Biguanides metabolism

Aromatic biguanides such as proguanil (181) have been found useful as antimalarial agents. Investigation of the metabolism of this class of drugs revealed that the active compound was in fact the triazine produced by oxidative cyclization onto the terminal alkyl group. The very rapid excretion of the active entity means that it cannot be used as such in therapy. Consequently, treatment usually consists in administration of either the metabolic precursor or, alternately, the triazine as some very insoluble salt to provide slow but continual release of drug. 

Helsby, N.A., Ward, S.A., Howells, R.E. and Breckenridge, A.M. (1990) in vitro metabolism of the biguanide antimalarials in human liver microsomes evidence for a role of the mephenytoin hydroxylase (P450 MP)... 

Adverse effect Lactic acidosis due to biguanides Dose-relation toxic effect Time-course time-independent Susceptibility factors genetic (slow phenformin metabolizers) age disease (impaired liver, kidney, or cardiac function, alcoholism)... 

Mechanism and susceptibility factors Biguanides in high doses inhibit the oxidation of carbohydrate substrates by affecting mitochondrial function. Anoxidative carbohydrate metabolism stimulates the production of lactate. High lactate production leads to lactic acidosis (type B) with a low pH (<6.95). Hyperlactatemia was common in patients taking buformin, even without alcoholism or impaired liver, kidney, or cardiac function (70). 

Metformin has a half-life of 1.5-3 hours, is not bound to plasma proteins, is not metabolized, and is excreted by the kidneys as the active compound. As a consequence of metformin s blockade of gluconeogenesis, the drug may impair the hepatic metabolism of lactic acid. In patients with renal insufficiency, biguanides accumulate and thereby increase the risk of lactic acidosis, which appears to be a dose-related complication. 

Biguanides Metformin -5.5 Not metabolized excreted by kidneys may be used alone or in combination with sulfonylureas... 

Proguanil is one of the antimalarial drugs most widely used for prophylactic purposes, usually in combination with chloroquine or atovaquone in malaria prophylaxis, and with atovaquone in malaria treatment (SEDA-21, 297). A biguanide, it is rapidly absorbed in standard doses and mainly excreted by the kidneys. Its antimalarial effect is due to its metabolite cycloguanU. However, its metabolism varies individually, and this is reflected in a variable degree of efficacy (SEDA-17, 328). 

Phenformin is 50% absorbed from the gastrointestinal tract. Its protein binding ability is very poor, which is 20%. Phenformin is distributed throughout the major organs and it is mainly metabolized in the liver by hydroxylation. On hydroxylation, it produces N-P-hydroxy-B-phenyl-ethyl biguanide as... 

Phenformin is the only biguanide to have been marketed in the United States and removed from the market by the US Food and Drug Administration (FDA) in 1977 because of its association with the development of lactic acidosis, a metabolic aberration that results in mortality in 50-75% of cases. Ethanol intake before the administration of phenformin therapeutic doses or excessive dose appears to predispose the patient to the development of lactic acidosis with a serious outcome. Phenformin and its other relative biguanides are still sold in European and other countries worldwide. 

Exogenous insulin or insulinotropic oral agents such as sulphonylureas are not suitable for improving insulin resistance. Non-insulinotropic hypoglycaemic medication such as biguanides and/or acarbose, however, is recommended if diet alone fails to achieve sufficient metabolic control. It is still controversial, however, whether the reduction of endogenous insulin also reduces the synthesis of islet amyloid polypeptide (IAPP) sufficiently to slow down the progression of NIDDM (Clark et al., 1987). 

In conclusion, it can be stated, that biguanides, preferably metformin, have been shown in innumerable clinical trials to be highly effective as antihyper-glycaemic drugs. Together with acarbose, they may be the first-choice drug for the treatment of obese hyperinsulinaemic, insulin resistant Type-II diabetics with dietary failure. They help to correct most of the unwanted aspects of the metabolic syndrome, which is felt to contribute most to the high mortality rate of NIDDM patients with heart disease. 

Wright JD, Helsby NA, Ward SA. The role of S-mephenytoin hydroxylase (CYP2C19) in the metabolism of the antimalarial biguanides. Br J Chn Pharmacol 1995 39 441-4. 

Metformin is slowly and incompletely absorbed and rapidly eliminated without hepatic metabolism. This pharmacokinetic profile may make drug accumulation and lactic acidosis less likely to occur with metformin than with other biguanides. Sales of the longer-acting biguanide phenformin (10), for instance, which is metabolized in the liver by aromatic... 

Moreover, the relative sensitivity of the tissues was in the same order as the relative sensitivity of the three species to the hypoglycemic action of the biguanides. In another investigation, a number of the effects of phenformin on metabolism in rat adipose tissue,— Inhibition of glucose oxidation and lipogenesis, both basal and insulin stimulated— were traced to an inhibition of pyruvate oxidation, presumably resulting from interference with electron transport. 

The suggestion that the biguanides potentiate the action of insulin by increasing the uptake of insulin by inuscle seems questionable. If this were the case, one would expect the effects of the biguanides on metabolism to parallel those of insulin, but in fact, they are usually the opposite. Insulin promotes glycogen deposition, lipogenesxs, and protein synthesis, all of which the biguanides oppose. 

Drug interactions with sulfonylureas and biguanides are common non-steroidal antiinflammatory drugs, warfarin, alcohol, monoamine oxidase inhibitors, some uricosurics, some antibacterials and some antifungals can interact with them. All increase the risk of hypoglycaemia. The mechanism is probably competition for metabolizing enzymes or displacement from plasma protein binding sites. 

---