The effect of quercetin on the pharmacokinetics of chlorzoxazone, a CYP2E1 substrate, in healthy subjects.

PURPOSE: Previous in vitro studies have demonstrated that quercetin inhibits CYP2E1 enzyme, but there are no available data to indicate that quercetin inhibits CYP2E1 enzyme in humans. The purpose of the present study was to assess the effect of quercetin on CYP2E1 enzyme activity in healthy subjects using chlorzoxazone (CHZ) as a CYP2E1 substrate. METHODS: An open-label, two-period, sequential study was conducted in 12 healthy subjects. A single dose of CHZ 250 mg was given to subjects during control phase and after treatment phases. Quercetin at a dose of 500 mg was given to subjects twice daily for a period of 10 days. The blood samples were collected at predetermined time intervals after CHZ dosing and analyzed to determine the concentrations of CHZ and 6-hydroxychlorzoxazone (6-OHCHZ). RESULTS: Treatment with quercetin significantly enhanced the maximum plasma concentration (C max), area under the curve (AUC), and half-life (t 1/2) by 47.8, 69.3, and 36.4%, respectively, while significantly decreased the elimination rate constant (k el) and apparent oral clearance (CL/F) of CHZ by 25.1 and 41.6%, respectively, in comparison with the control. On the other hand, C max and AUC of 6-OHCHZ were decreased by 30.1 and 32.6%, respectively, after quercetin treatment when compared to control. In addition, geometric mean ratios and 90% confidence intervals for C max and AUC of CHZ and 6-OHCHZ were both out of the no-effect boundaries of 0.80-1.25, which indicates a significant pharmacokinetic interaction present between CHZ and quercetin. Furthermore, treatment with quercetin significantly decreased the metabolic ratios of C max and AUC by 57.1 and 60.1%, respectively, as compared to control suggesting that reduced formation of CHZ to 6-OHCHZ. CONCLUSIONS: 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.

Evaluation of the effect of quercetin treatment on CYP2C9 enzyme activity of diclofenac in healthy human volunteers.

The purpose of present study was to evaluate the effect of quercetin on pharmacokinetics of diclofenac sodium (DIC) in healthy volunteers. The open-label, 2 period, sequential study was conducted in 12 healthy volunteers. DIC 100 mg was administered during control and after quercetin phases. Quercetin 500 mg was administered twice daily for 10 days during quercetin phase. Treatment with quercetin significantly enhanced maximum plasma concentration (Cmax ), area under the curve (AUC0-∞ ), and half life, while significantly decreased elimination rate constant (kel ) and apparent oral clearance (CL/F) of DIC compared with control. On the other hand, Cmax and AUC0-∞ of 4-hydroxydiclofenac (4-OHDIC) were decreased after quercetin treatment. In addition, geometric mean ratios and 90% confidence intervals for Cmax and AUC0-∞ of DIC and 4-OHDIC were both out of the no-effect limits of 0.80-1.25, which indicates a significant pharmacokinetic interaction between quercetin and DIC. Furthermore, quercetin treatment significantly decreased metabolic ratios of Cmax and AUC0-∞ suggesting that reduced formation of DIC to 4-OHDIC. The results suggest that quercetin might have inhibited CYP2C9-mediated metabolism of DIC. Accordingly, caution should be taken when quercetin is used in combination with therapeutic drugs metabolized by CYP2C9, and dose adjustment of CYP2C9 substrates may be necessary.

Modulation of CYP3A enzyme activity by diosmin and its consequence on carbamazepine pharmacokinetics in rats.

Diosmin is a widely used flavonoid for the treatment of varicose veins and hemorrhoids. Epileptic patients with hemorrhoids and varicose veins may use diosmin along with carbamazepine (CBZ) therapy, which leads to pharmacokinetic interaction between diosmin and CBZ. Therefore, the present study was performed to evaluate the effect of diosmin on the pharmacokinetics of CBZ in rats. Diosmin-mediated altered CYP3A enzyme activity in human and rat liver microsomes was examined using CYP3A dependent erythromycin N-demethylase assay. Further, an in vivo pharmacokinetic study of oral administered CBZ in rats with and without diosmin pretreatment was performed. The CYP3A enzyme activity in human and rat liver microsomes was significantly (p < 0.05) decreased by diosmin when compared to control. Pretreatment with diosmin significantly (p < 0.05) enhanced maximum plasma concentration (C max), area under the curve (AUC), and half life (t 1/2), while significantly (p < 0.05) decreased elimination rate constant (k el) and apparent oral clearance (CL/F) of CBZ as compared to control rats. On the other hand, C max, AUC, and t 1/2 of carbamazepine 10, 11-epoxide (CBZE) were significantly (p < 0.05) decreased after diosmin pretreatment. Furthermore, diosmin pretreatment significantly (p < 0.05) decreased metabolic ratios of C max and AUC when compared to control, suggesting reduced formation of CBZ to CBZE. The results suggest that diosmin pretreatment might have inhibited CYP3A-mediated metabolism of CBZ. Accordingly, caution should be taken when diosmin is used in combination with therapeutic drugs metabolized by CYP3A enzyme in addition to CBZ.

