Drug-drug interaction between pachymic acid and repaglinide in rats and its potential mechanism

Abstract

Both repaglinide and pachymic acid are useful for reducing blood glucose, but the drug interactions between them are not known. This study aimed to explore the effect of pachymic acid on the pharmacokinetics of repaglinide in rats and to elucidate its mechanism. The effects of pachymic acid (5 and 10 mg/kg) on the pharmacokinetics of repaglinide (0.5 mg/kg) were investigated in Sprague-Dawley rats (n = 6) with a single dose of repaglinide as a control. LC-MS/MS was used to determine the plasma concentration of repaglinide. Furthermore, the effect of pachymic acid on the metabolic stability of repaglinide and CYP3A4 activity was assessed in rat liver microsomes (RLMs). The co-administration of repaglinide and pachymic acid caused considerable changes in the pharmacokinetics of repaglinide, as shown by an increase in Cmax, t1/2, and AUC(0-t), and a decrease in CLz/F. The effect of pachymic acid was enhanced with increasing concentration. In vitro, pachymic acid showed a significant improvement of the metabolic stability of repaglinide in RLMs and inhibited the activity of CYP3A4. Co-administration of repaglinide with pachymic acid increased the systemic exposure of repaglinide and improved its metabolic stability in rats, which was mediated by CYP3A4. The results of animal studies cannot be directly applied to clinical practice, but concomitant administration of repaglinide and pachymic acid should be avoided or monitored until interaction studies are performed in humans.