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1. Antimicrob Agents Chemother. 2012 Apr 16. [Epub ahead of print]

The anthelmintic triclabendazole and its metabolites inhibit the membrane
transporter ABCG2/BCRP.

Barrera B, Otero JA, Egido E, Prieto JG, Seelig A, Alvarez AI, Merino G.

Departamento de Ciencias Biomédicas -Fisiología, Facultad de Veterinaria.

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 concentration 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 MDCKII 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 μM. Transepithelial transport assays of ABCG2 substrates in
presence of both TCBZ metabolites at 15 μM showed a 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
sulphonamide 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.

PMID: 22508302 [PubMed - as supplied by publisher]