Metformin Hydrochloride

Breast Feeding; Lactation; Milk, Human; Hypoglycemic Agents; Biguanides

FDA approved drugs -> Active ingredient

FDA approved drugs -> Active ingredient

Hazardous decomposition products formed under fire conditions - Carbon oxides, nitrogen oxides (NOx), hydrogen chloride gas. /Metformin hydrochloride/

When heated to decomposition it emits toxic fumes of /nitric oxides/.

MW: 165.63. Prisms from water, MP 232 °C; crystals from propanol, MP 218-220 °C. Freely soluble in water; slightly soluble in alcohol. Practically insoluble in ether, chloroform, acetone, methylene chloride. /Metformin hydrochloride/

MW: 315.76 /Metformin p-chlorophenoxyacetate (salt)/

MW: 646.70 /Metoformin embonate/

Warning

H302 (99.6%): Harmful if swallowed [Warning Acute toxicity, oral]

P261, P264, P264+P265, P270, P271, P273, P280, P301+P317, P302+P352, P304+P340, P305+P351+P338, P319, P321, P330, P332+P317, P337+P317, P362+P364, P403+P233, P405, and P501 (click each P-code to see the statement)

Aggregated GHS information provided per 265 reports by companies from 19 notifications to the ECHA C&L Inventory. Each notification may be associated with multiple companies.

Warning

H302: Harmful if swallowed [Warning Acute toxicity, oral]

Status: Active Update: 13-08-2020 https://echa.europa.eu/registration-dossier/-/registered-dossier/18705

Metformin hydrochloride: Does not have an individual approval but may be used under an appropriate group standard

The Approved Drug Products with Therapeutic Equivalence Evaluations identifies currently marketed prescription drug products, including metformin hydrochloride, approved on the basis of safety and effectiveness by FDA under sections 505 of the Federal Food, Drug, and Cosmetic Act. /Metformin hydrochloride/

Suitable extinguishing media: Use water spray, alcohol-resistant foam, dry chemical or carbon dioxide. /Metformin hydrochloride/

Advice for firefighters: Wear self-contained breathing apparatus for firefighting if necessary. /Metformin hydrochloride/

ACCIDENTAL RELEASE MEASURES: Personal precautions, protective equipment and emergency procedures: Use personal protective equipment. Avoid dust formation. Avoid breathing vapors, mist or gas. Ensure adequate ventilation. Avoid breathing dust. Environmental precautions: Do not let product enter drains. Methods and materials for containment and cleaning up: Pick up and arrange disposal without creating dust. Sweep up and shovel. Keep in suitable, closed containers for disposal. /Metformin hydrochloride/

SRP: Expired or waste pharmaceuticals shall carefully take into consideration applicable DEA, EPA, and FDA regulations. It is not appropriate to dispose by flushing the pharmaceutical down the toilet or discarding to trash. If possible return the pharmaceutical to the manufacturer for proper disposal being careful to properly label and securely package the material. Alternatively, the waste pharmaceutical shall be labeled, securely packaged and transported by a state licensed medical waste contractor to dispose by burial in a licensed hazardous or toxic waste landfill or incinerator.

Product Offer surplus and non-recyclable solutions to a licensed disposal company. Contact a licensed professional waste disposal service to dispose of this material; Contaminated packaging: Dispose of as unused product. /Metformin hydrochloride/

ACCIDENTAL RELEASE MEASURES: Personal precautions, protective equipment and emergency procedures: Use personal protective equipment. Avoid dust formation. Avoid breathing vapors, mist or gas. Ensure adequate ventilation. Avoid breathing dust. Environmental precautions: Do not let product enter drains. /Metformin hydrochloride/

Precautions for safe handling: Avoid contact with skin and eyes. Avoid formation of dust and aerosols. Further processing of solid materials may result in the formation of combustible dusts. The potential for combustible dust formation should be taken into consideration before additional processing occurs. Provide appropriate exhaust ventilation at places where dust is formed. /Metformin hydrochloride/

Appropriate engineering controls: Handle in accordance with good industrial hygiene and safety practice. Wash hands before breaks and at the end of workday. /Metformin hydrochloride/

Gloves must be inspected prior to use. Use proper glove removal technique (without touching glove's outer surface) to avoid skin contact with this product. Dispose of contaminated gloves after use in accordance with applicable laws and good laboratory practices. Wash and dry hands. /Metformin hydrochloride/

SRP: Local exhaust ventilation should be applied wherever there is an incidence of point source emissions or dispersion of regulated contaminants in the work area. Ventilation control of the contaminant as close to its point of generation is both the most economical and safest method to minimize personnel exposure to airborne contaminants. Ensure that the local ventilation moves the contaminant away from the worker.

