Pharmacokinetic study on the interaction between succinic acid and irbesartan in rats and its potential mechanism

Context Succinic acid and irbesartan are commonly used drugs in cardiovascular disease treatment. The interaction might occur during their co-administration, which was still unclear. Objective To reveal the effect of succinic acid on the metabolism of irbesartan and its potential mechanism. Materials and methods The Sprague-Dawley rats (n = 6) were treated with a single dose of 30 mg/kg irbesartan (control) or the co-administration with the pre-treatment of 200 mg/kg succinic acid for 7 d. The effect of succinic acid on the metabolic stability and the activity of CYP2C9 was evaluated in rat liver microsomes. Results Succinic acid increased the AUC (5328.71 +/- 959.31 mu g/L x h vs. 3340.23 +/- 737.75 mu g/L x h) and prolonged the half-life of irbesartan (from 12.79 +/- 0.73 h to 20.59 +/- 6.35 h). The T (max) (2.83 +/- 0.75 h vs. 3.83 +/- 1.10 h) and clearance rate (3.46 +/- 1.13 L/h/kg vs. 6.91 +/- 1.65 L/h/kg) of irbesartan was reduced by succinic acid. Consistently, succinic acid improved the metabolic stability (half-life from 23.32 +/- 3.46 to 27.35 +/- 2.15 min, intrinsic clearance rate from 59.43 +/- 6.12 to 50.68 +/- 5.64 mu L/min/mg protein). Succinic acid was also found to inhibit the activity of CYP2C9 with the IC50 value of 13.87 mu M. Discussion and conclusions Succinic acid increased the system exposure of irbesartan via inhibiting CYP2C9. The experiment design of this study also provides a reference for the further validation of this interaction in humans.