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

Abstract

dABCG2/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.

Effects of triclabendazole on secretion of danofloxacin and moxidectin into the milk of sheep: Role of triclabendazole metabolites as inhibitors of the ruminant ABCG2 transporter

“…Much of the information related to ABCG2-mediated interactions derived from human and rodent studies appears to be applicable to other mammalian species (Mealey, 2012), since previous work has demonstrated that TCBZSO and TCBZSO 2 are murine and human ABCG2 inhibitors (Barrera et al, 2012). In addition, the in vivo experiments reported here using sheep may be also applicable to other ruminant species, such as cattle, where a study of the differences dependent upon the Y581S genotype might be of interest in the light of the differences in the inhibition profile for the two bovine variants observed in the present study (Fig.…”

“…This modulation strategy has already been attempted for a number of drugs by coadministration of P-glycoprotein inhibitors (Fairweather, 2009) and ABCG2 inhibitors (Perez et al, 2009b;Real et al, 2011a). However, it should be noted that the use of TCBZ for this purpose may be controversial in animals whose products are destined for human consumption, or in areas of parasite endemicity, owing to the potential development of resistance (Barrera et al, 2012).…”

“…The parent drug TCBZ is not detected in plasma or milk after its oral administration in sheep, because it is rapidly metabolised into triclabendazole sulfoxide (TCBZSO) and triclabendazole sulfone (TCBZSO 2 ) (Hennessy et al, 1987;Imperiale et al, 2011). Triclabendazole metabolites are good inhibitors of the murine and human variants of ABCG2 (Barrera et al, 2012). However, their relevance for drug-drug interactions in ruminants remains to be established.…”

Assessment of the pharmacological interactions between the nematodicidal fenbendazole and the flukicidal triclabendazole: In vitro studies with bovine liver microsomes and slices

“…An enhanced OFZ accumulation was observed both in the culture medium and within the tissue (see Figure and Table ). In this regard, both TCBZ and TCBZSO were shown to be inhibitors of the transporters P‐glycoprotein (P‐gp) (Dupuy, Alvinerie, Ménez, & Lespine, ) and breast cancer resistance protein (BCRP) (Barrera et al., ), at least in murine and human cellular models. FBZ has been shown not to interact with BCRP, P‐gp, or the multidrug‐resistant protein 2 (MRP2) in MDCK cells transduced with human cDNAs of these transporters (Merino et al., ).…”

“…In livestock, BZDs including fenbendazole (FBZ), triclabendazole (TCBZ) and albendazole (ABZ) are routinely used to treat and prevent a variety of endoparasitosis (Campbell, ). FBZ, its active metabolite oxfendazole (OFZ), and ABZ are indicated for the treatment of gastrointestinal and respiratory worms, whereas TCBZ is used against both juvenile (immature) and adult specimens of the liver fluke Fasciola hepatica (Barrera et al., ). Therefore, combinations of TCBZ and FBZ, OFZ or ABZ may result in an increased spectrum of efficacy compared with single‐drug dosages.…”