Flavonoid Interactions with Renal Organic Anion Transporters OAT1 and OAT3: Structure–Activity Relationships and Clinical Implications

Renal organic anion transporters 1 (OAT1) and 3 (OAT3) mediate the excretion of endogenous metabolites and xenobiotics. Flavonoids interact significantly with these transporters, but the structural determinants—especially regarding in vivo phase II metabolism—remain unclear. This review integrates recent cryogenic electron microscopy (cryo-EM) structural biology and transporter kinetics to delineate the molecular basis of flavonoid–OAT interactions. We highlight phase II metabolites as key in vivo effectors. Structurally, OAT1 strictly favors compact, planar anionic scaffolds, whereas OAT3 accommodates bulkier, conjugated forms. Crucially, flavonoids exert a “double-edged” toxicological effect: high-affinity OAT inhibition risks herb–drug interactions, yet competitively limits the tubular uptake of nephrotoxins. Furthermore, disease states and post-translational regulation reshape these interactions. By bridging structural insights with biomarker-guided pharmacokinetics, we propose a mechanistic framework to improve the precise safety assessment of flavonoid-containing therapeutics.