title: Protease inhibitors atazanavir, lopinavir and ritonavir are potent blockers, but poor substrates, of ABC transporters in a broad panel of ABC transporter-overexpressing cell lines.
abstract: OBJECTIVE
  A possible mechanism for HIV therapy failure is the efflux of HIV drugs from viral target cells or certain body compartments by ATP-binding cassette (ABC) transporters, allowing ongoing viral replication. Here, we investigated the interaction between protease inhibitors (PIs) and ABC transporters.
  
  
  METHODS
  To explore the potential blocking capacity of PIs, we exposed cells overexpressing multidrug resistance 1 P-glycoprotein (MDR1 P-gp), multidrug resistance protein 1 (MRP1) and breast cancer resistance protein (BCRP) to established cytotoxic substrates with or without one of the PIs atazanavir, lopinavir or ritonavir. Furthermore, to assess whether PIs serve as substrates, cell growth-inhibitory effects of these PIs were evaluated on cells overexpressing 1 of 11 ABC transporters and their parental counterparts.
  
  
  RESULTS
  Atazanavir, lopinavir and ritonavir were highly effective in reversing resistance against established substrates in cells overexpressing MDR1 P-gp and MRP1, and, to a lesser extent, BCRP. Concurrently, however, PIs appeared to be relatively poor substrates for ABC transporters. Only a moderate level of resistance to atazanavir was observed in cells overexpressing MRP6 and MRP9 [resistance factor (RF): 2.0-2.6]. Cells overexpressing MDR1 P-gp, MRP3, MRP4 and MRP5 displayed low levels of resistance to atazanavir (RF: 1.3-1.7); MRP7- and MRP9-overexpressing cells to lopinavir (RF: 1.4-1.5); and MRP9-overexpressing cells to ritonavir (RF: 1.4).
  
  
  CONCLUSIONS
  PIs can act as potent blockers of MDR1 P-gp, MRP1 and BCRP, but they are poor substrates for 11 ABC transporters. Consequently, ABC transporters are unlikely to play a major role in PI failure, but still may contribute to drug-specific adverse events and drug-drug interactions.
authors.affiliation: Department of Internal Medicine, VU University Medical Center, Secretariaat Inwendige Geneeskunde, De Boelelaan 1117, 1081 HV Amsterdam, The Netherlands. w.bierman@vumc.nl
authors.forename: Wouter F W
authors.initials: WF
authors.lastname: Bierman
authors.forename: George L
authors.initials: GL
authors.lastname: Scheffer
authors.forename: Antoinet
authors.initials: A
authors.lastname: Schoonderwoerd
authors.forename: Gerrit
authors.initials: G
authors.lastname: Jansen
authors.forename: Michiel A
authors.initials: MA
authors.lastname: van Agtmael
authors.forename: Sven A
authors.initials: SA
authors.lastname: Danner
authors.forename: Rik J
authors.initials: RJ
authors.lastname: Scheper
mesh_terms: D018528:ATP-Binding Cassette Transporters / Q000037:antagonists & inhibitors*; D000069446:Atazanavir Sulfate; D002460:Cell Line; D018432:Drug Resistance, Multiple / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000378:metabolism*; D017320:HIV Protease Inhibitors / Q000378:metabolism*; D006801:Humans; D061466:Lopinavir; D009842:Oligopeptides / Q000378:metabolism*; D011725:Pyridines / Q000378:metabolism*; D011744:Pyrimidinones / Q000378:metabolism*; D019438:Ritonavir / Q000378:metabolism*
chemical_list: D018528:ATP-Binding Cassette Transporters; D004791:Enzyme Inhibitors; D017320:HIV Protease Inhibitors; D009842:Oligopeptides; D011725:Pyridines; D011744:Pyrimidinones; D061466:Lopinavir; D000069446:Atazanavir Sulfate; D019438:Ritonavir