Eye/face protection: Safety glasses with side-shields conforming to EN166. Use equipment for eye protection tested and approved under appropriate government standards such as NIOSH (US) or EN 166(EU). /Metformin hydrochloride/

Skin protection: Handle with gloves. /Metformin hydrochloride/

Body Protection: Complete suit protecting against chemicals. The type of protective equipment must be selected according to the concentration and amount of the dangerous substance at the specific workplace. /Metformin hydrochloride/

Respiratory protection: For nuisance exposures use type P95 (US) or type P1 (EU EN 143) particle respirator. For higher level protection use type OV/AG/P99 (US) or type ABEK-P2 (EU EN 143) respirator cartridges. Use respirators and components tested and approved under appropriate government standards such as NIOSH (US) or CEN (EU). /Metformin hydrochloride/

The clinical use of doxorubicin, which is a strong antineoplastic agent, is limited due to its cardiotoxic side effects. Metformin is a drug with antihyperglycemic effects, and it has been shown to have a cardioprotective effect on left ventricular function in experimental animal models of myocardial ischemia. The present study investigated the cardioprotective effect of metformin in rats with doxorubicin cardiotoxicity. Wistar albino rats were used in the study. Forty male, 10-week-old Wistar albino rats were randomly divided four groups. The control group rats were intraperitoneally administered saline solution twice a week, four doses in total. The doxorubicin group rats received doxorubicin (4 mg/kg, twice a week, cumulative dose: 16 mg/kg) intraperitoneally. The metformin group rats received metformin (250 mg/kg/day, every day for 14 days) via gavage. The doxorubicin + metformin group rats received doxorubicin and metformin at the same dose. Left ventricular functions were evaluated by using M-mode echocardiography one day after the last dose of doxorubicin. Heart tissue samples were histopathologically examined. Cardiomyocyte apoptosis was detected using in situ terminal deoxynucleotide transferase assay (TUNEL). Serum brain natriuretic peptide and C-type natriuretic peptide levels were measured. Catalase, superoxide dismutase, glutathione peroxidase, and tumor necrosis factor alpha levels were analyzed in the heart tissue. The assumptions of equality of variances and normal distribution were checked for all variables (Shapiro-Wilk test and Q-Q graphics). To identify intergroup differences, one-way variant analysis or the Kruskal-Wallis test was used. A p<0.05 value was accepted as statistically significant. Our results showed that doxorubicin treatment caused significant deterioration in left ventricular functions by echocardiography, histological heart tissue damage, and increase in cardiomyocyte apoptosis. Doxorubicin + metformin group showed protection in left ventricular function, elimination of histopathologic change, and reduced of cardiomyocyte apoptosis. The present study provided evidence that metformin has cardioprotective effects against doxorubicin cardiotoxicity.

The link between inflammation and cancer has been confirmed by the use of anti-inflammatory therapies in cancer prevention and treatment. 5-aminosalicylic acid (5-ASA) was shown to decrease the growth and survival of colorectal cancer (CRC) cells. Studies also revealed that metformin induced apoptosis in several cancer cell lines. We investigated the combinatory effect of 5-ASA and metformin on HCT-116 and Caco-2 CRC cell lines. Apoptotic markers were determined using western blotting. Expression of pro-inflammatory cytokines was determined by RT-PCR. Inflammatory transcription factors and metastatic markers were measured by ELISA. Metformin enhanced CRC cell death induced by 5-ASA through significant increase in oxidative stress and activation of apoptotic machinery. Moreover, metformin enhanced the anti-inflammatory effect of 5-ASA by decreasing the gene expression of IL-1beta, IL-6, COX-2 and TNF-alpha and its receptors; TNF-R1 and TNF-R2. Significant inhibition of activation of NF-kappaB and STAT3 transcription factors, and their downstream targets was also observed. Metformin also enhanced the inhibitory effect of 5-ASA on MMP-2 and MMP-9 enzyme activity, indicating a decrease in metastasis. The current data demonstrate that metformin potentiates the antitumor effect of 5-ASA on CRC cells suggesting their potential use as an adjuvant treatment in CRC.

