The Anthelmintic Triclabendazole and Its Metabolites Inhibit the Membrane Transporter ABCG2/BCRP

Barrera, Borja and Otero, Jon A. and Egido, Estefanía and Prieto, Julio G. and Seelig, Anna and Alvarez, Ana I. and Merino, Gracia. (2012) The Anthelmintic Triclabendazole and Its Metabolites Inhibit the Membrane Transporter ABCG2/BCRP. Antimicrobial Agents and Chemotherapy, 56 (7). pp. 3535-3543.

Full text not available from this repository.

Official URL: http://edoc.unibas.ch/47701/

Downloads: Statistics Overview


ABCG2/BCRP is an ATP-binding cassette transporter that extrudes compounds from cells in the intestine, liver, kidney, and other organs, such as the mammary gland, affecting pharmacokinetics and milk secretion of antibiotics, anticancer drugs, and other compounds and mediating drug-drug interactions. In addition, ABCG2 expression in cancer cells may directly cause resistance by active efflux of anticancer drugs. The development of ABCG2 modulators is critical in order to improve drug pharmacokinetic properties, reduce milk secretion of xenotoxins, and/or increase the effective intracellular concentrations of substrates. Our purpose was to determine whether the anthelmintic triclabendazole (TCBZ) and its main plasma metabolites triclabendazole sulfoxide (TCBZSO) and triclabendazole sulfone (TCBZSO(2)) inhibit ABCG2 activity. ATPase assays using human ABCG2-enriched membranes demonstrated a clear ABCG2 inhibition exerted by these compounds. Mitoxantrone accumulation assays using murine Abcg2- and human ABCG2-transduced MDCK-II cells confirmed that TCBZSO and TCBZSO(2) are ABCG2 inhibitors, reaching inhibitory potencies between 40 and 55% for a concentration range from 5 to 25 ?M. Transepithelial transport assays of ABCG2 substrates in the presence of both TCBZ metabolites at 15 ?M showed very efficient inhibition of the Abcg2/ABCG2-mediated transport of the antibacterial agents nitrofurantoin and danofloxacin. TCBZSO administration also inhibited nitrofurantoin Abcg2-mediated secretion into milk by more than 2-fold and increased plasma levels of the sulfonamide sulfasalazine by more than 1.5-fold in mice. These results support the potential role of TCBZSO and TCBZSO(2) as ABCG2 inhibitors to participate in drug interactions and modulate ABCG2-mediated pharmacokinetic processes.
Faculties and Departments:05 Faculty of Science > Departement Biozentrum > Former Organization Units Biozentrum > Biophysical Chemistry (Seelig A)
UniBasel Contributors:Seelig-Löffler, Anna and Egido de Frutos, Estefania
Item Type:Article, refereed
Article Subtype:Research Article
Publisher:American Society for Microbiology
Note:Publication type according to Uni Basel Research Database: Journal article
Identification Number:
Last Modified:30 Nov 2017 10:50
Deposited On:30 Nov 2017 10:50

Repository Staff Only: item control page