title: Biochemical interaction of anti-HCV telaprevir with the ABC transporters P-glycoprotein and breast cancer resistance protein.
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.
  
  
  RESULTS
  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.
  
  
  CONCLUSIONS
  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.
authors.forename: Yuria
authors.initials: Y
authors.lastname: Fujita
authors.affiliation: Division of Chemotherapy, Faculty of Pharmacy, Keio University, 1-5-30 Shibakoen, Minato-ku, Tokyo 105-8512, Japan. noguchi-kj@pha.keio.ac.jp.
authors.forename: Kohji
authors.initials: K
authors.lastname: Noguchi
authors.forename: Tomonori
authors.initials: T
authors.lastname: Suzuki
authors.forename: Kazuhiro
authors.initials: K
authors.lastname: Katayama
authors.forename: Yoshikazu
authors.initials: Y
authors.lastname: Sugimoto
mesh_terms: D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000998:Antiviral Agents / Q000378:metabolism / Q000494:pharmacology*; D001667:Binding, Competitive; D001692:Biological Transport / Q000187:drug effects; D002462:Cell Membrane / Q000737:chemistry / Q000187:drug effects / Q000378:metabolism; D004970:Estrone / Q000031:analogs & derivatives / Q000378:metabolism; D006801:Humans; D007457:Iodine Radioisotopes; D020014:K562 Cells; D007700:Kinetics; D008727:Methotrexate / Q000378:metabolism; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D009842:Oligopeptides / Q000378:metabolism / Q000494:pharmacology*; D011485:Protein Binding; D013347:Subcellular Fractions / Q000737:chemistry / Q000187:drug effects / Q000378:metabolism; D014316:Tritium; D014750:Vincristine / Q000378:metabolism
chemical_list: C513055:ABCB1 protein, human; C116614:ABCG2 protein, human; D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters; D000998:Antiviral Agents; D007457:Iodine Radioisotopes; D009363:Neoplasm Proteins; D009842:Oligopeptides; D014316:Tritium; D004970:Estrone; D014750:Vincristine; C486464:telaprevir; C017296:estrone sulfate; D008727:Methotrexate