Previous studies suggest that metformin may exert a protective effect on cisplatin-induced cytotoxicity in cancer cells, and this finding has led to a caution for considering metformin use in the treatment of cancer patients. However, in this paper we provide the first demonstration that metformin synergistically augments cisplatin cytotoxicity in the esophageal squamous cancer cell line, ECA109, under glucose-deprivation conditions, which may be more representative of the microenvironment within solid tumors; this effect is very different from the previously reported cytoprotective effect of metformin against cisplatin in commonly used high glucose incubation medium. The potential mechanisms underlying the synergistic effect of metformin on cisplatin-induced cytotoxicity under glucose-deprivation conditions may include enhancement of metformin-associated cytotoxicity, marked reduction in the cellular ATP levels, deregulation of the AKT and AMPK signaling pathways, and impaired DNA repair function.

Concomitant treatment with the glucose-lowering drug metformin and the platelet aggregation inhibitor dipyridamole often occurs in patients with type 2 diabetes mellitus who have suffered a cerebrovascular event. The gastrointestinal uptake of metformin is mediated by the human equilibrative nucleoside transporter 4 (ENT4), which is inhibited by dipyridamole in preclinical studies. We hypothesized that dipyridamole lowers the plasma exposure to metformin. Eighteen healthy volunteers (mean age 23 years; 9 male) were randomized in an open-label crossover study. Subjects were allocated to treatment with metformin 500 mg twice daily in combination with dipyridamole slow-release 200 mg twice daily or to metformin alone for 4 days. After a washout period of 10 days, the volunteers were crossed over to the alternative treatment arm. Blood samples were collected during a 10-hr period after intake of the last metformin dose. The primary endpoint was the area under the plasma concentration-time curve (AUC0-12hr) and the maximum plasma metformin concentration (C max). In healthy subjects, dipyridamole did not significantly affect Cmax nor AUC0-12hr of metformin under steady-state conditions. Previous in vitro studies report that dipyridamole inhibits the ENT4 transporter that mediates gastrointestinal uptake of metformin. In contrast, co-administration of dipyridamole at therapeutic dosages to healthy volunteers does not have a clinically relevant effect on metformin plasma steady-state exposure.

For more Interactions (Complete) data for METFORMIN (23 total), please visit the HSDB record page.

TERRESTRIAL FATE: Based on a classification scheme(1), Koc values of 19, 16 and 12(2) indicate that metformin is expected to have very mobility in soil(SRC). Volatilization of metformin from moist soil surfaces is not expected to be an important fate process(SRC) given an estimated Henry's Law constant of 7.6X10-16 atm-cu m/mole(SRC), using a fragment constant estimation method(3). Metformin is not expected to volatilize from dry soil surfaces(SRC) based upon an estimated vapor pressure of 7.6X10-5 mm Hg at 25 °C(SRC), determined from a fragment constant method(4). Half-lives of 1-5 days when incubated in soil under aerobic conditions(2) suggest that biodegradation may be an important environmental fate procss in soil(SRC). However, the hydrochloride salt has been classified as not readily biodegradable(5).

AQUATIC FATE: Based on a classification scheme(1), Koc values of 19, 16 and 12(2) indicate that metformin is not expected to adsorb to suspended solids and sediment(SRC). Volatilization from water surfaces is not expected(3) based upon an estimated Henry's Law constant of 7.6X10-16 atm-cu m/mole(SRC), developed using a fragment constant estimation method(4). According to a classification scheme(6), an estimated BCF of 3(SRC), from an estimated log Kow of -2.63(6) and a regression-derived equation(6), suggests the potential for bioconcentration in aquatic organisms is low(SRC). Biodegradation data in water were not available(SRC). However, dissipation of 1.3 and 8.2% for metfromin hydrochloride in aerobic aquatic systems(7) suggest that biodegradation may be a slow environmental fate process in water(SRC). The majority of radioactivity applied (81.5%) was found in the sediment(7).

ATMOSPHERIC FATE: According to a model of gas/particle partitioning of semivolatile organic compounds in the atmosphere(1), metformin, which has an estimated vapor pressure of 7.6X10-5 mm Hg at 25 °C(SRC), determined from a fragment constant method(2), will exist in both the vapor and particulate phases in the ambient atmosphere. Vapor-phase metformin is degraded in the atmosphere by reaction with photochemically-produced hydroxyl radicals(SRC); the half-life for this reaction in air is estimated to be 2 hrs(SRC), calculated from its rate constant of 1.53X10-10 cu cm/molecule-sec at 25 °C(SRC) that was derived using a structure estimation method(3). Particulate-phase metformin may be removed from the air by wet and dry deposition(SRC). Metformin does not contain chromophores that absorb at wavelengths >290 nm(4) and, therefore, is not expected to be susceptible to direct photolysis by sunlight(SRC).

