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.

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Cytochrome P-450 3A4 (CYP3A4) and P-gp substrates exhibit poor bioavailability. Diltiazem, is a benzothiazepine derivative used in various cardiovascular conditions. It is a heart muscle and blood vessel relaxant that improves blood pumping to the heart and from the heart. It has low bioavailability because it is a substrate of CYP3A4 and P-gp. Hesperetin (a flavanone) inhibited CYP3A4 and P-gp in previous investigations. The major goal of this research was to see how hesperetin affected diltiazem pharmacokinetics (PK) in rats and employing everted intestinal sac. Male Wistar rats were given diltiazem (15 mg/kg) alone or in combination with hesperetin (12.5, 25, and 50 mg/kg) once daily for 15 days to hesperetin-pretreated animals. Blood samples were collected on the 1st day in single-dose PK study and on 15th day in multiple dosage PK studies. In vitro, diltiazem was incubated with rat everted intestinal sacs in the presence and absence of hesperetin and conventional P-gp blockers. Diltiazem C max , area under the curve, and half-life (T 1/2 ) rose two-fold in rats pretreated with Hesperetin compared to the diltiazem control group, although T max did not alter significantly. The value of Mean Residence Time increased by 37% to 47%. There has been a significant reduction in clearing and distribution rates. The results of an in vitro study showed that the transport of diltiazem was significantly increased in the presence of hesperetin and standard P-gp inhibitors. The current study found that hesperetin significantly increased diltiazem systemic absorption by inhibiting CYP3A4 and P-gp.

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Background Metoprolol is a substrate of CYP3A4, 2B6, CYP2D6, CYP2C9, and p-glycoprotein (p-gp). Hesperetin was reported as an inhibitor of cytochrome P-450 (CYP) enzymes and p-gp. The objective of this study was to investigate the effect of hesperetin on the pharmacokinetics of metoprolol in rats and in vitro models. In in vivo studies, male Wistar rats were treated with metoprolol (30 mg/kg) once a day for 15 consecutive days alone and in combination with hesperetin (25, 50, and 100 mg/kg). Blood samples were withdrawn from the tail vein on the 1st day in the single-dose pharmacokinetic study and on the 15th day in the repeated-dose pharmacokinetic study. In in vitro studies, metoprolol was incubated in the presence or absence of hesperetin and traditional p-gp inhibitors using rat-everted gut sacs. Reverse phase-high-performance liquid chromatography (RP-HPLC) was used to determine the amounts of metoprolol in the plasma and incubated samples (RP-HPLC). Results The Cmax, AUC, and half-life (t1/2) of metoprolol significantly increased by twofold compared to the metoprolol group in rats pre-treated with hesperetin. The clearance and volume of distribution both decreased significantly. Metoprolol transport was dramatically increased in the presence of hesperetin and quinidine (standard p-gp inhibitor) in in vitro study. Conclusion The present study results revealed that hesperetin significantly increased the absorption of metoprolol in rats and everted gut sacs in vitro might be due to the inhibition of CYP and p-gp.