{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,1]],"date-time":"2026-09-01T00:13:06Z","timestamp":1788221586971,"version":"build-2803163510"},"reference-count":45,"publisher":"American Chemical Society (ACS)","issue":"33","license":[{"start":{"date-parts":[[2026,8,11]],"date-time":"2026-08-11T00:00:00Z","timestamp":1786406400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100003625","name":"Ministry of Health and Welfare","doi-asserted-by":"publisher","award":["RS-2024-00459727"],"award-info":[{"award-number":["RS-2024-00459727"]}],"id":[{"id":"10.13039\/501100003625","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100003715","name":"Korea Research Institute of Bioscience and Biotechnology","doi-asserted-by":"publisher","award":["NA"],"award-info":[{"award-number":["NA"]}],"id":[{"id":"10.13039\/501100003715","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100003725","name":"National Research Foundation of Korea","doi-asserted-by":"publisher","award":["2021R1I1A3056261"],"award-info":[{"award-number":["2021R1I1A3056261"]}],"id":[{"id":"10.13039\/501100003725","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100014188","name":"Ministry of Science and ICT, South Korea","doi-asserted-by":"publisher","award":["RS-2024-00459727"],"award-info":[{"award-number":["RS-2024-00459727"]}],"id":[{"id":"10.13039\/501100014188","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2026,8,25]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>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\u2013drug 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\u2013activity relationships and transporter selectivity.<\/jats:p>","DOI":"10.1021\/acsomega.6c03122","type":"journal-article","created":{"date-parts":[[2026,8,12]],"date-time":"2026-08-12T00:01:37Z","timestamp":1786492897000},"page":"49579-49591","source":"Crossref","is-referenced-by-count":0,"title":["Transporter Interactions\nof Methoxyflavones and Their\n                    <i>In Vivo<\/i>\n                    Pharmacokinetic\nImplications"],"prefix":"10.1021","volume":"11","author":[{"given":"Min-Ji","family":"Kang","sequence":"first","affiliation":[{"name":"Woosuk University , , ,","place":["Wanju, Korea, 55338"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2175-8876","authenticated-orcid":true,"given":"Kyeong-Ryoon","family":"Lee","sequence":"additional","affiliation":[{"name":"Korea Research Institute of Bioscience and Biotechnology , , ,","place":["Cheongju, Republic of Korea, 28116"]},{"name":"University of Science and Technology , , ,","place":["Daejeon, Republic of Korea, 34113"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hyerim","family":"Song","sequence":"additional","affiliation":[{"name":"Woosuk University , , ,","place":["Wanju, Korea, 55338"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yunjin","family":"Seol","sequence":"additional","affiliation":[{"name":"Woosuk University , , ,","place":["Wanju, Korea, 55338"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4921-4192","authenticated-orcid":true,"given":"Yoon-Jee","family":"Chae","sequence":"additional","affiliation":[{"name":"Konyang University , , ,","place":["Daejeon, Republic of Korea, 35365"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"316","published-online":{"date-parts":[[2026,8,11]]},"reference":[{"key":"2026083119151248600_cit1","doi-asserted-by":"publisher","DOI":"10.1017\/jns.2016.41","article-title":"Flavonoids: an overview","volume":"5","author":"Panche","year":"2016","journal-title":"J. Nutr Sci."},{"issue":"5","key":"2026083119151248600_cit2","doi-asserted-by":"publisher","first-page":"100611","DOI":"10.1016\/j.advnut.2026.100611","article-title":"Flavonoids","volume":"17","author":"Cheok","year":"2026","journal-title":"Adv. Nutr."},{"key":"2026083119151248600_cit3","doi-asserted-by":"publisher","first-page":"132531","DOI":"10.1016\/j.foodchem.2022.132531","article-title":"Plant flavonoids: Classification,\ndistribution, biosynthesis, and\nantioxidant activity","volume":"383","author":"Shen","year":"2022","journal-title":"Food Chem."},{"key":"2026083119151248600_cit4","doi-asserted-by":"publisher","first-page":"15","DOI":"10.1039\/c0fo00103a","article-title":"Anti-inflammatory\nactivity of natural\ndietary flavonoids","volume":"1","author":"Pan","year":"2010","journal-title":"Food Funct."