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 [3H]-NMQ (P-gp); [3H]-E1S (BCRP); [3H]-TCA (BSEP); [3H]-E217βG (MRP1, 3 and 4) and [3H]-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.

ABC transporters, Drug-drug interactions, Membrane vesicles, Protein overexpression, Tuberculosis, Vesicular transport assay
dx.doi.org/10.1016/j.tube.2015.08.004, hdl.handle.net/1765/90043
Tuberculosis
Department of Medical Microbiology and Infectious Diseases

Te Brake, L.H.M, Russel, F.G.M, van den Heuvel, J.J.M, de Knegt, G.J, de Steenwinkel, J.E.M, Burger, D.M, … Koenderink, J.B. (2015). Inhibitory potential of tuberculosis drugs on ATP-binding cassette drug transporters. Tuberculosis, 96, 150–157. doi:10.1016/j.tube.2015.08.004