The purpose of the present study was to assess the effect of resveratrol (RSV) pretreatment on CYP3A4 enzyme activity and pharmacokinetics of carbamazepine (CBZ) in healthy human volunteers. The open-label, two period, sequential study was conducted in 12 healthy human volunteers. A single dose of RSV 500 mg was administered once daily for 10 days during treatment phase. A single dose of CBZ 200 mg was administered during control and after treatment phases under fasting conditions. The blood samples were collected after CBZ dosing at predetermined time intervals and analyzed by LC-MS/MS. In comparison with the control, RSV pretreatment significantly enhanced maximum plasma concentration (Cmax ), area under the curve (AUC), and half life (t1/2 ) and significantly decreased apparent oral clearance (CL/F) and apparent volume of distribution (Vd/F), while there was no significant change observed in time to reach maximum concentration (tmax ) and elimination rate constant (kel ) of CBZ. Furthermore, RSV pretreatment significantly decreased metabolite to parent (CBZE/CBZ) ratios of Cmax and AUC and significantly increased CBZE/CBZ ratios of CL/F and Vd/F, indicating the reduced formation of CBZE to CBZ. The results suggest that the altered CYP3A4 enzyme activity and pharmacokinetics of CBZ might be attributed to RSV-mediated inhibition of CYP3A4 enzyme. Thus, there is a potential pharmacokinetic interaction between RSV and CBZ including other CYP3A4 substrates.

The results suggest that altered pharmacokinetics and enhanced bioavailability of FEX might be attributed to PIP-mediated inhibition of P-gp drug efflux. Therefore, intake of PIP or dietary supplements containing PIP may potentially enhance the absorption or bioavailability of P-gp substrate drugs in addition to FEX.

The results suggest that altered pharmacokinetics of CHZ might be attributed to quercetin-mediated inhibition of CYP2E1 enzyme. Further, the inhibition of CYP2E1 by quercetin may represent a novel therapeutic approach for minimizing the ethanol-induced CYP2E1 enzyme activity and results in reduced hepatotoxicity of ethanol.

The purpose of the present study was to investigate the effect of resveratrol (RSV) pretreatment on CYP2E1 enzyme activity and pharmacokinetics of chlorzoxazone (CHZ) in healthy human volunteers. The open-label, two period, sequential study was conducted in 12 healthy human volunteers. A single dose of RSV 500 mg was administered once daily for 10 days during treatment phase. A single dose of CHZ 250 mg was administered during control and after treatment phases under fasting conditions. The blood samples were collected after CHZ dosing at predetermined time intervals and analyzed by HPLC. RSV pretreatment significantly enhanced the maximum plasma concentration (Cmax), area under the curve (AUC) and half life (T1/2) and significantly decreased elimination rate constant (Kel), apparent oral clearance (CL/F) and apparent volume of distribution (Vd/F) of CHZ as compared to that of control. In addition, RSV pretreatment significantly decreased the metabolite to parent (6-OHCHZ/CHZ) ratios of Cmax, AUC and T1/2 and significantly increased the Kel ratio of 6-OHCHZ/CHZ, which indicated the reduced formation of CHZ to 6-OHCHZ. The results suggest that the altered CYP2E1 enzyme activity and pharmacokinetics of CHZ might be attributed to RSV mediated inhibition of CYP2E1 enzyme. Thus, there is a potential pharmacokinetic interaction between RSV and CHZ. The inhibition of CYP2E1 by RSV may provide a novel approach for minimizing the hepatotoxicity of ethanol.

The purpose of the present study was to assess the effect of resveratrol (RSV) treatment on the pharmacokinetics of diclofenac (DIC) in healthy human volunteers. The open-label, two period, sequential study was conducted in 12 healthy human volunteers. A single dose of RSV 500 mg was administered daily for 10 days during treatment phase. A single dose of DIC 100 mg was administered during control and after treatment phases under fasting conditions. The blood samples were collected after DIC dosing and analyzed by HPLC. Treatment with RSV significantly enhanced maximum plasma concentration (Cmax) (1.73 to 2.91 µg/mL), area under the curve (AUC) (5.05 to 9.95 g h/mL), half life (T1/2) (1.12 to 1.76 h) and significantly decreased elimination rate constant (Kel ) (0.71 to 0.41 h(-1)), apparent oral clearance (CL/F) (14.58 to 6.48 L/h) of DIC as compared to control. The geometric mean ratios for Cmax, AUC, T1/2, Kel and CL/F of DIC were 1.75, 2.12, 1.65, 0.61 and 0.47, respectively were outside the limits of 0.8-1.25, which indicates clinically significant interaction between DIC and RSV. The results suggest that the altered pharmacokinetics of DIC might be attributed to RSV mediated inhibition of CYP2C9 enzyme. Therefore, combination therapy of DIC along with RSV may represent a novel approach to reduce dosage and results in reduced gastrointestinal side effects of DIC.