},{"key":"2026083119151248600_cit5","doi-asserted-by":"publisher","first-page":"2116","DOI":"10.1016\/j.lfs.2005.12.003","article-title":"Flavonoid\u2013drug\ninteractions: Effects of flavonoids on ABC\ntransporters","volume":"78","author":"Morris","year":"2006","journal-title":"Life Sci."},{"key":"2026083119151248600_cit6","doi-asserted-by":"publisher","first-page":"1421","DOI":"10.1002\/jat.4474","article-title":"Inhibitory\ninteraction of flavonoids with organic cation transporter 2 and their\nstructure\u2013activity relationships for predicting nephroprotective\neffects","volume":"43","author":"Tan","year":"2023","journal-title":"J. Appl. Toxicol."},{"key":"2026083119151248600_cit7","unstructured":"ICH.\n          \n          M12 Drug Interaction Studies, 2024. https:\/\/database.ich.org\/sites\/default\/files\/ICH_M12_Step4_Guideline_2024_0521_0.pdf."},{"issue":"1","key":"2026083119151248600_cit8","doi-asserted-by":"publisher","first-page":"52","DOI":"10.1038\/clpt.2013.74","article-title":"Emerging\ntransporters of clinical importance: an update from the International\nTransporter Consortium","volume":"94","author":"Hillgren","year":"2013","journal-title":"Clin. Pharmacol. Ther."},{"key":"2026083119151248600_cit9","doi-asserted-by":"publisher","first-page":"215","DOI":"10.1038\/nrd3028","article-title":"Consortium,\nMembrane transporters in drug development","volume":"9","author":"Giacomini","year":"2010","journal-title":"Nat.\nRev. 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Sci."},{"key":"2026083119151248600_cit13","doi-asserted-by":"publisher","first-page":"1357","DOI":"10.1124\/dmd.114.059337","article-title":"Flavonoids are inhibitors of human\norganic anion transporter 1 (OAT1)-mediated transport","volume":"42","author":"An","year":"2014","journal-title":"Drug Metab. Dispos."},{"key":"2026083119151248600_cit14","doi-asserted-by":"publisher","first-page":"802","DOI":"10.3389\/fphar.2020.00802","article-title":"Identification of Structural Features for the Inhibition\nof OAT3-Mediated Uptake of Enalaprilat by Selected Drugs and Flavonoids","volume":"11","author":"Ni","year":"2020","journal-title":"Front. Pharmacol."},{"key":"2026083119151248600_cit15","doi-asserted-by":"publisher","first-page":"110504","DOI":"10.1016\/j.cbi.2023.110504","article-title":"Strong inhibition\nof organic cation transporter 2 by flavonoids and attenuation effects\non cisplatin-induced cytotoxicity","volume":"379","author":"Shin","year":"2023","journal-title":"Chem. Biol.\nInteract."},{"key":"2026083119151248600_cit16","doi-asserted-by":"publisher","first-page":"1661","DOI":"10.3390\/molecules24091661","article-title":"Quantitative Structure\u2013Activity Relationships for\nthe Flavonoid-Mediated Inhibition of P-Glycoprotein in KB\/MDR1 Cells","volume":"24","author":"Xia","year":"2019","journal-title":"Molecules"},{"key":"2026083119151248600_cit17","doi-asserted-by":"publisher","first-page":"1219","DOI":"10.1080\/14786419.2024.2420333","article-title":"Identification of\nflavonol derivatives inhibiting MDR1: a strategy to overcome multidrug\nresistance in cancer","volume":"40","author":"Kang","year":"2026","journal-title":"Nat. Prod. Res."},{"key":"2026083119151248600_cit18","doi-asserted-by":"publisher","first-page":"112381","DOI":"10.1016\/j.fct.2021.112381","article-title":"Structure-activity\nrelationship and mechanism of flavonoids\non the inhibitory activity of P-glycoprotein (P-gp)-mediated transport\nof rhodamine123 and daunorubicin in P-gp overexpressed human mouth\nepidermal carcinoma (KB\/MDR) cells","volume":"155","author":"Fang","year":"2021","journal-title":"Food Chem.\nToxicol."},{"key":"2026083119151248600_cit19","doi-asserted-by":"publisher","first-page":"1208","DOI":"10.1124\/mol.65.5.1208","article-title":"Flavonoids\nare inhibitors of breast\ncancer resistance protein (ABCG2)-mediated transport","volume":"65","author":"Zhang","year":"2004","journal-title":"Mol. Pharmacol."},{"key":"2026083119151248600_cit20","doi-asserted-by":"publisher","first-page":"1296","DOI":"10.1007\/s11095-010-0108-8","article-title":"Effects of single and multiple flavonoids on BCRP-mediated\naccumulation, cytotoxicity and transport of mitoxantrone in vitro","volume":"27","author":"An","year":"2010","journal-title":"Pharm. Res."