Pharmacokinetic interaction between pachymic acid and tacrolimus and its potential mechanisms in rats

Tacrolimus is a novel immunosuppressor for its significant anti-inflammation and immune activity, which would induce hyperglycaemia, increasing its combination with hypoglycaemic drugs.Pachymic acid has been demonstrated to possess the pharmacological activity of anti-hyperglycaemia. Tacrolimus combining pachymic acid was investigated, aiming to guide the prescription of patients taking tacrolimus.In rats, 1.2 mg/kg tacrolimus was combined with three dosages of pachymic acid (50, 100, and 200 mg/kg) with the single dosage of tacrolimus as control. The blood glucose of rats with different medications was monitored and the pharmacokinetic changes of tacrolimus were assessed. Tacrolimus significantly increased the blood glucose of rats. Pachymic acid increased C_max, AUC, and t_1/2 and reduced the clearance rate of tacrolimus in rats, and the effects were promoted by its increasing dosage. The metabolic stability of tacrolimus in rat liver microsomes was also improved by pachymic acid, both of which enhanced its hyperglycaemic effect in rats. Significant inhibition of CYP3A1/2 by pachymic acid was observed with the IC₅₀ value of 12.25μM.Co-administration of tacrolimus with pachymic acid induced adverse interactions, suppressing the metabolism and enhancing the hyperglycaemic effect of tacrolimus through inhibiting CYP3A1/2.