Effect of Combining Obtusifolin and Amlodipine on Their Antihypertensive Effects and its Potential Mechanism

Abstract BACKGROUND Both amlodipine and obtusifolin have been demonstrated to possess antihypertensive effects, which increases their potential to be combined. The interaction between amlodipine and obtusifolin was evaluated with in vivo rat models and in vitro liver microsome experiment, aiming to guide the clinical prescription of these two drugs. METHODS The antihypertensive effects of amlodipine with or without the combination of obtusifolin were evaluated in hypertension rat models established by abdominal aortic coarctation in male Sprague-Dawley rats. Pharmacokinetics and metabolic stability of amlodipine were assessed in rats and liver microsomes, respectively. The effect of obtusifolin on the activity of CYP3A4 was estimated in liver microsomes. RESULTS Obtusifolin significantly enhanced the antihypertensive effect of amlodipine (P < 0.01). The metabolism of amlodipine was suppressed by the coadministration of obtusifolin with increasing Cmax (P < 0.01), prolonging t1/2 (P < 0.01), and decreasing clearance rate (P < 0.001). In vitro results also confirmed the improving metabolic stability of amlodipine by obtusifolin. Obtusifolin showed a significant inhibitory effect on the activity of CYP3A4 in a concentration-dependent manner with the IC50 value of 15.13 μM. CONCLUSIONS Coadministration of amlodipine with obtusifolin induced increasing systemic exposure of amlodipine through inhibiting CYP3A4. Hypotension should be vigilant under their combination.