Drug-drug interaction between danshensu and irbesartan and its potential mechanism

Abstract

To uncover the effect of danshensu on irbesartan pharmacokinetics and its underlying mechanisms.To investigate the effect of danshensu on the pharmacokinetics of irbesartan, Sprague-Dawley rats (n = 6) were orally administered 30 mg/kg irbesartan alone (control group) or pre-treated with 160 mg/kg danshensu (experimental group). The effect of danshensu on the metabolic stability of irbesartan in RLMs was examined by LC-MS/MS method. The effect of danshensu on CYP2C9 activity was also determined.Danshensu markedly increased the AUC_(0-t) (9573 ± 441 vs. 16157 ± 559 μg/L*h) and C_max (821 ± 24 vs. 1231 ± 44 μg/L) of irbesartan. Danshensu prolonged the t_1/2 (13.39 ± 0.98 vs. 16.04 ± 1.21 h) and decreased the clearance rate (2.27 ± 0.14 vs. 1.19 ± 0.10 L/h/kg) of irbesartan. Danshensu enhanced the metabolic stability of irbesartan in vitro with prolonged t_1/2 (36.34 ± 11.68 vs. 48.62 ± 12.03 min) and reduced intrinsic clearance (38.14 ± 10.24 vs. 28.51 ± 9.06 μL/min/mg protein). Additionally, the IC₅₀ value for CYP2C9 inhibition by danshensu was 35.74 μM.Danshensu enhanced systemic exposure of irbesartan by suppressing CYP2C9. The finding can also serve as a guidance for further investigation of danshensu-irbesartan interaction in clinical practice.

Keywords: CYP2C9; Irbesartan; danshensu; drug-drug interaction; metabolism.