Transporter Interactionsof Methoxyflavones and Their In Vivo PharmacokineticImplications

Abstract

Abstract Flavonoids are widely consumed dietary polyphenols that modulate drug disposition via membrane transporters. Increasing attention has been paid to methoxyflavones (MeO-FLVs) because methoxylation can increase membrane permeability and metabolic stability, potentially elevating transporter-mediated drug–drug interaction risk; however, position-specific effects are poorly defined. We profiled a series of structurally related flavones (3-OH-FLV, 3-MeO-FLV, 5-MeO-FLV, 6-MeO-FLV, and 7-MeO-FLV) across major uptake and efflux transporters. In vitro uptake and bidirectional transport assays demonstrated that methoxyflavones inhibited renal organic anion transporters 1 and 3 (OAT1/OAT3), organic cation transporter 2 (OCT2), and efflux transporters P-glycoprotein (MDR1)/breast cancer resistance protein (BCRP) more potently than 3-OH-FLV, although the inhibitory potency varied depending on the methoxy substitution position, particularly for OAT1 and OCT2. Cytotoxicity reversal assays supported functional inhibition of MDR1 and BCRP by the methoxyflavones. In vivo interaction studies were performed for the selected methoxyflavones using metformin and furosemide as transporter-relevant probe drugs in rats. Metformin pharmacokinetics were measurably altered by 3-MeO-FLV and 7-MeO-FLV, consistent with transporter-related modulation of metformin disposition, potentially involving OCT2. For furosemide, a clear interaction was observed with 6-MeO-FLV and 7-MeO-FLV. Overall, these findings suggest that the methoxylation pattern influences transporter inhibition profiles and in vivo pharmacokinetic effects, although further studies with larger compound sets are needed to define structure–activity relationships and transporter selectivity.