Metabolism of Flavonoids and Implications for Their Biological Activities: An Updated Review

Background/Objectives: Flavonoids are a diverse group of dietary polyphenolic compounds associated with a range of important biological activities. However, their low systemic bioavailability and extensive metabolism raise questions about how they exert their purported benefits. Methods: A comprehensive survey of literature published over the past 10 years was conducted, focusing on human, animal, and in vitro studies addressing the metabolic fate of major flavonoid subclasses. Results: Original research articles (n = 159) were selected following predetermined inclusion criteria. Data from diverse experimental models—including intestinal and hepatic systems—demonstrate that flavonoids undergo substantial transformation by Phase I and Phase II enzymes, alongside extensive biotransformation by the gut microbiota. In this critical narrative review we summarize dietary sources, bioavailability patterns, metabolic pathways, and analytical strategies, emphasizing advances enabled by high-resolution mass spectrometry. Recent findings indicate that enterohepatic recirculation and the biological activities of circulating and tissue-associated metabolites contribute significantly to the observed health effects, despite limited levels of parent compounds. Conclusions: Flavonoids exhibit limited oral bioavailability and undergo complex metabolic processing, yet growing evidence indicates that their metabolites play key roles in mediating beneficial effects. Understanding these metabolic pathways is essential for interpreting epidemiological associations and designing more effective intervention studies.