THE INFLUENCE OF MULTIPLE DOSING AND AGE ON THE PHARMACOKINETICS AND PHARMACODYNAMICS OF GLIPIZIDE IN PATIENTS WITH TYPE-II DIABETES-MELLITUS

Objectives. To determine the pharmacokinetics and pharmacodynamics of glipizide after a single dose and 12 weeks of dosing in patients with type II diabetes mellitus, and evaluate the influence of aging. Design . Comparison of single and multiple doses of glipizide. Setting. Unive rsity-affiliated outpatient internal medicine clinic and diabetes rare unit. Patients. Twenty patients (11 men, 9 women, mean age 55.2 +/- 9 .9 yrs) with type II diabetes mellitus who were currently receiving or al hypoglycemic agents or were hyperglycemic with diet. Interventions. A 24-hour pharmacokinetic evaluation of glipizide was assessed after a 5-mg dose at the start of therapy and after 12 weeks of therapy. Pha rmacokinetic parameters were assessed using compartmental population a nalysis techniques. Glipizide pharmacodynamic evaluation was assessed by serum glucose, insulin, and C-peptide responses during a 4-hour Sus tacal tolerance test performed at baseline before instituting glipizid e therapy, with the first 5-mg dose, and at week 12 of therapy Glipizi de dosages were titrated to a targeted goal of fasting plasma glucose of 7.8 mmol/L or less or to reach maximum daily doses of 40 mg. Measur ements and Main Results. No significant differences in time to peak co ncentration, apparent volumes of distribution for the central and peri pheral compartments, apparent oral clearance from the central compartm ent, distributional clearance between the;central and peripheral compa rtments, or terminal elimination half-life were observed with a single dose and long-term dosing. The mean +/- SD, terminal elimination half -lives were 9.6 +/- 5.6 and 9.35 +/- 4.6 hours after a single dose and 12 weeks, respectively: Fasting plasma glucose concentrations decreas ed from 12.3 +/- 3.6 mmol/L before the first dose of glipizide to 9.2 +/- 1.7 mmol/L after 12 weeks of treatment. The values for area under the serum concentration-time curve from zero to 4 hours for glucose (A UC(0-4.glucose)) were significantly reduced at week 12 (baseline 49.8 +/- 15.6, week 12 37.8 +/- 9.8 mmol/L/hr). Glipizide provoked an incre ase in serum insulin and C-peptide concentrations (AUC(0-4.insulin): b aseline 698 +/- 327, single dose 954 +/- 461, long-term dosing 945 +/- 600 pmol/L/hr). No significant change in insulin response cs as obser ved between single and multiple doses. No age-related differences in t he pharmacokinetic parameters or the pharmacodynamic responses of glip izide were observed. Conclusions, Long-term dosing and aging have litt le effect on the pharmacokinetic profile of glipizide. In addition, gl ipizide stimulates insulin secretion to a similar extent following glu cose challenge after a single dose and long-term administration.