Hepatic and intestinal metabolism, intestinal transport, and ABCB1 interaction of 6-prenylnaringenin

Abstract 6-prenylnaringenin (6-PN) has recently attracted attention for its chemopreventive, cytotoxic, and analgesic activities; however, information on its pharmacokinetic properties remains limited, making it difficult to interpret its biological effects. This study thus investigated the metabolism of 6-PN in humans, mice, and rats, as well as its intestinal transport and interaction with ABCB1 in humans. 6-PN (10 µM) was efficiently metabolized predominantly via phase II conjugation across all studied species. Overall, 13 phase I/II metabolites were detected, including novel sulfoglucuronide diconjugates not previously reported for structurally similar hop prenylflavonoids. Importantly, murine hepatic metabolism of 6-PN more closely resembled its human hepatic biotransformation profile, favoring murine over rat models in pharmacokinetics studied. Further, 6-PN showed appreciable transport in the absorptive AB direction, while the observed BA-over-AB asymmetry was not reduced by ABCB1/ABCG2 inhibition, although it modulated ABCB1 substrate transport in a model- and substrate-dependent manner. Overall, these data indicate that 6-PN can undergo transepithelial transport in the absorptive direction, whereas extensive phase II metabolism may substantially shape its bioavailability.