Absorbed over 6 hours, bioavailability is 50 to 60% under fasting conditions. Administration with food decreases and delays absorption. Some evidence indicates that the level of absorption is not dose-related, suggesting that absorption occurs through a saturable process. Limited data from animal and human cell cultures indicate that absorption occurs through a passive, non-saturable process, possibly involving a paracellular route. Peak action occurs 3 hours after oral administration.

EXPERIMENTAL: Metformin improves the endocrinopathy of polycystic ovary syndrome (PCOS), facilitates conception, appears to reduce first trimester miscarriage and gestational diabetes and does not appear to be teratogenic. The concentrations of metformin in breast milk are generally low and the mean infant exposure to metformin has been reported in the range 0.28-1.08% of the weight-normalized maternal dose, well below the level of concern for breastfeeding. No adverse effects on blood glucose of nursing infants have been reported. Metformin during lactation versus formula feeding appears to have no adverse effects on infants' growth, motor-social development and intercurrent illness during the first 6 months of life. Systematic studies have not yet been done assessing how hyperinsulinemia, polycystic ovary syndrome and metformin may affect lactation.

IDENTIFICATION AND USE: Metformin is antihyperglycemic, not hypoglycemic agent. It does not cause insulin release from the pancreas and does not cause hypoglycemia, even in large doses. HUMAN EXPOSURE AND TOXICITY: Metformin is believed to work by inhibiting hepatic glucose production and increasing the sensitivity of peripheral tissue to insulin. It does not stimulate insulin secretion, which explains the absence of hypoglycemia. Metformin also has beneficial effects on the plasma lipid concentrations and promotes weight loss. Accumulation of metformin may occur in patients with renal impairment, and such accumulation rarely can result in lactic acidosis, a serious, potentially fatal metabolic disease. Lactic acidosis constitutes a medical emergency requiring immediate hospitalization and treatment; lactic acidosis is characterized by elevated blood lactate concentrations, decreased blood pH, electrolyte disturbances with an increased anion gap, and an increased lactate/pyruvate ratio. Lactic acidosis also may occur in association with a variety of pathophysiologic conditions, including diabetes mellitus, and whenever substantial tissue hypoperfusion and hypoxemia exist. Approximately 50% of cases of metformin-associated lactic acidosis have been reported to be fatal. No evidence of mutagenicity or chromosomal damage was observed in in vitro test systems, including human lymphocytes assay. ANIMAL STUDIES: No evidence of carcinogenic potential was seen in a 104-week study in male and female rats receiving metformin hydrochloride dosages up to and including 900 mg/kg daily or in a 91-week study in male and female mice receiving metformin hydrochloride at dosages up to and including 1500 mg/kg daily. Cancer preventive effect of metformin (MF) has been studied in mice, rats and hamsters. In the majority of cases metformin treatment leads to inhibition of carcinogenesis. No evidence of impaired fertility was observed in rats following administration of metformin hydrochloride dosages of 600 mg/kg daily. Reproduction studies in rats and rabbits given metformin hydrochloride dosages of 600 mg/kg daily have not revealed teratogenicity. No evidence of mutagenicity or chromosomal damage was observed in vivo in a micronucleus test in mice or in in vitro test systems, including microbial (Ames test) and mammalian (mouse lymphoma) assays. Pretreatment of rat cerebellar granule neurons with metformin greatly enhanced cell viability against glutamate-induced neurotoxicity. In aged male mice fed high-fat diet supplemented with metformin for 6 months, metformin decreased body fat composition and attenuated declines in motor function induced by a high fat diet. Performance in the Morris water maze test of hippocampal based memory function, showed that metformin prevented impairment of spatial reference memory associated with the high fat diet. ECOTOXICITY STUDIES: Adult fathead minnows (Pimephales promelas) were chronically exposed to metformin for 4 wk, at 40 ug/L. Metformin treatment induced significant up-regulation of messenger ribonucleic acid (mRNA) encoding the egg-protein vitellogenin in male fish, an indication of endocrine disruption.

