (羧甲基纤维素)
口服配方 5: 溶解于0.25% Tween 80 and 0.5% Carboxymethyl cellulose (羧甲基纤维素)
口服配方 6: 做成粉末与食物混合

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注意: 以上为较为常见方法，仅供参考， InvivoChem并未独立验证这些配方的准确性。具体溶剂的选择首先应参照文献已报道溶解方法、配方或剂型，对于某些尚未有文献报道溶解方法的化合物，需通过前期实验来确定（建议先取少量样品进行尝试），包括产品的溶解情况、梯度设置、动物的耐受性等。

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请根据您的实验动物和给药方式选择适当的溶解配方/方案：
1、请先配制澄清的储备液(如：用DMSO配置50 或 100 mg/mL母液(储备液));
2、取适量母液，按从左到右的顺序依次添加助溶剂，澄清后再加入下一助溶剂。以 下列配方为例说明 (注意此配方只用于说明，并不一定代表此产品 的实际溶解配方):
10% DMSO → 40% PEG300 → 5% Tween-80 → 45% ddH2O (或 saline);
假设最终工作液的体积为 1 mL, 浓度为5 mg/mL: 取 100 μL 50 mg/mL 的澄清 DMSO 储备液加到 400 μL PEG300 中，混合均匀/澄清；向上述体系中加入50 μL Tween-80，混合均匀/澄清；然后继续加入450 μL ddH2O (或 saline)定容至 1 mL；
3、溶剂前显示的百分比是指该溶剂在最终溶液/工作液中的体积所占比例;
4、 如产品在配制过程中出现沉淀/析出，可通过加热(≤50℃)或超声的方式助溶;
5、为保证最佳实验结果，工作液请现配现用！
6、如不确定怎么将母液配置成体内动物实验的工作液，请查看说明书或联系我们;
7、 以上所有助溶剂都可在 Invivochem.cn网站购买。