Lindsey H M Te Brake1, Frans G M Russel2, Jeroen J M W van den Heuvel3, Gerjo J de Knegt4, Jurriaan E de Steenwinkel5, David M Burger6, Rob E Aarnoutse7, Jan B Koenderink8. 1. 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. 2. 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. 3. 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. 4. Department of Medical Microbiology and Infectious Diseases, Erasmus Medical Center, 's-Gravendijkwal 230, 3015 CE, Rotterdam, The Netherlands. Electronic address: g.deknegt@erasmusmc.nl. 5. Department of Medical Microbiology and Infectious Diseases, Erasmus Medical Center, 's-Gravendijkwal 230, 3015 CE, Rotterdam, The Netherlands. Electronic address: j.desteenwinkel@erasmusmc.nl. 6. 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. 7. 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. 8. 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.
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.
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.
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