COMPARISON OF PHARMACOKINETICS AND PHARMACODYNAMICS OF SHORT-TERM ANDLONG-TERM GLYBURIDE THERAPY IN NIDDM

OBJECTIVE - To examine the pharmacokinetics and pharmacodynamics of gl yburide after single- and multiple-dose administration in patients wit h type II diabetes. RESEARCH DESIGN AND METHODS - Twenty patients with type II diabetes between 40 and 70 years of age participated in the s tudy. A 24-h pharmacokinetic evaluation including a 4-h Sustacal toler ance test was conducted before instituting glyburide therapy (baseline ), after the first 2.5-mg test dose of glyburide and at weeks 6 and 12 of chronic glyburide therapy. Glyburide doses were titrated with a ta rget goal of achieving a fasting plasma glucose of less than or equal to 7.8 mmol/l or to reach maximum daily doses of 20 mg. RESULTS - A si gnificant prolongation in the elimination half-life (t(1/2): week 0, 4 .0 +/- 1.9 h; week 6, 13.7 +/- 10.5 h; and week 12, 12.1 +/- 8.2 h) an d an increased volume of distribution of glyburide was observed during chronic dosing. These results strongly suggest possible drug accumula tion. No differences in pharmacokinetic parameters were noted between evaluations at week 6 or week 12. Changes in pharmacodynamic response of glucose, insulin, and C-peptide to chronic glyburide therapy were o bserved. Glyburide therapy significantly reduced plasma glucose levels at weeks 6 and 12 (percent changes in AUCO(0-->4.glucose) from baseli ne: week 0, -3 +/- 11%; week 6, -29 +/- 13%; and week 12, -26 +/- 19%) . Pancreatic insulin secretion was acutely enhanced and maintained dur ing long-term therapy. Responsiveness to therapy as assessed by the ra tio of AUC(0-->4.glucose):AUC(0-->4.C-peptide) was significantly impro ved at all weeks compared with baseline. No pharmacodynamic response d ifferences were observed between the week 6 and the week 12 evaluation s. CONCLUSIONS - This study demonstrates that significant differences in glyburide pharmacokinetics and pharmacodynamics exist between singl e-dose and steady-state conditions. These differences support the need for careful dosage titration of glyburide to achieve a desired therap eutic response in patients with type II diabetes.