The effect of stress on the pharmacokinetics and pharmacodynamics of glibenclamide in diabetic rats

Optimal management of the diabetic patient includes normalization of glucose concentration. Attainment of this goal is difficult because stress 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 pharmacokinetics and dynamics of glibenclamide in normal and diabetic rats. In this respect, administration of glibenclamide (1.4 mg/kg, p.o.) significantly reduced the blood glucose level estimated after an intravenous challenge dose (4 ml/kg) of 50% dextrose. Peak drug effect occurred at about 2 h in the control on diabetic group and this effect was clearly evident over a 6 h period in the diabetic group. The stressed diabetic group showed consistently higher blood glucose level at all time points than the non-stressed diabetic controls. Stress was also associated with significant reductions in glibenclamide Cp-max and AUC0−8 and an increase in the Tmax. These results suggest that the response to glibenclamide in diabetics may be strongly modified by stress through a number of mechanisms. Changes in the bioavailability of the drug and activation of sympathetic nervous system and the hypothalamic-pituitary-adrenocortical axis are potential candidates. Further clinical and experimental studies in relevant models may, however, be needed to characterize fully and relate this effect to rational pharmacotherapy of type II diabetes.