},{"key":"2026083119151248600_cit21","doi-asserted-by":"publisher","first-page":"353","DOI":"10.1080\/10286020.2023.2240722","article-title":"Inhibitory\ninteraction of flavonoids with organic anion transporter 3 and their\nstructure-activity relationships for predicting nephroprotective effects","volume":"26","author":"Wang","year":"2024","journal-title":"J. Asian Nat. Prod. Res."},{"key":"2026083119151248600_cit22","doi-asserted-by":"publisher","first-page":"890","DOI":"10.1039\/D3MD00078H","article-title":"Investigating the interactions\nof flavonoids with human OATP2B1:\ninhibition assay, IC50 determination, and structure\u2013activity\nrelationship analysis","volume":"14","author":"Peng","year":"2023","journal-title":"RSC Med. Chem."},{"key":"2026083119151248600_cit23","doi-asserted-by":"publisher","first-page":"28558","DOI":"10.1038\/s41598-025-13908-1","article-title":"Inhibition of breast cancer resistance\nprotein by flavonols:\nin vitro, in vivo, and in silico implications of the interactions","volume":"15","author":"Lee","year":"2025","journal-title":"Sci. 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Funct.\nFoods"},{"issue":"5","key":"2026083119151248600_cit27","doi-asserted-by":"publisher","first-page":"379","DOI":"10.2133\/dmpk.20.379","article-title":"Inui, Metformin\nis a superior substrate\nfor renal organic cation transporter OCT2 rather than hepatic OCT1","volume":"20","author":"Kimura","year":"2005","journal-title":"Drug Metab. Pharmacokinet."},{"key":"2026083119151248600_cit28","doi-asserted-by":"publisher","first-page":"250","DOI":"10.1007\/s11095-020-02964-z","article-title":"Physiologically\nBased Pharmacokinetic Models of Probenecid and Furosemide to Predict\nTransporter Mediated Drug-Drug Interactions","volume":"37","author":"Britz","year":"2020","journal-title":"Pharm. Res."},{"key":"2026083119151248600_cit29","doi-asserted-by":"publisher","first-page":"115635","DOI":"10.1016\/j.jpba.2023.115635","article-title":"Determination\nof furosemide and its glucuronide metabolite in plasma, plasma ultrafiltrate\nand urine by HPLC-MS\/MS with application to secretion and metabolite\nformation clearances in non-pregnant and pregnant women","volume":"235","author":"de Lime Benzi","year":"2023","journal-title":"J. Pharm. Biomed. Anal."},{"key":"2026083119151248600_cit30","doi-asserted-by":"publisher","first-page":"1347","DOI":"10.1007\/s44211-022-00166-8","article-title":"Sensitive\nand valid assay for reliable\nevaluation of drug interactions mediated by human organic anion transporter\n1 and 3 using 5-carboxyfluorescein","volume":"38","author":"Lee","year":"2022","journal-title":"Anal. Sci."},{"key":"2026083119151248600_cit31","doi-asserted-by":"publisher","first-page":"106177","DOI":"10.1016\/j.ejps.2022.106177","article-title":"Role of the efflux\ntransporters Abcb1 and Abcg2 in the brain distribution of olaparib\nin mice","volume":"173","author":"Song","year":"2022","journal-title":"Eur. J. Pharm. Sci."},{"key":"2026083119151248600_cit32","doi-asserted-by":"publisher","first-page":"110886","DOI":"10.1016\/j.cbi.2024.110886","article-title":"Pharmacokinetic interactions of niclosamide\nin rats:\nInvolvement of organic anion transporters 1 and 3 and organic cation\ntransporter 2","volume":"390","author":"Kang","year":"2024","journal-title":"Chem. Biol. Interact."},{"key":"2026083119151248600_cit33","doi-asserted-by":"publisher","first-page":"486","DOI":"10.3390\/pharmaceutics18040486","article-title":"Structure-Guided\nIdentification of Phytochemical OCT2 Inhibitors and Their Functional\nRelevance to Cisplatin-Induced Cytotoxicity","volume":"18","author":"Song","year":"2026","journal-title":"Pharmaceutics"},{"key":"2026083119151248600_cit34","doi-asserted-by":"publisher","first-page":"12473","DOI":"10.1021\/acs.jmedchem.5c00056","article-title":"Substrate\nSpecificity of the Organic Cation Transporters MATE1 and MATE2K and\nFunctional Overlap with OCT1 and OCT2","volume":"68","author":"Redeker","year":"2025","journal-title":"J. Med.\nChem."},{"key":"2026083119151248600_cit35","doi-asserted-by":"publisher","first-page":"F57","DOI":"10.1152\/ajprenal.00318.2015","article-title":"The multidrug transporter\nMATE1 sequesters OCs within an intracellular compartment that has\nno influence on OC secretion in renal proximal tubules","volume":"310","author":"Marti\u0301nez-Guerrero","year":"2016","journal-title":"Am. J. Physiol. Renal Physiol."