Effects of Caffeic Acid and Quercetin on In Vitro Permeability, Metabolism and In Vivo Pharmacokinetics of Melatonin in Rats: Potential for Herb-Drug Interaction.

Background And Objectives: Melatonin is a popular dietary supplement and also considered as pharmaceutical product for sleep disorders. Caffeic acid and quercetin are widely distributed in leafy vegetables, fruits, tea extract, and both are used as natural antioxidant. There is an immense concern for health researchers to study the herb/food-drug interactions of melatonin. It is mainly metabolized by CYP1A2 in human so that herbs/foods containing cytochrome P450 (CYP) inhibitors can affect pharmacokinetics of melatonin. By considering pharmacokinetic aspects, the present study was undertaken to evaluate the effects of caffeic acid and quercetin on Caco-2 cells permeability, metabolism, CYP1A inhibition in vitro assay systems and a single dose pharmacokinetics of melatonin in vivo rats.

Methods: The effects of caffeic acid and quercetin on melatonin permeability were tested in Caco-2 cells. Metabolic stability and CYP1A activity were investigated in rat liver microsomes (RLMs) using probe substrates (melatonin/phenacetin in vitro). Melatonin and phenacetin were incubated in RLMs with or without caffeic acid and quercetin, and the IC values were determined. The pharmacokinetics of melatonin conducted in rats after a single dose (15 mg/kg) pre-treatment with caffeic acid, quercetin and caffeic acid plus quercetin followed by oral dose of melatonin at 5 mg/kg. Analysis of all samples was with LC-MS/MS.

Results: Caffeic acid and quercetin did not alter Caco-2 permeability of melatonin in apical to basolateral direction and vice versa. Melatonin was metabolized in rat liver microsomes, which was inhibited by both caffeic acid and quercetin through CYP1A. The concomitant oral administration of melatonin along with 15 mg/kg of caffeic acid or quercetin or caffeic acid plus quercetin significantly (p < 0.05) increased the AUC of melatonin by 30.0, 66.7 and 114.0%, respectively. The apparent oral rat plasma clearance (CL/F) of melatonin also decreased significantly (p < 0.05) by 28.78, 47.87 and 50% in presence of caffeic acid, quercetin and caffeic acid plus quercetin, respectively.

Conclusion: These findings suggest that caffeic acid and quercetin improved oral exposure of melatonin via CYP1A inhibition pathway.