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.

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 (C) (3.14-4.96 μg/mL) area under the curve (AUC) (10.46-17.78 μg h/mL), half life (T) (1.26-1.82 h) and significantly decreased elimination rate constant (K) (0.57-0.41 h ), apparent oral clearance (CL/F) (24.76-13.65 L/h) of CHZ when compared to control. In addition, treatment with PIP significantly decreased C (0.22-0.15 μg/mL), AUC (0.94-0.68 μg h/mL), T (2.54-1.68 h) and significantly increased K (0.32-0.43 h ) of 6-hydroxychlorzoxazone (6-OHCHZ) as compared to control. Furthermore, treatment with PIP significantly decreased metabolite to parent (6-OHCHZ/CHZ) ratios of C, AUC, T and significantly increased K 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.

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 (C) (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 (T) (1.23-1.65 h, p < 0.05) and significantly decreased elimination rate constant (K) (0.62-0.41 h, 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.

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.

Carbamazepine (CBZ) is a widely used antiepileptic drug with narrow therapeutic window and it may be prone to drug interactions. The purpose of present study was to investigate the effect of PIP on metabolism and pharmacokinetics of CBZ in healthy volunteers. An open-label, 2 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 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 method. Treatment with PIP significantly enhanced maximum plasma concentration (C), area under the curve (AUC) and half life (T) of CBZ by 68.7, 47.9 and 43.2%, respectively as compared to control. On the other hand, elimination rate constant (K) and apparent oral clearance (CL/F) of CBZ were significantly decreased by 23.8 and 38.9%, respectively upon PIP treatment as compared to control. Furthermore, PIP treatment significantly decreased metabolic (CBZE/CBZ) ratios of C and AUC, indicating the decreased formation of CBZ to CBZE. The results suggest that the altered CYP3A4 enzyme activity and pharmacokinetics of CBZ might be attributed to PIP mediated inhibition of CYP3A4 enzyme. Thus, there is a potential pharmacokinetic interaction present between PIP and CBZ. Accordingly, caution should be taken when PIP is used in combination with therapeutic drugs metabolized by CYP3A4 in addition to CBZ.