Pharmacology: Pharmacokinetics: Metformin: Absorption: After an oral dose of metformin hydrochloride tablet, maximum plasma concentration (Cmax) is reached in approximately 2.5 hours (tmax). Absolute bioavailability of a 500 mg or 850 mg metformin hydrochloride tablet is approximately 50-60% in healthy subjects. After an oral dose, the non-absorbed fraction recovered in faeces 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 recommended metformin doses and dosing schedules, steady state plasma concentrations are reached within 24 to 48 hours and are generally less than 1 microgram/ml. In controlled clinical trials, maximum metformin plasma levels (Cmax) did not exceed 5 microgram/ml, even at maximum doses. Food decreases the extent and slightly delays the absorption of metformin. Following oral administration of a 850 mg tablet, a 40% lower plasma peak concentration, a 25% decrease in AUC (area under the curve) and a 35 minute prolongation of the time to peak plasma concentration were observed. The clinical relevance of these findings is unknown.
Distribution and Plasma protein binding: 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 between 63-276 L.
Metabolism: 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.
Gliclazide: Single oral dose of Gliclazide, 40 to 120 mg results in a Cmax of 2.2 to 8 mg/l within 2 to 8 hours. Steady state concentrations are achieved after 2 days of administration of 40-120 mg of Gliclazide. Administration of Gliclazide with food reduces Cmax and delays Tmax. The volume of distribution is low due to extensive protein binding (85-97%). The half life of Gliclazide varies from 8.1-20.5 hours after single dose administration. Gliclazide is extensively metabolised to 7 metabolites predominantly excreted in the urine, the most abundant being the carboxylic acid derivative; 60-70% of the dose is excreted in the urine and 10-20% in the faeces.