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Valsartan is a potent, orally active non-peptide tetrazole derivative and selectively inhibits angiotensin II receptor type 1 which causes reduction in blood pressure and is used in treatment of hypertension. The risk of heart disease mortality decreased significantly as flavonoid intake increased. Interestingly, the flavonoid-containing foods contain a high amount of Quercetin. The objective of this study was to evaluate the influence of quercetin on the pharmacokinetics of valsartan. In vivo studies were performed on rats. Rats were treated with quercetin (10 mg/kg) and valsartan (10 mg/kg), blood samples were collected at 1, 1.5, 2, 2.5, 3, 3.5, 4, 6 and 8 h. Plasma concentration of valsartan was estimated by Reverse Phase (RP-HPLC). Quercetin significantly increases the plasma concentration of valsartan and peak concentration (70.45 µg/mL) was achieved at 3.5 h. In vitro studies were performed on rat intestinal everted sacs. The transport of valsartan from serosal side to mucosal side decreased from 53.12 ± 1.27 to 40.15 ± 0.45 µg/mL in the presence of quercetin and from 53.12 ± 1.27 to 28.68 ± 0.31 µg/mL in the presence of verapamil (standard P-glycoprotein (P-gp) inhibitor) at 120 min. Verapamil is a potent P-gp and CYP3A4 inhibitor. Quercetin is a P-gp inhibitor and may be an inhibitor of CYP3A4. The simultaneous administration of quercetin significantly increases the intestinal absorption and decreases the efflux of valsartan. The observed effect may be beneficial to develop oral valsartan dosage forms using safe P-gp inhibitor (quercetin) to improve its oral bioavailability.

The aim of this study was to investigate the effect of naringenin on the pharmacokinetics (PK) of felodipine in rats and membrane permeability across rat everted gut sacs in vitro. Rats were simultaneously co-administered with felodipine 10 mg/kg, p.o. and naringenin (25, 50 and 100 mg/kg, p.o.) for 15 consecutive days. Rats of the control groups received the corresponding volume of vehicle. Blood samples were withdrawn from retro-orbital plexus on first day in single dose PK study (SDS) and on 15th day in multiple dosing PK study (MDS). The PK parameters were calculated using Thermo kinetica. The co-administration of naringenin significantly elevated the Cmax and increased the AUCtotal of felodipine in dose-dependent manner. The Cmax of felodipine was increased from 173.25 ± 14.65 to 275.61 ± 44.62 and 223.26 ± 26.35 to 561.32 ± 62.53 ng/mL in SDS and MDS, respectively, at the dose of naringenin 100 mg/kg. The AUCtotal of felodipine was significantly (p < 0.001) increased from 2050.48 ± 60.57 to 3650.22 ± 78.61 and 3276.51 ± 325.61 to 7265.25 ± 536.11 (ng/mL/h) in SDS and MDS, respectively. The permeability of felodipine was increased in presence of naringenin and ritonavir (standard P-glycoprotein (P-gp) and Cytochrome P450 (CYP)3A4 inhibitor). Felodipine is a substrate of CYP3A4, and naringenin was reported to be a modulator of P-gp and CYP3A4. These results suggest that naringenin significantly increased the Cmax and AUC of felodipine is due to P-gp and CYP3A4 inhibition.

The aim of present study was to investigate the effects of apigenin and rutin on the pharmacokinetics of paclitaxel after oral administration of paclitaxel with apigenin and rutin to rats. Paclitaxel (40 mg/kg) was administered orally alone and in combination with apigenin and rutin (10, 20, and 40 mg/kg) for 15 consecutive days. In the single-dose pharmacokinetic study (SDS), blood samples were collected on 1st day whereas on 15th day in the multiple-dose pharmacokinetic study (MDS). The plasma concentrations of paclitaxel were increased dose-dependently in the combination of apigenin and rutin compared to that of paclitaxel control in SDS and MDS (p < 0.01). The areas under the plasma concentration-time curve (AUC) and the plasma peak concentrations (C max) of paclitaxel with apigenin and rutin were significantly higher (p < 0.01) than that of the control. The AUCs and C max of paclitaxel were increased with apigenin and rutin in the dose-dependent manner. The half-life (t 1/2) was significantly longer than that of the control. Non-everted sacs were filled with paclitaxel 100 μM in the presence and absence of verapamil (50 μM), apigenin, and rutin (50, 100 μM) and incubated at 37 ºC for 60 min. The absorption of paclitaxel was increased in the presence of apigenin, rutin, and verapamil, a typical P-glycoprotein and Cyp3A4 inhibitor. If these results are confirmed in humans in a clinical setting, the paclitaxel dose should be adjusted when it is given concomitantly with apigenin and rutin.