Effect of 5,7-dimethoxyflavone on Bcrp1-mediated transport of sorafenib in vitro and in vivo in mice

Eur J Pharm Sci. 2018 May 30;117:27-34. doi: 10.1016/j.ejps.2018.02.004. Epub 2018 Feb 6.

Abstract

Tyrosine kinase inhibitors (TKI) are a novel and target-specific class of anticancer drugs. One drawback of TKI therapy is cancer resistance to TKI. An important TKI resistance mechanism is enhanced efflux of TKI by efflux transporters, such as Breast Cancer Resistance Protein (BCRP), in cancer cells. 5,7-Dimethoxyflavone (5,7-DMF) is a natural flavonoid which was recently reported to be a potent BCRP inhibitor. In the current study, the effect of 5,7-DMF on the disposition of sorafenib, a TKI which is a good substrate of BCRP, was investigated both in vitro in efflux transporter expressing cells and in vivo in mice. 5,7-DMF significantly inhibited Bcrp1-mediated sorafenib efflux in a concentration dependent manner in MDCK/Bcrp1 cells, with EC50 value of 8.78 μM. The pharmacokinetics and tissue distribution of sorafenib (10 mg/kg) with and without co-administration of 75 mg/kg 5,7-DMF were determined. With 5,7-DMF, the AUC of sorafenib in plasma was 47,400 ± 4790 ng·h/mL, which was significantly higher than 27,300 ± 2650 ng·h/mL in sorafenib alone group. In addition, compared to sorafenib alone group, great increase in sorafenib AUC was observed in most tissues collected when sorafenib was given with 5,7-DMF. Our results indicated that 5,7-DMF may represent a novel and very promising chemosensitizing agent for BCRP-mediated anticancer drug resistance due to its low toxicity and potent BCRP inhibition.

Keywords: 5,7-Dimethoxyflavone; Breast cancer resistance protein; Drug-drug interactions; Pharmacokinetics; Tyrosine kinase inhibitors.

MeSH terms

  • ATP Binding Cassette Transporter, Subfamily B / genetics
  • ATP Binding Cassette Transporter, Subfamily G, Member 2 / antagonists & inhibitors*
  • ATP Binding Cassette Transporter, Subfamily G, Member 2 / genetics
  • Animals
  • Antineoplastic Agents / blood
  • Antineoplastic Agents / pharmacokinetics*
  • Antineoplastic Agents / pharmacology
  • Biological Transport
  • Dogs
  • Drug Interactions
  • Drug Resistance, Neoplasm
  • Flavonoids / pharmacology*
  • LLC-PK1 Cells
  • Madin Darby Canine Kidney Cells
  • Male
  • Mice
  • Niacinamide / analogs & derivatives*
  • Niacinamide / blood
  • Niacinamide / pharmacokinetics
  • Niacinamide / pharmacology
  • Phenylurea Compounds / blood
  • Phenylurea Compounds / pharmacokinetics*
  • Phenylurea Compounds / pharmacology
  • Protein Kinase Inhibitors / blood
  • Protein Kinase Inhibitors / pharmacokinetics*
  • Protein Kinase Inhibitors / pharmacology
  • Sorafenib
  • Swine
  • Tissue Distribution

Substances

  • ABCB1 protein, human
  • ATP Binding Cassette Transporter, Subfamily B
  • ATP Binding Cassette Transporter, Subfamily G, Member 2
  • Abcg2 protein, mouse
  • Antineoplastic Agents
  • Flavonoids
  • Phenylurea Compounds
  • Protein Kinase Inhibitors
  • 5,7-dimethoxyflavone
  • Niacinamide
  • Sorafenib