title: Import and efflux of flubendazole in Haemonchus contortus strains susceptible and resistant to anthelmintics.
abstract: Drug entry into the body of a helminth is a key factor in the efficacy of anthelmintics. The present project was designed to study the ex vivo uptake and efflux of the benzimidazole anthelmintic flubendazole (FLU) in four strains of H. contortus: the ISE strain (fully susceptible to anthelmintics), the ISE-S strain (resistant to ivermectin), the BR strain (resistant to benzimidazoles) and the WR strain (multi-resistant). The transport of FLU between dead and living nematodes was also compared as well as the effect of verapamil, an inhibitor of the main efflux ABCB1 transporter (P-glycoprotein), on FLU accumulation in nematodes. The obtained results showed that FLU is able to effectively enter H. contortus adults due to high FLU lipophilicity. Passive diffusion is probably the only mechanism in both FLU import and efflux from nematodes. No differences in FLU transport were found among four H. contortus strains with different sensitivity to anthelmintics. No active FLU efflux from H. contortus and no effect of verapamil were observed, indicating that H. contortus cannot protect itself against FLU by the active removal of this anthelmintic from its body.
authors.affiliation: Faculty of Pharmacy, Charles University, Hradec Králové, Czech Republic.
authors.forename: Hana
authors.initials: H
authors.lastname: Bártíková
authors.forename: Ivan
authors.initials: I
authors.lastname: Vokřál
authors.forename: Vladimír
authors.initials: V
authors.lastname: Kubíček
authors.forename: Barbora
authors.initials: B
authors.lastname: Szotáková
authors.forename: Lukáš
authors.initials: L
authors.lastname: Prchal
authors.forename: Jiří
authors.initials: J
authors.lastname: Lamka
authors.forename: Marián
authors.initials: M
authors.lastname: Várady
authors.forename: Lenka
authors.initials: L
authors.lastname: Skálová
mesh_terms: D000818:Animals; D000871:Anthelmintics / Q000378:metabolism / Q000493:pharmacokinetics / Q000494:pharmacology*; D004347:Drug Interactions; D004351:Drug Resistance; D006189:Haemonchus / Q000187:drug effects*; D008463:Mebendazole / Q000031:analogs & derivatives* / Q000378:metabolism / Q000493:pharmacokinetics / Q000494:pharmacology; D027361:Organic Anion Transporters / Q000037:antagonists & inhibitors; D014700:Verapamil / Q000493:pharmacokinetics
chemical_list: D000871:Anthelmintics; D027361:Organic Anion Transporters; D008463:Mebendazole; D014700:Verapamil; C018945:flubendazole