Effect of excipients on breast cancer resistance protein substrate uptake activity

J Control Release. 2007 Dec 4;124(1-2):1-5. doi: 10.1016/j.jconrel.2007.08.021. Epub 2007 Aug 24.

Abstract

Breast cancer resistance protein (BCRP/ABCG2) plays an important role in drug disposition. To examine whether some currently used excipients could inhibit its function, we measured the uptake of [(3)H]mitoxantrone in BCRP-, P-glycoprotein (P-gp)- or green fluorescent protein (GFP)-expressing cells, in the presence or absence of 15 kinds of currently used excipients. Of 15 excipients, five (Cremophor EL, Tween 20, Span 20, Pluronic P85 and Brij 30) increased the uptake of [(3)H]mitoxantrone in BCRP-expressing cells. On the other hand, ten (Cremophor EL, Cremophor RH40, Tween 20, Tween 80, Span 20, Pluronic P85, vitamin E TPGS, Brij 30, Myrj 52 and Gelucire 44/14) significantly increased uptake in P-gp-expressing cells. No significant effects on intracellular ATP levels were observed following treatments with the excipients that inhibited BCRP function. Taken together, this study demonstrated that some excipients might be potent BCRP inhibitors, and there may be differences in the effects of excipients on the functions of BCRP and P-gp.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • ATP Binding Cassette Transporter, Subfamily G, Member 2
  • ATP-Binding Cassette Transporters / antagonists & inhibitors*
  • ATP-Binding Cassette Transporters / biosynthesis
  • ATP-Binding Cassette Transporters / genetics
  • Animals
  • Antineoplastic Agents / chemistry
  • Antineoplastic Agents / pharmacokinetics*
  • Biological Availability
  • Breast Neoplasms / metabolism*
  • Breast Neoplasms / pathology
  • Cell Line, Tumor
  • Dogs
  • Drug Resistance, Neoplasm / drug effects*
  • Excipients / chemistry
  • Excipients / pharmacology*
  • Female
  • Mitoxantrone / chemistry
  • Mitoxantrone / pharmacokinetics*
  • Neoplasm Proteins / antagonists & inhibitors*
  • Neoplasm Proteins / biosynthesis
  • Neoplasm Proteins / genetics
  • Substrate Specificity
  • Tissue Distribution
  • Transfection

Substances

  • ABCG2 protein, human
  • ATP Binding Cassette Transporter, Subfamily G, Member 2
  • ATP-Binding Cassette Transporters
  • Antineoplastic Agents
  • Excipients
  • Neoplasm Proteins
  • Mitoxantrone