Метформин

Описание

The study of metformin and its hypoglycemic effects originated from the study of goat’s rue plants, also known as Galega officinalis(French lilac). Goat’s rues are native plants in the Middle East and introduced to Europe later and have been used as forage and ornamental plants throughout the world, including China. As early as in the Middle Ages in Europe, it was found that goat’s rues could ease polyuria, which is one of the typical symptoms of diabetes. While goat’s rues were used to treat a variety of other diseases in the Middle Ages, it was found to cause poisoning symptoms in livestock. Goat’s rues are still used as medical plants at present, mainly for diabetes, diuretic, hepatoprotection, aiding in digestion and promoting lactation, etc. In China, goat’s rues were recorded first in the dictionary of Chinese seed plants and mainly used for the treatment of diabetes. However, because of high toxicity, it is rarely used in traditional Chinese medicines at present.

Физические свойства

Appearance: white crystalline or crystalline powder, odorless. Solubility: freely soluble in water, soluble in methanol, slightly soluble in ethanol, and insoluble in chloroform or ether. Melting point: 223–226°C.

История

Metformin is a biguanide compound which originated from the extraction of goat’s rue plants. The structure of metformin was identified by British scholars in the early 1920s. In 1922, Werner and Bell et?al. first synthesized metformin in 31 institutes in Dublin, Ireland. In 1929, Slotta and Tschesche found metformin’s hypoglycemic action. However, because of other potent antidiabetic drugs such as insulin which were widely used in clinical practice, the pharmacological effects of metformin didn’t receive much attention.
Until the 1950s, a French diabetic scientist Jean Sterne found the hypoglycemic effect of metformin through the study of galegine. Then the drug was used in diabetic patients for the first time, and the results were published in 1957. UKPDS, which began from 1977 and ended in 1997 and was then followed up for 10?years, is the longest in the history of clinical trials and has a significant impact on practice and guidelines for prevention and treatment of diabetes mellitus. In this trial, metformin was found to reduce the risk of diabetic complications by 32%. In addition, it was proved for the first time that metformin can reduce blood glucose and protect against cardiovascular function, especially in obese patients. In 1994, metformin was approved by the US FDA for type 2 diabetes treatment. Currently, metformin has become the world’s most widely used antidiabetic drug.
Aiming at improving the stability of the absorption of metformin, chemists have also carried out a series of structural renovation and modification. Metformin activates with carbonyl, esters, chlorides, and aldehydes to form triazine compounds, with 1,3-diketone to produce pyrimidine compounds, and with disulfides to produce C-S coupling products, etc.

Использование

non-insulin dependent diabetes mellitus

Показания

Metformin (Glucophage) was used in Europe for many years before it was approved for use in the United States in 1995. Metformin is the only approved biguanide for the treatment of patients with NIDDM that are refractory to dietary management alone. Metformin does not affect insulin secretion but requires the presence of insulin to be effective. The exact mechanism of metformin’s action is not clear, but it does decrease hepatic glucose production and increase peripheral glucose uptake. When used as monotherapy, metformin rarely causes hypoglycemia.

Определение

ChEBI: Metformin is a member of the class of guanidines that is biguanide the carrying two methyl substituents at position 1. It has a role as a hypoglycemic agent, a xenobiotic, an environmental contaminant and a geroprotector. It is functionally related to a biguanide. It is a conjugate base of a metformin(1+).

Биологические функции

Metformin can lower free fatty acid concentrations by 10 to 30%. This antilipolytic effect may help to explain the reduction in gluconeogenesis through reduced levels of available substrate (65). When given as a monotherapy, metformin treatment does not lead to hypoglycemia, so it is better described as an antihyperglycemic agent rather than a hypoglycemic agent.

Механизм действия

The mechanism of action of biguanides is still not fully understood. Three major tissues have been identified as pharmacological sites of action: (1) the small intestinal wall, (2) the liver, and (3) peripheral tissues, mainly the skeletal muscle: 1. For the small intestine an inhibition of glucose absorption was described, however, this is, at least for metformin, of minor significance and not important for the blood glucose lowering effect. However, the intestinal glucose metabolization to lactate is stimulated and reduces the postprandial uptake of glucose by the liver. 2. Numerous studies have shown that biguanides inhibit hepatic gluconeogenesis and this may contribute to the blood glucose lowering effect, particularly in the fasting state. Again, metformin has probably less impact on  gluconeogenesis than phenformin and buformin. 3. In the peripheral tissues, metformin increases the glucose disposal and utilization particularly in the skeletal muscle, which is probably the major contribution to the blood glucose lowering activity. In vitro studies using cell cultures have shown that metformin potentiates insulin action. In vivo studies in animals and diabetic patients have demonstrated that metformin reduces insulin resistance, at least in obese individuals.

Клиническое использование

Metformin works best in patients with significant hyperglycemia and is often considered first-line therapy in the treatment of mild to moderate type II overweight diabetics who demonstrate insulin resistance. The United Kingdom Prospective Diabetes Study demonstrated a marked reduction in cardiovascular comorbidities and diabetic complications in metformintreated individuals. Metformin has also been used to treat hirsutism in individuals with polycystic ovarian syndrome and may enhance fertility in these women, perhaps by decreasing androgen levels and enhancing insulin sensitivity.

Профиль безопасности

Poison by subcutaneous and intraperitoneal routes. Mildly toxic by parenteral route. Experimental teratogenic effects. Mutation data reported. When heated to decomposition it emits toxic fumes of NOx

Метаболизм

Metformin is quickly absorbed from the small intestine. Bioavailability is from 50 to 60%, and the drug is not protein bound. Peak plasma concentrations occur at approximately 2 hours. The drug is widely distributed in the body and accumulates in the wall of the small intestine. This depot of drug serves to maintain plasma concentrations. Metformin is excreted in the urine, via tubular excretion, as unmetabolized drug with a half-life of approximately 2 to 5 hours; therefore, renal impairment as well as hepatic disease are contraindications for the drug.