THE EFFECT OF STRESS ON THE PHARMACOKINETICS AND PHARMACODYNAMICS OF GLIBENCLAMIDE IN DIABETIC RATS

Optimal management of the diabetic patient includes normalization of g lucose concentration. Attainment of this goal is difficult because str ess has long been shown to have a major effect on metabolic activity. The aim of this study was to assess the effect of stress on the pharma cokinetics and dynamics of glibenclamide in normal and diabetic rats. In this respect, administration of glibenclamide (1.4 mg/kg, p.o.) sig nificantly reduced the blood glucose level estimated after an intraven ous challenge dose (4 ml/kg) of 50% dextrose. Peak drug effect occurre d at about 2 h in the control on diabetic group and this effect was cl early evident over a 6 h period in the diabetic group. The stressed di abetic group showed consistently higher blood glucose level at all tim e points than the nonstressed diabetic controls. Stress was also assoc iated with significant reductions in glibenclamide Cp-max and AUC(0-in finity) and an increase in the T-max. These results suggest that the r esponse to glibenclamide in diabetics may be strongly modified by stre ss through a number of mechanisms. Changes in the bioavailability of t he drug and activation of sympathetic nervous system and the hypothala mic-pituitary-adrenocortical axis are potential candidates. Further cl inical and experimental studies in relevant models may, however, be ne eded to characterize fully and relate this effect to rational pharmaco therapy of type II diabetes.