rmin components of Glipizide and Metformin HCl Tablets 5 mg/500 mg were bioequivalent to coadministered GLUCOTROL and GLUCOPHAGE. Following administration of a single Glipizide and Metformin HCl Tablets 5 mg/500 mg tablet in healthy subjects with either a 20% glucose solution or a 20% glucose solution with food, there was a small effect of food on peak plasma concentration (C) and no effect of food on area under the curve (AUC) of the glipizide component. Time to peak plasma concentration (T) for the glipizide component was delayed 1 hour with food relative to the same tablet strength administered fasting with a 20% glucose solution. C for the Metformin component was reduced approximately 14% by food whereas AUC was not affected. Tfor the Metformin component was delayed 1 hour after food.
Glipizide
Gastrointestinal absorption of glipizide is uniform, rapid, and essentially complete. Peak plasma concentrations occur 1 to 3 hours after a single oral dose. glipizide does not accumulate in plasma on repeated oral administration. Total absorption and disposition of an oral dose was unaffected by food in normal volunteers, but absorption was delayed by about 40 minutes.
Metformin Hydrochloride
The absolute bioavailability of a 500 mg metformin Hydrochloride tablet given under fasting conditions is approximately 50% to 60%. Studies using single oral doses of metformin tablets of 500 mg and 1500 mg, and 850 mg 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 peak concentration and a 25% lower AUC in plasma and a 35-minute prolongation of time to peak plasma concentration 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.
Distribution
Glipizide
Protein binding was studied in serum from volunteers who received either oral or intravenous glipizide and found to be 98% to 99% one hour after either route of administration. The apparent volume of distribution of glipizide after intravenous administration was 11 liters, indicative of localization within the extracellular fluid compartment. In mice, no glipizide or metabolites were detectable autoradiographically in the brain or spinal cord of males or females, nor in the fetuses of pregnant females. In another study, however, very small amounts of radioactivity were detected in the fetuses of rats given labeled drug.
Metformin Hydrochloride
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. Metformin partitions into erythrocytes, most likely as a function of time. At usual clinical doses and dosing schedules of metformin, steady state plasma concentrations of metformin are reached within 24 to 48 hours and are generally <1 μg/mL. During controlled clinical trials, maximum metformin plasma levels did not exceed 5 μg/mL, even at maximum doses.
Metabolism and Elimination
Glipizide
The metabolism of glipizide is extensive and occurs mainly in the liver. The primary metabolites are inactive hydroxylation products and polar conjugates, and are excreted mainly in the urine. Less than 10% unch
