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

Article Details

Citation

Copy to clipboard

Te Brake LH, Russel FG, van den Heuvel JJ, de Knegt GJ, de Steenwinkel JE, Burger DM, Aarnoutse RE, Koenderink JB

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

Tuberculosis (Edinb). 2016 Jan;96:150-7. doi: 10.1016/j.tube.2015.08.004. Epub 2015 Oct 9.

PubMed ID

26682943 [ View in PubMed

]

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.

DrugBank Data that Cites this Article

Drugs

Clofazimine

Drug Transporters

Drug	Transporter	Kind	Organism	Pharmacological Action	Actions
Clofazimine	ATP-binding cassette sub-family G member 2	Protein	Humans	Unknown	Inhibitor	Details
Clofazimine	Multidrug resistance-associated protein 1	Protein	Humans	Unknown	Inhibitor	Details
Clofazimine	P-glycoprotein 1	Protein	Humans	Unknown	Substrate Inhibitor	Details