Naringenin has an inhibitory effect on rivaroxaban in rats both in vitro and in vivo

Food-drug interactions are reported to have some impacts on the pharmacokinetics and pharmacodynamics of various oral drugs. To better understand the effects of naringenin, one natural product in many fruits, on the pharmacokinetics of rivaroxaban, drug-drug interactions (DDIs) between naringenin and rivaroxaban in vitro were investigated in Sprague-Dawley (SD) rat liver microsomes. For the DDIs in vivo, 12 male SD rats were randomly divided into the experimental group and the control group with six rats in each group. Rats in the experimental group were pre-treated with naringenin (10 mg/kg/day) for 2 weeks before the administration of rivaroxaban (10 mg/kg) by oral gavage, while the rats in the control group were given rivaroxaban (10 mg/kg) only once. The plasma concentration of rivaroxaban in rats was then measured by UPLC-MS/MS. In vitro data indicated that naringenin could decrease the metabolic clearance rate of rivaroxaban with the IC50 value of 38.89 mu M, and exhibited a mixed inhibition to rivaroxaban (Ki =54.91 mu M, aKi =73.33 mu M, a = 0.74). In vivo data in rats revealed that as compared with that of the control group, the AUC((0-t)) value of rats in the experimental group was increased from 2406.28 +/- 519.69 mu g/h/L to 4005.04 +/- 1172.76 mu g/h/L, the C-max value was increased from 310.23 +/- 85.76 mu g/L to 508.71 +/- 152.48 mu g/L, and the V-z/F and CLz/F were decreased from 23.03 +/- 4.81 L/kg to 16.2 +/- 8.42 L/kg, 4.26 +/- 0.91 L/h/kg to 2.57 +/- 0.73 L/h/kg, respectively. These data indicated that naringenin had an inhibitory effect on the pharmacokinetics of rivaroxaban in rats, suggesting that the DDIs between naringenin and rivaroxaban might occur when they were co-administered in the clinic.