Flavonoids are important dietary phytochemicals with broad human exposures and a variety of claimed biological effects. Although traditional sources of flavonoids are fruits and vegetables, dietary supplements have become an important source of flavonoids. The enthusiasm for all things about flavonoids expressed by scientists and public alike has sometimes overlooked an important point: these compounds are usually not bioavailable or have very low bioavailability. The current review focused on factors that affect bioavailability of flavonoids, which in turn impact their efficacy and toxicity. These factors include physicochemical and biological ones, with the emphasis on the latter, including membrane permeation, enzymatic metabolism, and excretion by efflux transporters. Current evidence indicates that naturally occurring flavonoid glycosides typically need to be de-glycosylated before they are absorbed, because intact flavonoid glycosides are poorly absorbed. However, once absorbed, flavonoid aglycones undergo rapid and extensive first-pass metabolism via conjugation and subsequent excretion of the conjugates, which makes them poorly bioavailable. Fortunately, the presence of enteric and enterohepatic recycling allows the flavonoids to be accumulated in vivo over time, because the recycling increases contact time between the flavonoids and target tissues. We believe that continued studies in this area will help scientists devise a better means to improve oral bioavailability of flavonoids so we can one day fully enjoy the health benefits of ingesting flavonoids.

Introduction: Polyphenols, which are widely distributed in plants and the human diets, are known to have numerous biological activities. However, the low bioavailability of polyphenols is mediated by coupled metabolic pathways. Areas covered: The key role of the interplay between drug metabolic enzymes (DMEs) and efflux transporters (ETs), nuclear receptors (NRs), and intestinal microflora in the disposition of polyphenols is summarized. Expert opinion: ETs are shown to act as a ‘revolving door’, facilitating and/or controlling cellular polyphenol glucuronide/sulfate excretion. Elucidating the mechanisms underlying the glucuronidation/sulfation–transport interplay and structure-activity relationships (SAR) of glucuronide/sulfate efflux by an ET is important. Some new physiologically based pharmacokinetic (PBPK) models could be developed to predict the interplay between glucuronides/sulfates and ETs. Additionally, the combined actions of uridine-5′-diphosphate glucuronosyltransferases, ETs, and intestinal microflora/enterocyte-derived β-glucuronidase enable triple recycling (local, enteric, and enterohepatic recycling), thereby increasing the residence time of polyphenols and their glucuronides in the local intestine and liver. Further studies are necessary to explore these recycling mechanisms and interactions between polyphenols and the intestinal microbiota. Since NRs govern the inducible expression of target genes that encode DMEs and ETs. Determination of the regulation mechanism mediated by NRs using transgenic and knockout animals is still needed.