Rapid evaluation of apigenin bioavailability and hypouricemic bioactivity by targeted metabolomics study in enterohepatic microenvironment mimetic cell culture model.

Apigenin was previously identified as a potent hypouricemic agent by comparative metabolomics and in silico analysis. Bioavailability (absorption, distribution, metabolism, and excretion) is the major concern for bioefficacy of phytochemicals administered orally. Therefore, the objective of this study was to establish an enterohepatic microenvironment biomimetic model comprised of intestine epithelial cells and liver cells to evaluate the bioavailability and hypouricemic bioactivity of apigenin. The results indicated that cumulative 26 % of the supplemented apigenin was absorbed by intestinal epithelium over 240 min. With a maximum 24 % (1.37 μg/mL) of the absorbed apigenin, in its parent form, was distributed to the basolateral extra-enterohepatic compartment. Extensive phase I and phase II metabolism occurred in both enterocytes and hepatocytes. Ten and eighteen metabolites were detected in apical and basolateral medium representing intestinal excretion and systemic distribution, respectively. Apigenin-7-sulfate was the predominant metabolite released in intestinal lumen, while apigenin sulfation, acetylation, and taurine-conjugated products were the major metabolites likely distributed systemically. Importantly, apigenin supplementation significantly lowered uric acid level in the basolateral compartment, which demonstrated its hypouricemic bioactivity after the absorption through intestinal epithelium and supported its potential as a nutraceutical for hyperuricemia prevention. This in vitro enterohepatic model provides a valuable tool for rapidly assessing the bioavailability and bioactivity of dietary components.