Rhea Metformin Hydrochloride Mechanism of Action

Pharmacology: Pharmacodynamics: Metformin is a biguanide with antihyperglycemic effects, lowering both basal and postprandial plasma glucose. It does not stimulate insulin secretion and therefore does not produce hypoglycemia.
Metformin may act via 3 mechanisms: (1) reduction of hepatic glucose production by inhibiting gluconeogenesis and glycogenolysis, (2) increasing insulin sensitivity in muscles, improving peripheral glucose uptake and utilization and (3) delay of intestinal glucose absorption.
Metformin stimulates intracellular glycogen synthesis by acting on glycogen synthase. Metformin increases the transport capacity of all types of membrane glucose transporters (GLUT).
In clinical studies, use of metformin was associated with either a stable body weight or modest weight loss.
In humans, independently of its action on glycemia, metformin has favorable effects on lipid metabolism. This has been shown at therapeutic doses in controlled, medium- term or long-term clinical studies: metformin reduces total cholesterol, LDL cholesterol and triglyceride levels.
Pharmacokinetics: Absorption: After an oral dose of metformin, maximum plasma concentration (C_max) is reached in 2.5 hours (T_max). Absolute bioavailability of a 500 mg or 850 mg metformin tablet is approximately 50-60% in healthy subjects. After an oral dose, the non-absorbed fraction recovered in feces was 20-30%.
After oral administration, metformin absorption is saturable and incomplete. It is assumed that the pharmacokinetics of metformin absorption is non-linear.
At the usual metformin doses and dosing schedules, steady state plasma concentrations are reached within 24 to 48 hours and are generally less than 1 μg/mL. In controlled clinical trials, maximum metformin plasma levels (C_max) did not exceed 4 μg/mL, even at maximum doses.
Food decreases the extent and slightly delays the absorption of metformin. Following administration of a dose of 850 mg, a 40% lower plasma peak concentration, a 25% decrease in AUC (area under the curve) and a 35 minute prolongation in the time to peak plasma concentration were observed. The clinical relevance of these decreases is unknown.
Distribution: Plasma protein binding is negligible. Metformin partitions into erythrocytes. The blood peak is lower than the plasma peak and appears at approximately the same time. The red blood cells most likely represent a secondary compartment of distribution. The mean volume of distribution (Vd) ranged from 63 to 276 L.
Metabolism: Metformin is excreted unchanged in the urine. No metabolites have been identified in humans.
Elimination: Renal clearance of metformin is > 400 mL/min, indicating that metformin is eliminated by glomerular filtration and tubular secretion. Following an oral dose, the apparent terminal elimination half-life is approximately 6.5 hours.
When renal function is impaired, renal clearance is decreased in proportion to that of creatinine and thus the elimination half - life is prolonged, leading to increased levels of metformin in plasma.
A randomized, open-label bioequivalence study in 16 healthy volunteers showed, on the basis of C_max and AUC determinations, that one tablet of metformin 1 gram can replace two tablets of metformin 500 mg.
The relative bioavailability of metformin 1 gram compared to metformin 500 mg tablets is 92.6% for AUC and 88% for C_max.
Toxicology: Preclinical Safety Data: Preclinical safety data revealed no special hazard for humans based on conventional studies on safety, pharmacology, repeated dose toxicity, genotoxicity, on carcinogenic potential, toxicity in reproduction.