Inhibitory potential of tuberculosis drugs on ATP-binding cassette drug transporters

LHM te Brake, FGM Russel, JJMW van den Heuvel, Gerjo Knegt, Jurriaan de Steenwinkel, DM Burger, RE Aarnoutse, JB Koenderink

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Abstract

Background: Multiple-drug therapy for tuberculosis (TB) and TB-associated co-morbidity increase the likelihood of drugedrug 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 [H-3]-NMQ (P-gp); [3H]-E1S (BCRP); [H-3]-TCA (BSEP); [H-3]-E217 beta G (MRP1, 3 and 4) and [H-3]-MTX (MRP2 and 5). Results: A strong inhibition (IC50 value < 15 mu M) 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. (C) 2015 Elsevier Ltd. All rights reserved.
Original languageUndefined/Unknown
Pages (from-to)150-157
Number of pages8
JournalTuberculosis
Volume96
DOIs
Publication statusPublished - 2016

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