Effect of Resveratrol on the Pharmacokinetics of Carbamazepine in Healthy Human Volunteers

Abstract

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.

Resveratrol in Cancer Patients: From Bench to Bedside

“…However, the time to reach maximum drug concentration and elimination rate constant had not significantly changed. Additionally, carbamazepine metabolite/parent ratios of C max and AUC (Area Under the Curve) had also significantly decreased [128]. Several experiments strongly support an induction effect of resveratrol of several phase II enzymes including glutathione S-transferase (GST), nicotinamide hydrogenase (NADH), UDP-glucuronosyl transferase, (UGT) and catechol-O-methyl transferase (COMT).…”

Effect of Piperine on the Metabolism and Pharmacokinetics of Carbamazepine in Healthy Volunteers

“…Each subject underwent 2 phases separated by a washout period of 2 weeks. During the control phase, on the morning of day, a single CBZ 200 mg (Tegretol, Novartis Pharma Ltd, India) oral dose [19] was administered with 240 mL of water under fasting conditions of more than 10 h. During the treatment phase, each subject received PIP 20 mg (Ambe Phytoextracts Ltd, India) oral dose [20] once daily for 10 days under fasting conditions.…”

“…LC-MS/MS method was used for simultaneous estimation of CBZ and CBZE concentrations in human plasma samples [19,21] The lower limit of quantification for CBZ and CBZE were 0.001 and 0.005 µg/mL, respectively and the assay ranges used were 0.001-7 µg/mL for CBZ and 0.005-0.4 µg/mL for CBZE. Correlation coefficients for CBZ and CBZE calibration curves were 0.995 and 0.998, respectively.…”

“…It has been well documented that the CYP3A4 enzyme is involved in the metabolism and elimination of CBZ. Alterations in the catalytic activity of CYP3A4 enzyme with various drugs such as ciprofloxacin [15], ketoconazole [18] and certain herbal constituents such as resveratrol [19] are well documented.…”

Incorporating Natural Products, Pharmaceutical Drugs, Self-Care and Digital/Mobile Health Technologies into Molecular-Behavioral Combination Therapies for Chronic Diseases

“…The use of resveratrol in epilepsy and status epilepticus has been discussed [191, 192]. Potential pharmacokinetic interactions between resveratrol and carbamazepine may prevent this particular combination to treat epileptic seizures [193], similarly to potential interactions between n-3 PUFA and carbamazepine [194]. …”