title: Inhibitory potential of tuberculosis drugs on ATP-binding cassette drug transporters.
abstract: BACKGROUND
  Multiple-drug therapy for tuberculosis (TB) and TB-associated co-morbidity increase the likelihood of drug-drug interactions (DDIs). Inhibition of membrane transporters is an important mechanism underlying DDIs. In this study, we assessed the in vitro inhibitory potential of currently used first and second-line TB drugs and of proposed mycobacterial efflux pump inhibitors (EPIs) on the major ABC transporters relevant to drug transport, namely P-gp, BCRP, BSEP and MRP1-5.
  
  
  METHODS
  Membrane vesicles isolated from transporter-overexpressing HEK293 cells were used to study the inhibitory action of TB drugs and EPIs on the transport of model substrates [(3)H]-NMQ (P-gp); [(3)H]-E1S (BCRP); [(3)H]-TCA (BSEP); [(3)H]-E217βG (MRP1, 3 and 4) and [(3)H]-MTX (MRP2 and 5).
  
  
  RESULTS
  A strong inhibition (IC50 value <15 μM) was observed for clofazimine (P-gp, BCRP and MRP1), thioridazine (BCRP), timcodar (P-gp, BSEP and MRP1) and SQ109 (P-gp and BCRP). Rifampicin inhibited all transporters, but less potently.
  
  
  CONCLUSIONS
  Co-administration of clofazimine, thioridazine, timcodar, SQ109 and possibly rifampicin with drugs that are substrates for the inhibited transporters may lead to DDIs. The mycobacterial EPIs potently inhibited a wider range of human ABC transporters than previously reported. These vesicular transport data are especially valuable considering the current emphasis on development of TB drug regimens.
authors.affiliation: Department of Pharmacology and Toxicology, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Geert Grooteplein 26, 6525 GA, Internal Postal Code 149, Nijmegen, The Netherlands; Department of Pharmacy, Radboud Institute for Health Sciences, Radboud University Medical Center, Geert Grooteplein 10, 6525 GA, Internal Postal Code 864, Nijmegen, The Netherlands. Electronic address: Lindsey.teBrake@radboudumc.nl.
authors.forename: Lindsey H M
authors.initials: LH
authors.lastname: Te Brake
authors.affiliation: Department of Pharmacology and Toxicology, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Geert Grooteplein 26, 6525 GA, Internal Postal Code 149, Nijmegen, The Netherlands. Electronic address: Frans.Russel@radboudumc.nl.
authors.forename: Frans G M
authors.initials: FG
authors.lastname: Russel
authors.affiliation: Department of Pharmacology and Toxicology, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Geert Grooteplein 26, 6525 GA, Internal Postal Code 149, Nijmegen, The Netherlands. Electronic address: Jeroen.vandenHeuvel@radboudumc.nl.
authors.forename: Jeroen J M W
authors.initials: JJ
authors.lastname: van den Heuvel
authors.affiliation: Department of Medical Microbiology and Infectious Diseases, Erasmus Medical Center, 's-Gravendijkwal 230, 3015 CE, Rotterdam, The Netherlands. Electronic address: g.deknegt@erasmusmc.nl.
authors.forename: Gerjo J
authors.initials: GJ
authors.lastname: de Knegt
authors.affiliation: Department of Medical Microbiology and Infectious Diseases, Erasmus Medical Center, 's-Gravendijkwal 230, 3015 CE, Rotterdam, The Netherlands. Electronic address: j.desteenwinkel@erasmusmc.nl.
authors.forename: Jurriaan E
authors.initials: JE
authors.lastname: de Steenwinkel
authors.affiliation: Department of Pharmacy, Radboud Institute for Health Sciences, Radboud University Medical Center, Geert Grooteplein 10, 6525 GA, Internal Postal Code 864, Nijmegen, The Netherlands. Electronic address: David.Burger@radboudumc.nl.
authors.forename: David M
authors.initials: DM
authors.lastname: Burger
authors.affiliation: Department of Pharmacy, Radboud Institute for Health Sciences, Radboud University Medical Center, Geert Grooteplein 10, 6525 GA, Internal Postal Code 864, Nijmegen, The Netherlands. Electronic address: Rob.Aarnoutse@radboudumc.nl.
authors.forename: Rob E
authors.initials: RE
authors.lastname: Aarnoutse
authors.affiliation: Department of Pharmacology and Toxicology, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Geert Grooteplein 26, 6525 GA, Internal Postal Code 149, Nijmegen, The Netherlands. Electronic address: Jan.Koenderink@radboudumc.nl.
authors.forename: Jan B
authors.initials: JB
authors.lastname: Koenderink
mesh_terms: D018435:ATP Binding Cassette Transporter, Subfamily B / Q000037:antagonists & inhibitors / Q000378:metabolism; D000074020:ATP Binding Cassette Transporter, Subfamily B, Member 11; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D000995:Antitubercular Agents / Q000494:pharmacology*; D002462:Cell Membrane / Q000187:drug effects* / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D057809:HEK293 Cells; D006801:Humans; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D014162:Transfection
chemical_list: D018435:ATP Binding Cassette Transporter, Subfamily B; D000074020:ATP Binding Cassette Transporter, Subfamily B, Member 11; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters; D000995:Antitubercular Agents; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D009363:Neoplasm Proteins; C513055:ABCB1 protein, human; C093491:ABCB11 protein, human; C116614:ABCG2 protein, human
keywords: ABC transporters; Drug-drug interactions; Membrane vesicles; Protein overexpression; Tuberculosis; Vesicular transport assay