Abstract

Purpose:To study the in vitro metabolism of CPU0213 in rat liver microsomes, and explore changes in the metabolism of CPU0213 by CYP450 3A under oxidative stress. Methods: An in vitro incubation of liver microsomes was carried out and RP-HPLC was used to determine changes in the concentrations of CPU0213 among 1, a normal group (microsomes +CPU0213); 2, a ketoconazole (ket) group (microsomes +CPU0213 + ket); 3, a hydrogen peroxide (H₂O₂) group (microsomes + CPU0213 + ket + H₂O₂); 4, an isoproterenol (ISO) group (microsomes + CPU0213 + ket + ISO) at 30 and 60 min respectively. Results: Ket specifically inhibited the activity of CYP3A, resulting in a reduction in the metabolic rate of CPU0213 compared with the normal group. The action of hydrogen peroxide or isoproterenol, which induces oxidative stress, antagonized the inhibition of CYP3A by ket, resulting in a significant reversal of metabolic rate of CPU0213 compared with the ket group. Conclusion: CYP3A is induced in liver microsomes in vitro under oxidative stress, which causes an increase in enzymatic activity to reverse the metabolic inhibition of the endothelin receptor antagonist CPU0213 by ket. Thus, oxidative stress may cause adverse reactions by inducing CYP450 3A activity.


Keywords:  CYP450 3A   Oxidative stress   Drug enzyme induction