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

• Published in: Tuberculosis (Edinburgh, Scotland) Scotland), 2016-01, Vol.96, p.150-157
• Main Authors: te Brake, Lindsey H.M, Russel, Frans G.M, van den Heuvel, Jeroen J.M.W, de Knegt, Gerjo J, de Steenwinkel, Jurriaan E, Burger, David M, Aarnoutse, Rob E, Koenderink, Jan B
• Format: Article
• Language: English
• Subjects: ABC transporters; Antitubercular Agents - pharmacology; ATP Binding Cassette Subfamily B Member 11; ATP Binding Cassette Transporter, Sub-Family B - antagonists & inhibitors; ATP Binding Cassette Transporter, Sub-Family B - metabolism; ATP Binding Cassette Transporter, Sub-Family G, Member 2; ATP-Binding Cassette Transporters - antagonists & inhibitors; ATP-Binding Cassette Transporters - genetics; ATP-Binding Cassette Transporters - metabolism; Cell Membrane - drug effects; Cell Membrane - metabolism; Dose-Response Relationship, Drug; Drug Interactions; Drug-drug interactions; HEK293 Cells; Humans; Infectious Disease; Membrane vesicles; Multidrug Resistance-Associated Proteins - antagonists & inhibitors; Multidrug Resistance-Associated Proteins - metabolism; Neoplasm Proteins - antagonists & inhibitors; Neoplasm Proteins - metabolism; Protein overexpression; Pulmonary/Respiratory; Transfection; Tuberculosis; Vesicular transport assay
• ISSN: 1472-9792; 1873-281X
• DOI: 10.1016/j.tube.2015.08.004

Summary 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]-E1 S (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