Metformin's mechanisms of action differ from other classes of oral antihyperglycemic agents. Metformin decreases blood glucose levels by decreasing hepatic glucose production, decreasing intestinal absorption of glucose, and improving insulin sensitivity by increasing peripheral glucose uptake and utilization. These effects are mediated by the initial activation by metformin of AMP-activated protein kinase (AMPK), a liver enzyme that plays an important role in insulin signaling, whole body energy balance, and the metabolism of glucose and fats. Activation of AMPK is required for metformin's inhibitory effect on the production of glucose by liver cells. Increased peripheral utilization of glucose may be due to improved insulin binding to insulin receptors. Metformin administration also increases AMPK activity in skeletal muscle. AMPK is known to cause GLUT4 deployment to the plasma membrane, resulting in insulin-independent glucose uptake. The rare side effect, lactic acidosis, is thought to be caused by decreased liver uptake of serum lactate, one of the substrates of gluconeogenesis. In those with healthy renal function, the slight excess is simply cleared. However, those with severe renal impairment may accumulate clinically significant serum lactic acid levels. Other conditions that may precipitate lactic acidosis include severe hepatic disease and acute/decompensated heart failure.

/AQUATIC SPECIES/ ... Adult fathead minnows (Pimephales promelas) were chronically exposed to metformin for 4 wk, at 40 ug/L, a level similar to the average found in /wastewater treatment plant/ (WWTP) effluent in Milwaukee, Wisconsin, USA. Genetic endpoints related to metabolism and endocrine function as well as reproduction-related endpoints were examined. Metformin treatment induced significant up-regulation of messenger ribonucleic acid (mRNA) encoding the egg-protein vitellogenin in male fish, an indication of endocrine disruption. The present study, the first to study the effects of environmentally relevant metformin exposure in fathead minnows, demonstrates the need for further study of the endocrine-disrupting effects of metformin in aquatic organisms.

Acute oral toxicity (LD₅₀): 350 mg/kg [Rabbit]. It would be expected that adverse reactions of a more intense character including epigastric discomfort, nausea, and vomiting followed by diarrhea, drowsiness, weakness, dizziness, malaise and headache might be seen.

EPA has released the Interactive Chemical Safety for Sustainability (iCSS) Dashboard. The iCSS Dashboard provides an interactive tool to explore rapid, automated (or in vitro high-throughput) chemical screening data generated by the Toxicity Forecaster (ToxCast) project and the federal Toxicity Testing in the 21st century (Tox21) collaboration. /The title compound was tested by ToxCast and/or Tox21 assays/[USEPA; ICSS Dashboard Application; Available from, as of October 28, 2016: http://actor.epa.gov/dashboard/]

Metformin was the most frequently detected pharmaceutical in Lake Michigan samples offshore from the South Shore Water Reclamation Facility, Milwaukee WI. A maximum concentration of 9200 ng/L (mean 1200 ng/L) was reported in the treatment plant effluent. Sampling was conducted from May 16, 2009 to June 16, 2010(1). Metformin concentrations of 26,000 and 11,000 ng/L in influent and effluent samples, respectively, (a removal efficientcy of 59%) from the 26th Ward Wastewater treatment Plant, Jamaica Bay, Long Island, NY, an urban estuary(2). Sampling was conducted in February 2005(2).

Koc values of 19, 16 and 12 were measured using an alluvial agricultural soil (pH 6.6; 7.2% organic matter; 60.5% clay), loessy brown soil (pH 6.5; 6.5% organic matter; 47.4% clay), and a podsolic soil (pH 4.3; 3.9% organic matter; 28.2% clay) typical of Poland(1). According to a classification scheme(2), this estimated Koc value suggests that metformin is expected to have very high mobility in soil.