Capsaicin pretreatment enhanced the bioavailability of fexofenadine in rats by P-glycoprotein modulation: in vitro, in situ and in vivo evaluation.

BACKGROUND AND OBJECTIVE: Capsaicin is the main pungent principle present in chili peppers has been found to possess P-glycoprotein (P-gp) inhibition activity in vitro, which may have the potential to modulate bioavailability of P-gp substrates. Therefore, purpose of this study was to evaluate the effect of capsaicin on intestinal absorption and bioavailability of fexofenadine, a P-gp substrate in rats. METHODS: The mechanistic evaluation was determined by non-everted sac and intestinal perfusion studies to explore the intestinal absorption of fexofenadine. These results were confirmed by an in vivo pharmacokinetic study of oral administered fexofenadine in rats. RESULTS: The intestinal transport and apparent permeability (Papp) of fexofenadine were increased significantly by 2.8 and 2.6 fold, respectively, in ileum of capsaicin treated rats when compared to control group. Similarly, absorption rate constant (Ka), fraction absorbed (Fab) and effective permeability (Peff) of fexofenadine were increased significantly by 2.8, 2.9 and 3.4 fold, respectively, in ileum of rats pretreated with capsaicin when compared to control group. In addition, maximum plasma concentration (Cmax) and area under the concentration-time curve (AUC) were increased significantly by 2.3 and 2.4 fold, respectively, in rats pretreated with capsaicin as compared to control group. Furthermore, obtained results in rats pretreated with capsaicin were comparable to verapamil (positive control) treated rats. CONCLUSIONS: Capsaicin pretreatment significantly enhanced the intestinal absorption and bioavailability of fexofenadine in rats likely by inhibition of P-gp mediated cellular efflux, suggesting that the combined use of capsaicin with P-gp substrates may require close monitoring for potential drug interactions.

Study on influence of piperine treatment on the pharmacokinetics of diclofenac in healthy volunteers.

1. Diclofenac sodium (DIC) is a widely used anti-inflammatory drug and its administration in humans receiving long-term therapy with herbal drugs containing piperine (PIP) may occur, which leads to drug-phytochemical interactions. The purpose of the present study was to investigate the influence of PIP treatment on the pharmacokinetics of DIC in healthy volunteers. 2. The open-label, two period, sequential study was conducted in 12 healthy volunteers. PIP 20 mg was administered once 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 at predetermined time intervals and analyzed by HPLC. 3. Treatment with PIP significantly enhanced maximum plasma concentration (Cmax) (2.24-3.68 µg/mL, p < 0.05), area under the curve (AUC) (7.09-11.81 µg h/mL, p < 0.05), half-life (T1/2) (1.23-1.65 h, p < 0.05) and significantly decreased elimination rate constant (Kel) (0.62-0.41 h-1, p < 0.05), apparent oral clearance (CL/F) (7.57-4.52 L/h, p < 0.05) of DIC as compared to that of control phase. 4. The results suggest that the altered pharmacokinetics of DIC might be attributed to PIP mediated inhibition of CYP2C9 enzyme, which indicates the clinically significant interaction present between DIC and PIP. Therefore, the combination therapy of DIC along with PIP may represent a novel approach to reduce dosage and result in reduced incidence of gastrointestinal side effects seen with DIC alone at higher doses.

The influence of piperine on the pharmacokinetics of fexofenadine, a P-glycoprotein substrate, in healthy volunteers.

PURPOSE: Piperine (PIP) has been found to inhibit P-glycoprotein (P-gp) function in rats, suggesting that it may have the potential to modulate P-gp-mediated drug efflux in humans. The aim of this study was to evaluate the effect of PIP on the pharmacokinetics of fexofenadine (FEX), a P-gp substrate, in healthy volunteers. METHODS: An open-label, two-period, sequential study involving 12 healthy volunteers was conducted. A single oral dose of FEX 120 mg was given to volunteers during the control phase and after the treatment phase. A once-daily oral dose of PIP 20 mg was given to volunteers during the treatment phase (10 days). Blood samples were collected at predefined time intervals, and plasma samples containing FEX were analyzed by liquid chromatography-tandem mass spectrometry. RESULTS: Treatment with PIP significantly increased maximum plasma concentration of FEX [406.9 (control) vs. 767 ng/mL (treatment)] and area under the plasma concentration-time curve [3403.7 (control) vs. 5724.7 ng.h/mL (treatment)] when compared to the control phase. In contrast, PIP treatment significantly decreased apparent oral clearance of FEX [35.4 (control) vs. 20.7 L/h (treatment)] as compared to the control. There was no significant change observed in the half life and renal clearance of FEX between the treatment phase and control phase. CONCLUSIONS: 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.

