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]-E217betaG (MRP1, 3 and 4) and [(3)H]-MTX (MRP2 and 5). RESULTS: A strong inhibition (IC50 value <15 muM) 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.