/HUMAN EXPOSURE STUDIES/ The link between metformin and lactic acidosis in metformin therapy may be causal, associated or coincidental. Our objective was to investigate this link by studying and analyzing published reports of so-called 'metformin-associated lactic acidosis'. Systematically searched in the BIOSIS, DERWENT, EMBASE, MEDLINE, and PASCAL databases of the English language and non-English language literature for all reports of so-called 'metformin-associated lactic acidosis' published from May 1995 through January 2000. Reports related to metformin overdose or contrast media-induced renal failure /were not included/. Metformin accumulation and concurrent pathologies were critically reviewed as precipitating factors for metformin-associated lactic acidosis. Metformin accumulation was assessed in terms of the recorded measurement of metformin concentration in plasma or, if not available, by the presence of primary renal failure, i.e. renal failure that was not secondary to a shock syndrome. We found 21 reports describing a total of 26 patients. Criteria of lactic acidosis (lactate > 5 mmol/L, pH <or= 7.35) were not met in four patients. In the remaining 22 patients, plasma metformin concentration was determined in only four, of whom one had a normal value. In the 18 patients with lactic acidosis where plasma metformin concentration data was not available, the presence of primary renal failure was absent or unlikely in six patients, uncertain in two, and likely or proven in 14. With regard to these 14 patients, the precipitating factor was metformin in 12 patients (in the context of renal failure either chronic or acute) and intercurrent pathologies in two others. Overall, lactic acidosis was either absent (n = 4), precipitated by concurrent pathology (n = 8), precipitated by metformin without apparent associated pathology (n = 12) or of uncertain origin (n = 2). Death occurred 10 times but only once in the 12 patients with metformin-induced lactic acidosis and this was not related to metformin. While the term 'metformin-associated lactic acidosis' is commonly used to depict all situations of lactic acidosis in metformin therapy, true metformin-associated lactic acidosis, i.e. one which refers to metformin and concurrent pathologies as co-precipitating factors, was never observed in the studied reports ... /Salt not specified/

/SIGNS AND SYMPTOMS/ Overdose of metformin hydrochloride has occurred, including ingestion of amounts greater than 50 grams. Hypoglycemia was reported in approximately 10% of cases, but no causal association with metformin hydrochloride has been established. Lactic acidosis has been reported in approximately 32% of metformin overdose cases.

/SIGNS AND SYMPTOMS/ Accumulation of metformin may occur in patients with renal impairment, and such accumulation rarely can result in lactic acidosis, a serious, potentially fatal metabolic disease. The risk of developing lactic acidosis is much lower (e.g., 10-fold lower) with metformin than with phenformin (no longer commercially available in the US). However, lactic acidosis constitutes a medical emergency requiring immediate hospitalization and treatment; in such cases, metformin should be discontinued and general supportive therapy (e.g., volume expansion, diuresis) should be initiated immediately. Prompt hemodialysis also is recommended. Lactic acidosis is characterized by elevated blood lactate concentrations (exceeding 45 mg/dL), decreased blood pH (less than 7.35), electrolyte disturbances with an increased anion gap, and an increased lactate/pyruvate ratio. Lactic acidosis also may occur in association with a variety of pathophysiologic conditions, including diabetes mellitus, and whenever substantial tissue hypoperfusion and hypoxemia exist. Approximately 50% of cases of metformin-associated lactic acidosis have been reported to be fatal. However, it has been suggested that in such cases of lactic acidosis not accompanied by conditions predisposing to tissue anoxia (e.g., heart failure, renal or pulmonary disease), techniques for the elimination of metformin from the body may allow recovery rates exceeding 80%.

/CASE REPORTS/ Metformin-associated lactic acidosis (MALA) is one of the most important drug toxicities with a high morbidity and mortality rate. We report herein a case of suicide attempt with metformin presenting as MALA and acute renal failure on admission to emergency department and acute myocardial injury later on hospitalizaation. An obvious improvement of metabolic parameters was seen in our patient provided by anti-ischemic treatment together with bicarbonate infusion and hemodialysis. Although myocardial injury due to MALA is not a common disorder, we must be aware that metformin overdose with lack of tissue oxygenation, hypoperfusion, and arrhythmias may cause myocardial ischaemia.

For more Human Toxicity Excerpts (Complete) data for METFORMIN (19 total), please visit the HSDB record page.

The Approved Drug Products with Therapeutic Equivalence Evaluations identifies currently marketed prescription drug products, including metformin hydrochloride, approved on the basis of safety and effectiveness by FDA under sections 505 of the Federal Food, Drug, and Cosmetic Act. /Metformin hydrochloride/

Metformin is widely used to treat hyperglycemia. However, metformin treatment may induce intrahepatic cholestasis and liver injury in a few patients with type II diabetes through an unknown mechanism. Here we show that metformin decreases SIRT1 protein levels in primary hepatocytes and liver. Both metformin-treated wild-type C57 mice and hepatic SIRT1-mutant mice had increased hepatic and serum bile acid levels. However, metformin failed to change systemic bile acid levels in hepatic SIRT1-mutant mice. Molecular mechanism study indicates that SIRT1 directly interacts with and deacetylates Foxa2 to inhibit its transcriptional activity on expression of genes involved in bile acids synthesis and transport. Hepatic SIRT1 mutation elevates Foxa2 acetylation levels, which promotes Foxa2 binding to and activating genes involved in bile acids metabolism, impairing hepatic and systemic bile acid homeostasis. Our data clearly suggest that hepatic SIRT1 mediates metformin effects on systemic bile acid metabolism and modulation of SIRT1 activity in liver may be an attractive approach for treatment of bile acid-related diseases such as cholestasis.