Influence of diosmin on the metabolism and disposition of carbamazepine in healthy subjects.

1. Carbamazepine (CBZ) is an antiepileptic drug with narrow therapeutic window and administration in humans receiving long-term therapy with diosmin (DSN) may occur, which leads to CYP3A4-mediated drug interactions. The purpose of the present study was to assess the influence of DSN on the metabolism and pharmacokinetics of CBZ in healthy volunteers. 2. An open-label, sequential, two-period study was conducted in 12 healthy male volunteers. A single dose of DSN 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. 3. Treatment with DSN significantly enhanced the maximum plasma concentration (Cmax), area under the curve (AUC), half-life (t1/2) and significantly decreased the apparent oral clearance (CL/F) and elimination rate constant (Kel) of CBZ. On the other hand, treatment with DSN significantly decreased the Cmax and AUC of carbamazepine 10, 11-epoxide (CBZE). Furthermore, treatment with DSN significantly decreased the metabolite to parent ratios of Cmax and AUC, indicating the reduced metabolism of CBZ to CBZE. 4. The results suggest that the altered CYP3A4 enzyme activity and pharmacokinetics of CBZ might be attributed to DSN-mediated inhibition of CYP3A4 enzyme, which indicates pharmacokinetic interaction present between DSN and CBZ. Therefore, we conclude that DSN has an inhibiting effect on the metabolism and disposition of CBZ.

Effect of piperine on CYP2E1 enzyme activity of chlorzoxazone in healthy volunteers.

1. The purpose of the present study was to investigate the effect of piperine (PIP) on CYP2E1 enzyme activity and pharmacokinetics of chlorzoxazone (CHZ) in healthy volunteers. 2. An open-label, two period, sequential study was conducted in 12 healthy volunteers. A single dose of PIP 20 mg was administered 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 at predetermined time intervals after CHZ dosing and analyzed by HPLC. 3. Treatment with PIP significantly enhanced maximum plasma concentration (Cmax) (3.14-4.96 µg/mL), area under the curve (AUC) (10.46-17.78 µg h/mL), half life (T1/2) (1.26-1.82 h) and significantly decreased elimination rate constant (Kel) (0.57-0.41 h - 1), apparent oral clearance (CL/F) (24.76-13.65 L/h) of CHZ when compared to control. In addition, treatment with PIP significantly decreased Cmax (0.22-0.15 µg/mL), AUC (0.94-0.68 µg h/mL), T1/2 (2.54-1.68 h) and significantly increased Kel (0.32-0.43 h - 1) of 6-hydroxychlorzoxazone (6-OHCHZ) as compared to control. Furthermore, treatment with PIP significantly decreased metabolite to parent (6-OHCHZ/CHZ) ratios of Cmax, AUC, T1/2 and significantly increased Kel ratio of 6-OHCHZ/CHZ, which indicate the decreased formation of CHZ to 6-OHCHZ. 4. The results suggest that altered pharmacokinetics of CHZ might be attributed to PIP mediated inhibition of CYP2E1 enzyme, which indicate significant pharmacokinetic interaction present between PIP and CHZ. The inhibition of CYP2E1 by PIP may represent a novel therapeutic benefit for minimizing ethanol induced CYP2E1 enzyme activity and results in reduced hepatotoxicity of ethanol.

The effect of diosmin on the pharmacokinetics of fexofenadine in healthy human volunteers.

