title: 5,7-Dimethoxyflavone and multiple flavonoids in combination alter the ABCG2-mediated tissue distribution of mitoxantrone in mice.
abstract: OBJECTIVE
  The objective of our study was to investigate the effect of 5,7-DMF on the accumulation of mitoxantrone (MX) in BCRP-expressing normal cells and to investigate its impact on the PK and tissue distribution of MX in mice.
  
  
  METHODS
  The in vitro effect of 5,7-DMF on MX accumulation was examined in MDCK cells transfected with BCRP. The pharmacokinetic and tissue distribution of mitoxantrone, with and without co-administration of 5,7-DMF or multiple flavonoid combinations, were determined in mice.
  
  
  RESULTS
  In the presence of 2.5 μM or 25 μM of 5,7-DMF, the intracellular concentration of MX was significantly increased in MDCK/Bcrp1 and MDCK/BCRP cells, but not in MDCK/Mock cells. The AUC values of MX in several tissues were significantly increased when MX was co-administered with 5,7-DMF. The most substantial elevations of MX AUC in the presence of 5,7-DMF occurred in the liver (94.5%) and kidneys (61.9%), which is in apparent agreement with the relatively high levels of mouse Bcrp1 expression in these two tissues.
  
  
  CONCLUSIONS
  Bcrp1-mediated DMF-MX interactions occur both in vitro and in vivo. 5,7-DMF represents a novel and very promising chemosensitizing agent for the BCRP-mediated MDR due to its low toxicity and potent BCRP inhibition.
authors.affiliation: Department of Pharmaceutical Sciences School of Pharmacy and Pharmaceutical Sciences, University at Buffalo, State University of New York, 517 Hochstetter Hall, Amherst, New York 14260-1200, USA.
authors.forename: Guohua
authors.initials: G
authors.lastname: An
authors.forename: Fang
authors.initials: F
authors.lastname: Wu
authors.forename: Marilyn E
authors.initials: ME
authors.lastname: Morris
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000235:genetics; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters / Q000235:genetics / Q000378:metabolism; D000818:Animals; D000970:Antineoplastic Agents / Q000493:pharmacokinetics*; D002460:Cell Line; D045744:Cell Line, Tumor; D004285:Dogs; D004347:Drug Interactions; D019008:Drug Resistance, Neoplasm; D005419:Flavonoids / Q000494:pharmacology*; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008297:Male; D051379:Mice; D008942:Mitoxantrone / Q000493:pharmacokinetics*; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism*; D009369:Neoplasms / Q000188:drug therapy
chemical_list: C116614:ABCG2 protein, human; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters; C501412:Abcg2 protein, mouse; D000970:Antineoplastic Agents; D005419:Flavonoids; D009363:Neoplasm Proteins; C060298:5,7-dimethoxyflavone; D008942:Mitoxantrone