Inhibition of Cytochrome P450 3A4 by oral delivery of Resveratrol Nanoformulation in rat

Aim and Background: The oral route is the most convenient, easy, and cost-effective method of non-invasive drug administration. Herb-drug interactions may occur through the modulation of cytochrome P450 (CYP) drug-metabolizing enzymes and drug transporters in the liver and gut. CYP3A4 is the most important P450 enzyme for drug metabolism. The aim of this work is to investigate the effect of oral delivery of resveratrol nanoformulation on the inhibition of CYP3A4 in rat model. Methods: A nanoemulsion containing Res and Res-conjugated gold nanoparticles was prepared and characterized. Western blotting was applied to demonstrate the hepatic CYP3A4 protein expression and Trans-well plates were used to show drug permeability through Caco-2 monolayers. Drug bioavailability was measured by HPLC technique. Results and discussion: The cytotoxicity of nanoformulation was assayed compared to Res and did not show a significant difference. Oral delivery of the nanoemulsion containing Res and Res-GNPs increased the AUC0-24 and Cmax of Simvastatin to 2.7 and 3.05 fold, compared with control, respectively. The results suggested that enhanced bioavailability of Simvastatin can be attributed to the potential of nanoformulation resulted by significant inhibition of P-gp and CYP3A4 in vitro and in vivo. Hematological indicators and liver enzymes were evaluated to determine the toxicity of nanoformulaion in rat. Nanoformulation had no toxic effect at 300 mg/kg orally in rat. Conclusion: We demonstrated that the prepared nanoformulation significantly increased pharmacokinetics of Simvastatin. This result suggests that this formulation can be investigated for other similar drugs that are a substrate of P-gp and CYP3A4