5,7-Dimethoxyflavone and multiple flavonoids in combination alter the ABCG2-mediated tissue distribution of mitoxantrone in mice

Pharm Res. 2011 May;28(5):1090-9. doi: 10.1007/s11095-011-0368-y. Epub 2011 Jan 29.

Abstract

Purpose: 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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • ATP Binding Cassette Transporter, Subfamily B, Member 1 / genetics
  • ATP Binding Cassette Transporter, Subfamily G, Member 2
  • ATP-Binding Cassette Transporters / genetics
  • ATP-Binding Cassette Transporters / metabolism
  • Animals
  • Antineoplastic Agents / pharmacokinetics*
  • Cell Line
  • Cell Line, Tumor
  • Dogs
  • Drug Interactions
  • Drug Resistance, Neoplasm
  • Flavonoids / pharmacology*
  • Gene Expression Regulation, Neoplastic
  • Humans
  • Male
  • Mice
  • Mitoxantrone / pharmacokinetics*
  • Neoplasm Proteins / genetics
  • Neoplasm Proteins / metabolism*
  • Neoplasms / drug therapy

Substances

  • ABCG2 protein, human
  • ATP Binding Cassette Transporter, Subfamily B, Member 1
  • ATP Binding Cassette Transporter, Subfamily G, Member 2
  • ATP-Binding Cassette Transporters
  • Abcg2 protein, mouse
  • Antineoplastic Agents
  • Flavonoids
  • Neoplasm Proteins
  • 5,7-dimethoxyflavone
  • Mitoxantrone