Pharmacokinetics and extensive intestinal first-pass effects of apigenin and its active metabolite, apigenin-7-O-glucuronide, in rats

This study investigated the metabolism and pharmacokinetics of apigenin and its metabolite, apigenin-7-O-glucuronide (A7G), using a newly developed UPLC-MS/MS method.

A simple and sensitive UPLC-MS/MS method was developed for simultaneous quantification of apigenin and A7G, and their pharmacokinetic properties were examined using an in vivo rat model. Moreover, stability under various conditions, protein binding, blood distribution, and metabolic studies were performed in vitro.

Apigenin showed poor stability in simulated intestinal fluid, whereas A7G was stable for 24 h. An in vivo pharmacokinetic study demonstrated that apigenin had a very low oral bioavailability (F) of 0.708% and was mainly metabolized to A7G. Notably, systemic exposure (C_max and AUC) of apigenin after oral administration of A7G was markedly higher (2.62- and 14.3-fold, respectively) than that after oral administration of apigenin. Apigenin and A7G were significantly metabolized in both hepatic and intestinal S9 fractions. Based on the well-stirred and Q_Gut model concepts, they were classified as compounds with low E_H (0.0167–0.0389) and moderate-to-high E_G (0.626–0.979) in rats, indicating that the intestine had a greater contribution than the liver to pre-systemic elimination of both phytochemicals.

The low F of apigenin could be attributed to its poor stability in the gastrointestinal lumen and extensive intestinal first-pass effect, which could be improved by oral administration of A7G, demonstrating the potential of A7G as a natural prodrug for improving the low F of apigenin.