Biochemical interaction of anti-HCV telaprevir with the ABC transporters P-glycoprotein and breast cancer resistance protein

BMC Res Notes. 2013 Nov 6;6:445. doi: 10.1186/1756-0500-6-445.

Abstract

Background: The ATP-binding cassette (ABC) transporters P-glycoprotein (P-gp)/ABCB1 and breast cancer resistance protein (BCRP)/ABCG2 are involved in the intestinal absorption and renal excretion of various substrate drugs. Their activities affect sub-therapeutic drug concentrations and excretion of natural transporter substrates. The new oral anti-HCV drug telaprevir has dramatically improved the efficacy of hepatitis-C virus (HCV) treatment, and recent studies have suggested a possible pharmacological interaction between telaprevir and P-gp. We studied the kinetics of in vitro interactions between telaprevir and P-gp and BCRP to understand the molecular basis of that interaction.

Findings: The effect of telaprevir on P-gp- and BCRP-mediated transport was evaluated by an in vitro vesicle transporter assay using different transport substrates, and the kinetics of transporter inhibition was determined. The results showed that telaprevir could inhibit P-gp- and BCRP-mediated transport in the in vitro vesicle transport assay, with each IC50 values of ≈ 7 μmol/L and ≈ 30 μmol/L, respectively. Analyses of Lineweaver-Burk plots showed that telaprevir was likely to be a competitive inhibitor against P-gp and BCRP. Photoaffinity labeling experiments were employed to observe competitive inhibition by telaprevir using iodoarylazidoprazosin (IAAP) as a binding substrate for P-gp and BCRP. These experiments revealed that telaprevir inhibited [125I]-IAAP-binding with P-gp and BCRP.

Conclusion: Telaprevir competitively inhibited P-gp and BCRP, and P-gp-mediated transport was more sensitive to telaprevir compared with BCRP-mediated transport. These data suggest that telaprevir represses the transporter functions of P-gp and BCRP via direct inhibition.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • ATP Binding Cassette Transporter, Subfamily B
  • ATP Binding Cassette Transporter, Subfamily B, Member 1 / antagonists & inhibitors*
  • ATP Binding Cassette Transporter, Subfamily B, Member 1 / metabolism
  • ATP Binding Cassette Transporter, Subfamily G, Member 2
  • ATP-Binding Cassette Transporters / antagonists & inhibitors*
  • ATP-Binding Cassette Transporters / metabolism
  • Antiviral Agents / metabolism
  • Antiviral Agents / pharmacology*
  • Binding, Competitive
  • Biological Transport / drug effects
  • Cell Membrane / chemistry
  • Cell Membrane / drug effects
  • Cell Membrane / metabolism
  • Estrone / analogs & derivatives
  • Estrone / metabolism
  • Humans
  • Iodine Radioisotopes
  • K562 Cells
  • Kinetics
  • Methotrexate / metabolism
  • Neoplasm Proteins / antagonists & inhibitors*
  • Neoplasm Proteins / metabolism
  • Oligopeptides / metabolism
  • Oligopeptides / pharmacology*
  • Protein Binding
  • Subcellular Fractions / chemistry
  • Subcellular Fractions / drug effects
  • Subcellular Fractions / metabolism
  • Tritium
  • Vincristine / metabolism

Substances

  • ABCB1 protein, human
  • ABCG2 protein, human
  • ATP Binding Cassette Transporter, Subfamily B
  • ATP Binding Cassette Transporter, Subfamily B, Member 1
  • ATP Binding Cassette Transporter, Subfamily G, Member 2
  • ATP-Binding Cassette Transporters
  • Antiviral Agents
  • Iodine Radioisotopes
  • Neoplasm Proteins
  • Oligopeptides
  • Tritium
  • Estrone
  • Vincristine
  • telaprevir
  • estrone sulfate
  • Methotrexate