Metformin is antihyperglycemic, not hypoglycemic. It does not cause insulin release from the pancreas and does not cause hypoglycemia, even in large doses. Metformin has no significant effects on the secretion of glucagon, cortisol, growth hormone or somatostatin. Metformin reduces glucose levels primarily by decreasing hepatic glucose production and by increasing insulin action in muscle and fat. ... May decrease plasma glucose by reducing the absorption of glucose from the intestine. /Salt not specified/

Metformin potentiates the effect of insulin by mechanisms not fully understood. Metformin does not stimulate pancreatic beta cells to increase secretion of insulin; insulin secretion must be present for metformin to work properly. It is postulated that metformin decreases hepatic glucose production and improves insulin sensitivity by increasing peripheral glucose uptake and utilization. /Salt not specified/

People with Type 2 diabetes mellitus (T2DM) have reduced bone mineral density and an increased risk of fractures due to altered mesenchymal stem cell (MSC) differentiation in the bone marrow. This leads to a shift in the balance of differentiation away from bone formation (osteogenesis) in favour of fat cell development (adipogenesis). The commonly used anti-diabetic drug, metformin, activates the osteogenic transcription factor Runt-related transcription factor 2 (Runx2), which may suppress adipogenesis, leading to improved bone health. Here we investigate the involvement of the metabolic enzyme, AMP-activated protein kinase (AMPK), in these protective actions of metformin. The anti-adipogenic actions of metformin were observed in multipotent C3H10T1/2 MSCs, in which metformin exerted reciprocal control over the activities of Runx2 and the adipogenic transcription factor, PPARgamma, leading to suppression of adipogenesis. These effects appeared to be independent of AMPK activation but rather through the suppression of the mTOR/p70S6K signalling pathway. Basal AMPK and mTOR/p70S6K activity did appear to be required for adipogenesis, as demonstrated by the use of the AMPK inhibitor, compound C. This observation was further supported by using AMPK knockout mouse embryo fibroblasts (MEFs) where adipogenesis, as assessed by reduced lipid accumulation and expression of the adipogeneic transcription factor, C/EBPbeta, was found to display an absolute requirement for AMPK. Further activation of AMPK in wild type MEFS, with either metformin or the AMPK-specific activator, A769662, was also associated with suppression of adipogenesis. It appears, therefore, that basal AMPK activity is required for adipogenesis and that metformin can inhibit adipogenesis through AMPK-dependent or -independent mechanisms, depending on the cellular context.

The principal plasma elimination half-life of metformin averages approximately 6.2 hours ... .

The drug distributes into salivary glands with a half-life of about 9 hours.

Metformin is not metabolized in the liver or GI tract and is not excreted in bile; no metabolites of the drug have been identified in humans.

Metformin is not metabolized. Route of Elimination: Intravenous single-dose studies in normal subjects demonstrate that metformin is excreted unchanged in the urine and does not undergo hepatic metabolism (no metabolites have been identified in humans) nor biliary excretion. Approximately 90% of the drug is eliminated in 24 hours in those with healthy renal function. Renal clearance of metformin is approximately 3.5 times that of creatinine clearance, indicating the tubular secretion is the primary mode of metformin elimination. Half Life: 6.2 hours. Duration of action is 8-12 hours.

METFORMIN ER 500 MG

Biguanide [EPC]; Biguanides [CS]

METFORMIN ER 750 MG

Biguanide [EPC]; Biguanides [CS]

METFORMIN HCL

Biguanides [CS]; Biguanide [EPC]

