Effect of naringenin on the pharmacokinetics of metoprolol succinate in rats.

The aim of the present study was to investigate the effect of naringenin (4,5,7-trihydroxy flavonone) on the pharmacokinetics of metoprolol, a substrate of Cytochrome P-450 3A4 (CYP3A4), CYP2C9, and CYP2D6 in rats.Male Wistar rats were treated orally with metoprolol (30 mg/kg) alone and in combination with naringenin (25, 50, and 100 mg/kg) once daily for 15 consecutive days.The plasma concentrations of metoprolol were determined using Reverse Phase-High Performance Liquid Chromatography (RP-HPLC) on the 1st day in single-dose pharmacokinetic (PK) study (SDS) and on the 15th day in multiple dosing PK studies (MDS).Compared to the metoprolol control group, the Cmax, AUC, and half-life (T1/2) of metoprolol increased in rats pre-treated with naringenin, while there was no significant change in Tmax. There is a significant decrease in clearance and volume of distribution.The present study results revealed that naringenin significantly enhanced the Cmax, AUC, MRT, t1/2, and decreased the clearance of metoprolol possibly through the inhibition of CYP enzymes involved in the metabolism of metoprolol.

Pharmacokinetic interaction study between flavanones (hesperetin, naringenin) and rasagiline mesylate in wistar rats.

Cytochrome P-450 (CYP) enzymes and P-glycoprotein (P-gp) play an important role in the oral bioavailability and first-pass-metabolism (FPM) of many drugs. Rasagiline is a selective, monoamine oxidase-B inhibitor and it undergoes significant FPM in the liver prior to excretion by CYP1A2. Hesperetin and naringenin are naturally occurring flavanones and are reported as modulators of CYP enzymes and P-gp. The objective of the present investigation was to evaluate the effect of hesperetin and naringenin on the pharmacokinetics (PK) of rasagiline in rats. Rats were treated orally with rasagiline (2 mg/kg) alone and co-administered with hesperetin and naringenin (12.5 and 25 mg/kg) for 15 consecutive days. Blood samples were collected from tail vein on the 1st day in a single dose PK study (SDS) and on 15th day in the multiple dose PK study (MDS). Hesperetin and naringenin co-administration significantly enhanced the area under the curve (AUC), maximum plasma concentration (Cmax) and elimination half life (t1/2) of rasagiline with a concomitant reduction in clearance (CL/F) in both SDS and MDS. Rasagiline concentrations were significantly increased when co-administered with hesperetin and naringenin in the brain. No significant difference was found in rasagiline transport from mucosal to serosal side in the presence of hesperetin and naringenin ex vivo (rat everted gut sacs used). Our findings suggested that hesperetin and naringenin enhanced the systemic exposure of rasagiline might be through the inhibition of CYP1A2 but not P-gp. Further studies are needed on CYP1A2 and P-gp over expressed cells to confirm this interaction at cellular level.