Nh Nh

Metformin hydrochloride is a white to off-white crystalline compound with the molecular formula of C4HnN5• HCl and a molecular weight of 165.63. Metformin hydrochloride is freely soluble in water and is practically insoluble in acetone, ether, and chloroform. The pKa of metformin is 12.4. The pH of a 1% aqueous solution of metformin hydrochloride is 6.68.

2.3. Pharmacology

Metformin is an antihyperglycemic agent that improves glucose tolerance in patients with type II diabetes, lowering both basal and postprandial plasma glucose. Its pharmacologic mechanisms of action are different from other classes of oral antihyperglycemic agents. Metformin decreases hepatic glucose production, decreases intestinal absorption of glucose, and improves insulin sensitivity by increasing peripheral glucose uptake and utilization. Unlike sulfonylureas, metformin does not produce hypoglycemia in either patients with type II diabetes or normal subjects (except in special circumstances) and does not cause hyper-insulinemia. With metformin therapy, insulin secretion remains unchanged while fasting insulin levels and daylong plasma insulin response may actually decrease.

2.4. Pharmacokinetics

2.4.1. Absorption and Bioavailability

The absolute bioavailability of a metformin 500-mg tablet given under fasting conditions is approximately 50% to 60%. Studies using single oral doses of metformin 500 to 1500 and 850 to 2550 mg indicate that there is a lack of dose proportionality with increasing doses, which is due to decreased absorption rather than an alteration in elimination. Food decreases the extent of and slightly delays the absorption of metformin, as shown by approximately a 40% lower mean peak plasma concentration (Cmax), a 25% lower area under the plasma concentration versus time curve (AUC), and a 35-minute prolongation of time to peak plasma concentration (imax) following administration of a single 850-mg tablet of metformin with food, compared to the same tablet strength administered fasting. The clinical relevance of these decreases is unknown. Peak plasma levels are approximately 0.6, 1.1, 1.4, and 1.8 |ig/mL for 500, 1000, 1500, and 2000 mg once-daily doses, respectively.

2.4.2. Distribution

The apparent volume of distribution (V/F) of metformin following single oral doses of 850 mg averaged 654 + 358 L. Metformin is negligibly bound to plasma proteins, in contrast to sulfonylureas, which are more than 90% protein bound. Metformin partitions into erythrocytes, most likely as a function of time. At usual clinical doses and dosing schedules, steady state plasma concentrations of metformin are reached within 24 to 48 hours and are generally ! 1 mg/mL. During controlled clinical trials, maximum metformin plasma levels did not exceed 5 mg/mL, even at maximum doses.

2.4.3. Metabolism and 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. Renal clearance is approximately 3.5 times greater than creatinine clearance, which indicates that tubular secretion is the major route of metformin elimination. Following oral administration, approximately 90% of the absorbed drug is eliminated via the renal route within the first 24 hours, with a plasma elimination half-life (^(i/2)e) of approximately 6.2 hours. In blood, t(i/2)e is approximately 17.6 hours, suggesting that the erythrocyte mass may be a compartment of distribution.

2.5. Therapeutic Uses

Metformin is indicated as an adjunct to diet and exercise to improve glycemic control in patients with type II diabetes. Metformin may be used concomitantly with a sulfonylurea or insulin to improve glycemic control in adults (17 years of age and older).

2.6. Adverse Events

Most commonly reported adverse effects for metformin are diarrhea, nausea/vomiting, flatulence, asthenia, indigestion, abdominal discomfort, and headache. And less common adverse reactions were reported as abnormal stools, hypoglycemia, myalgia, light-headedness, dyspnea, nail disorder, rash, sweating increased, taste disorder, chest discomfort, chills, flu syndrome, and palpitation.

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