1. Diosmin (DSN) has been found to possess P-glycoprotein (P-gp) inhibition activity in vitro and in vivo in rats, which may have potential to cause P-gp-mediated interactions in humans. The purpose of the present study was to investigate the effect of DSN on pharmacokinetics of fexofenadine (FEX) in healthy human volunteers. 2. An open-label, two-period, sequential study was conducted in 12 healthy male volunteers. A single dose of FEX 120 mg was administered to volunteers during control and treatment phases. A single dose of DSN 500 mg was administered to volunteers daily for period of 10 days. The blood and urine samples were collected at predetermined time intervals after FEX dosing and analyzed by LC-MS/MS. 3. Treatment with DSN significantly increased the peak maximum plasma concentration (Cmax) and area under the plasma concentration-time curve (AUC) of FEX by 49.2% (523.28 versus 780.63 ng/mL) and 64.4% (3459.48 versus 5687.74 ng h/mL), respectively as compared to control phase. On the other hand, apparent oral clearance (CL/F) of FEX was significantly decreased by 41.3% (37.03 versus 21.75 L/h) and there was no significant change was observed in Tmax, T1/2, and CLr (renal clearance) upon treatment with DSN when compared to control. 4. The results suggest that altered pharmacokinetics of FEX might be attributed to DSN-mediated inhibition of P-gp-mediated efflux in humans. Therefore, we conclude that intake of DSN or dietary supplements containing DSN may potentially increase the absorption or bioavailability of FEX, a P-gp substrate in humans.

Effect of resveratrol on the pharmacokinetics of fexofenadine in rats: Involvement of P-glycoprotein inhibition.

BACKGROUND: Resveratrol (RSV) is a natural occurring antioxidant has been found to possess P-glycoprotein (P-gp) inhibition activity in vitro and in vivo, which may have the potential to cause drug-phytochemical interactions. The purpose of the present study was to evaluate the effect of RSV on the pharmacokinetics of fexofenadine (FEX), P-gp substrate in rats. METHODS: A mechanistic evaluation was undertaken using in vitro non-everted sac and in situ intestinal perfusion studies to determine the FEX intestinal transport and permeability. These results were confirmed by an in vivo pharmacokinetic study of oral administered FEX (10mg/kg) in rats. RESULTS: The intestinal transport and apparent permeability (Papp) of FEX were increased significantly in duodenum, jejunum and ileum of RSV and verapamil (VER) pretreated groups when compared to FEX alone group. Similarly absorption rate constant (Ka), fraction absorbed (Fab) and effective permeability (Peff) of FEX were increased significantly in ileum of RSV and VER pretreated groups when compared to FEX alone group. In comparison with FEX alone, RSV pretreatment significantly increased maximum plasma concentration (Cmax) and area under the concentration-time curve (AUC), while there was no significant change was observed in T1/2 and Tmax of FEX. CONCLUSIONS: RSV significantly enhanced the exposure of FEX in rats likely by the inhibition of P-glycoprotein (P-gp) mediated efflux during the intestinal absorption, suggesting that there is a potential pharmacokinetic interaction between RSV and FEX. Therefore, further studies are recommended to evaluate the potential drug-phytochemical interactions in humans.

Effect of Resveratrol Treatment on the Pharmacokinetics of Diclofenac in Healthy Human Volunteers.

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.

Resveratrol Pretreatment Affects CYP2E1 Activity of Chlorzoxazone in Healthy Human Volunteers.

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.

Effect of diosmin on the intestinal absorption and pharmacokinetics of fexofenadine in rats.

BACKGROUND: Diosmin is a natural flavone glycoside, a potent P-glycoprotein (P-gp) inhibitor in cultured cells and have the potential to alter the bioavailability of P-gp substrate drugs. However, the interaction between diosmin and fexofenadine is unreported. Hence, the present study was performed to investigate the effect of diosmin on the intestinal absorption and pharmacokinetics of fexofenadine, a P-gp substrate in rats. METHODS: Fexofenadine intestinal transport and permeability were evaluated by in vitro non-everted sac and in situ single pass intestinal perfusion (SPIP) studies. These results were confirmed by an in vivo pharmacokinetic study of oral administered fexofenadine (10mg/kg) in rats. RESULTS: The intestinal transport and apparent permeability (Papp) of fexofenadine were significantly increased in duodenum, jejunum and ileum of diosmin pretreated group as compared with the control. Similarly effective permeability (Peff) of fexofenadine was increased significantly in ileum of diosmin pretreated group as compared with control. In comparison with control, pretreatment with diosmin significantly increased peak plasma concentration (Cmax) and area under the concentration-time curve (AUC), while there was no significant change was observed in half life (T1/2), time to reach peak plasma concentration (Tmax) and elimination rate constant (Kel) of fexofenadine. CONCLUSIONS: Diosmin significantly enhanced the oral bioavailability of fexofenadine by the inhibition of P-gp mediated drug efflux during the intestinal absorption. Co-administration of diosmin with fexofenadine can reduce the dosage and results in reduced side effects of fexofenadine. The clinical relevance of this interaction should be further evaluated in human subjects.

Effect of resveratrol on the pharmacokinetics of carbamazepine in healthy human volunteers.

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.