PHARMACOKINETICS AND PHARMACODYNAMICS OF GLIPIZIDE AFTER ONCE-DAILY AND DIVIDED DOSES

Study Objective. To determine the pharmacokinetics and pharmacodynamic s of glipizide given as a single, oral, 20-mg dose, versus three diffe rent divided-dose regimens totaling 20 mg each. Design. Randomized (in order of dosing regimens), open-label, crossover study.Setting. Unive rsity medical center clinical research center. Patients. Six subjects with noninsulin-dependent diabetes mellitus. Interventions. Patients w ere studied on four separate occasions separated by at least 3 days. T he divided-dose regimens were designed to simulate delayed absorption of the drug over 2, 4, and 8 hours. Blood samples for measuring glipiz ide, glucose, and C-peptide were obtained over 24 hours. Measurements and Main Results. Glipizide peak concentrations and time to peak diffe red significantly with the dosage schedule; when smaller doses were ad ministered more often, peak concentrations were lower and more delayed . The mean values for area under the curve from time zero to infinity (range 7240.7-10,001.8 mu g . L(-1). hr(-1); 16,226-22,414 nmol . L(-1 ). hr(-1)), clearance (0.44-0.64 ml . min(-1). kg(-1); 0.07-0.11 ml . sec(-1). kg(-1)), post-distribution phase volume (0.17-0.25 L . kg(-1) ), and half-life (4.2-5.4 hrs) were not significantly different among regimens. Neither morning fasting glucose nor maximum and minimum time s and concentrations of glucose and C-peptide over 24 hours were stati stically different among regimens. Similarly, no significant differenc es were found in area under the concentration-time curve for glucose a nd C-peptide measured over 2.5 hours after each meal and from time zer o to 24 hours. Conclusions. The timing of a glipizide dose in relation to a meal and simulated delayed or prolonged absorption appear to hav e little influence on the drug's pharmacodynamic effects.