Metformin is slowly and incompletely absorbed from the GI tract, mainly from the small intestine; absorption is complete within 6 hours. The absolute oral bioavailability of the drug under fasting conditions is reported to be approximately 50-60% with metformin hydrochloride doses of 0.5-1.5 g; binding of the drug to the intestinal wall may explain the difference between the amount of drug absorbed (as determined by the urinary and fecal excretion of unchanged drug) and the amount bioavailable in some studies. In single-dose studies with metformin hydrochloride conventional tablets doses of 0.5-1.5 g or 0.85-2.55 g, plasma metformin concentrations did not increase in proportion to increasing doses, suggesting an active saturable absorption process. Similarly, in single-dose studies with an extended-release tablet preparation (Glumetza) at doses of 0.5-2.5 g, plasma metformin concentrations did not increase in proportion to increasing doses. At steady state after administration of a metformin hydrochloride extended-release tablet preparation (Glucophage XR), the AUC and peak plasma concentrations were not dose proportional within the range of 0.5-2 g. However, limited data from studies in animals and in human intestinal cell cultures suggest that transepithelial transfer of metformin in the intestine may occur through a passive, nonsaturable mechanism, possibly involving a paracellular route. In several studies with another metformin hydrochloride extended-release tablet preparation (Fortamet) using doses of 1-2.5 g, metformin exposure was dose-related.

Following oral administration of metformin hydrochloride (0.5-1.5 g) as conventional tablets in healthy individuals or in patients with type 2 diabetes mellitus, plasma concentrations decline in a triphasic manner. Following multiple-dose administration of metformin hydrochloride (500 mg twice daily for 7-14 days) as conventional tablets in a limited number of patients with type 2 diabetes mellitus, peak plasma concentrations remained unchanged, but trough drug concentrations were higher than with single-dose administration, suggesting some drug accumulation in a peripheral tissue compartment. No accumulation of metformin appears to occur following repeated oral doses of the drug as extended-release tablets. The principal plasma elimination half-life of metformin averages approximately 6.2 hours; 90% of the drug is cleared within 24 hours in patients with normal renal function. The decline in plasma metformin concentrations is slower after oral than after IV administration of the drug, indicating that elimination is absorption rate-limited. Urinary excretion data and data from whole blood indicate a slower terminal-elimination phase half-life of 8-20 hours (e.g., 17.6 hours)1 suggesting that the erythrocyte mass may be a compartment of distribution.

Metformin is distributed rapidly in animals and humans into peripheral body tissues and fluids, particularly the GI tract; the drug also appears to distribute slowly into erythrocytes and into a deep tissue compartment (probably GI tissues). The highest tissue concentrations of metformin (at least 10 times the plasma concentration) occur in the GI tract (e.g., esophagus, stomach, duodenum, jejunum, ileum), with lower concentrations (twice the plasma concentration) occurring in kidney, liver, and salivary gland tissue. The drug distributes into salivary glands with a half-life of about 9 hours. Metformin concentrations in saliva are tenfold lower than those in plasma and may be responsible for the metallic taste reported in some patients receiving the drug. Any local effect of metformin on glucose absorption in the GI tract may be associated with the relatively high GI concentrations of the drug compared with those in other tissues. It is not known whether metformin crosses the blood-brain barrier or the placenta in humans or if the drug is distributed into human milk; however, in lactating rats, metformin is distributed into breast milk at levels comparable to those in plasma.

Renal clearance is approximately 3.5 times greater than creatinine clearance, indicating that tubular secretion is the principal route of metformin elimination. Following a single 850-mg oral dose of metformin hydrochloride, renal clearance averaged 552, 491, or 412 mL/minute in nondiabetic adults, diabetic adults, or healthy geriatric individuals, respectively. Renal impairment results in increased peak plasma concentrations of metformin, a prolonged time to peak plasma concentration, and a decreased volume of distribution. Renal clearance is decreased in patients with renal impairment (as measured by decreases in creatinine clearance) and, apparently because of reduced renal function with age, in geriatric individuals. In geriatric individuals, decreased renal and plasma clearance of metformin also results in increased plasma concentrations of the drug; volume of distribution remains unaffected.

For more Absorption, Distribution and Excretion (Complete) data for METFORMIN (12 total), please visit the HSDB record page.

MEDICATION (VET)

MEDICATION

Hypoglycemic Agents

For use as an adjunct to diet and exercise in adult patients (18 years and older) with NIDDM. May also be used for the management of metabolic and reproductive abnormalities associated with polycystic ovary syndrome (PCOS). Jentadueto is for the treatment of patients when both linagliptin and metformin is appropriate.

By reaction of dimethylamine hydrochloride with dicyandiamide to yield the base. /Metformin hydrochloride/

Preparation: ... J.J. Sterne, United States of America patent 3174901 (1965 to Jan Marcel Didier Aron-Samuel). /Metformin/

Table: Metformin Hydrochloride Preparations [Table#6700]

Table: Metformin Hydrochloride Combinations Preparations [Table#6701]