},{"key":"2026083119151248600_cit36","doi-asserted-by":"publisher","first-page":"809","DOI":"10.1007\/s13318-020-00634-4","article-title":"Potential\nRisk of Food-Drug Interactions: Citrus Polymethoxyflavones\nand Flavanones as Inhibitors of the Organic Anion Transporting Polypeptides\n(OATP) 1B1, 1B3, and 2B1","volume":"45","author":"Bajraktari-Sylejmani","year":"2020","journal-title":"Eur. J. Drug Metab.\nPharmacokinet."},{"key":"2026083119151248600_cit37","doi-asserted-by":"publisher","first-page":"230","DOI":"10.1016\/S0022-3565(24)39224-9","article-title":"Polymethoxylated\nflavones\nin orange juice are inhibitors of P-glycoprotein but not cytochrome\nP450 3A4","volume":"293","author":"Takanaga","year":"2000","journal-title":"J. Pharmacol. Exp. Ther."},{"key":"2026083119151248600_cit38","doi-asserted-by":"publisher","first-page":"C353","DOI":"10.1152\/ajpcell.00388.2006","article-title":"Methoxyflavones protect\ncells against endoplasmic reticulum stress\nand neurotoxin","volume":"292","author":"Takano","year":"2007","journal-title":"Am. J. Physiol. Physiol."},{"key":"2026083119151248600_cit39","doi-asserted-by":"publisher","first-page":"F867","DOI":"10.1152\/ajprenal.00528.2007","article-title":"Overlapping in vitro and in vivo\nspecificities of the\norganic anion transporters OAT1 and OAT3 for loop and thiazide diuretics","volume":"294","author":"Vallon","year":"2008","journal-title":"Am. J. Physiol. Physiol."},{"key":"2026083119151248600_cit40","doi-asserted-by":"publisher","DOI":"10.1136\/bmjdrc-2019-000816","article-title":"Increasing\nmetformin\nconcentrations and its excretion in both rat and porcine ex vivo normothermic\nkidney perfusion model","volume":"8","author":"Posma","year":"2020","journal-title":"BMJ Open Diabetes Res.\nCare"},{"key":"2026083119151248600_cit41","doi-asserted-by":"publisher","first-page":"2543","DOI":"10.1002\/jps.20744","article-title":"Dose-Independent\nPharmacokinetics\nof Metformin in Rats: Hepatic and Gastrointestinal First-Pass Effects","volume":"95","author":"Choi","year":"2006","journal-title":"J. Pharm. Sci."},{"key":"2026083119151248600_cit42","doi-asserted-by":"publisher","first-page":"6310","DOI":"10.1016\/j.bmc.2010.07.020","article-title":"Selective inhibition of methoxyflavonoids on human\nCYP1B1 activity","volume":"18","author":"Takemura","year":"2010","journal-title":"Bioorg. Med. Chem."},{"key":"2026083119151248600_cit43","doi-asserted-by":"publisher","first-page":"849","DOI":"10.1016\/j.xphs.2024.10.037","article-title":"Kinetics of the inhibition\nof CYP3A4 and CYP2C19 activity\nby jabara juice and identification of the responsible inhibitory components","volume":"114","author":"Koinuma","year":"2025","journal-title":"J. Pharm. Sci."},{"key":"2026083119151248600_cit44","doi-asserted-by":"publisher","first-page":"2245","DOI":"10.1016\/j.xphs.2017.04.078","article-title":"Transporters Involved in Metformin\nPharmacokinetics\nand Treatment Response","volume":"106","author":"Liang","year":"2017","journal-title":"J. Pharm. Sci."},{"key":"2026083119151248600_cit45","doi-asserted-by":"publisher","first-page":"32939","DOI":"10.1021\/acsomega.0c03930","article-title":"Contribution\nof Uptake and Efflux Transporters to Oral Pharmacokinetics of Furosemide","volume":"5","author":"Chapa","year":"2020","journal-title":"ACS Omega"}],"container-title":["ACS Omega"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/pubs.acs.org\/doi\/pdf\/10.1021\/acsomega.6c03122","content-type":"application\/pdf","content-version":"vor","intended-application":"unspecified"},{"URL":"https:\/\/pubs.acs.org\/acsodf\/article-pdf\/11\/33\/49579\/66503754\/acsomega.6c03122.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/pubs.acs.org\/acsodf\/article-pdf\/11\/33\/49579\/66503754\/acsomega.6c03122.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,8,31]],"date-time":"2026-08-31T23:15:19Z","timestamp":1788218119000},"score":1,"resource":{"primary":{"URL":"https:\/\/pubs.acs.org\/acsodf\/article\/11\/33\/49579\/5253004\/Transporter-Interactions-of-Methoxyflavones-and"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,8,11]]},"references-count":45,"journal-issue":{"issue":"33","published-online":{"date-parts":[[2026,8,11]]},"published-print":{"date-parts":[[2026,8,25]]}},"URL":"https:\/\/doi.org\/10.1021\/acsomega.6c03122","relation":{},"ISSN":["2470-1343"],"issn-type":[{"value":"2470-1343","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,8,11]]}}}