title: Biopharmaceutic evaluation of novel anthelmintic (1H-benzimidazol-5(6)-yl)carboxamide derivatives.
abstract: Benzimidazole 2-carbamates, such as albendazole (ABZ) and mebendazole (MBZ), used for the treatment of helmintic infections, have low aqueous solubility and poor bioavailability, both of which lead to high interindividual variability when used for human systemic helmintiosis; therefore, it is necessary to search for new anthelmintics with better biopharmaceutical properties. In the present study the solubility, pKa, logP and apparent permeability in the Caco-2 cells system of four novel anthelmintic (1H-benzimidazol-5(6)-yl)carboxamide derivatives (compounds 1-4) with a 2-methylthyo group were evaluated. Also the pharmacokinetic parameters of compound 1 which in previous studies showed activity similar to ABZ against T. spirallis, was evaluated in BALB/c mice, as a representative molecule of the series. The novel anthelmintics, showed better solubility than ABZ in aqueous acid pH and in organic solvents. The logP, P(app) and Caco-2 data indicate that the 4 derivatives are highly permeable drugs, but it is possible that an efflux system could be involved in the transport of these compounds. Plasma levels of compound 1 and its sulfoxide (compound 5) were high after the first 5 min. This fact strongly suggests that compound 1 is rapidly metabolized in the small intestine. On the other hand, the sulfone metabolite (compound 6) levels were lower than those of compound 5. The half life and mean residence time (MRT) of compound 1 and its main metabolites indicate that their elimination is very rapid. More studies in mammalian species are necessary in order to understand the pharmacokinetic behavior of these novel compounds.
authors.affiliation: Departamento de Farmacia, Facultad de Química, Universidad Nacional Autónoma de México, México, D.F. 04510, Mexico.
authors.forename: Julio C
authors.initials: JC
authors.lastname: Rivera
authors.forename: Lilián
authors.initials: L
authors.lastname: Yépez-Mulia
authors.forename: Alicia
authors.initials: A
authors.lastname: Hernández-Campos
authors.forename: Rafael
authors.initials: R
authors.lastname: Moreno-Esparza
authors.forename: Rafael
authors.initials: R
authors.lastname: Castillo
authors.forename: Gabriel
authors.initials: G
authors.lastname: Navarrete-Vázquez
authors.forename: Inés
authors.initials: I
authors.lastname: Fuentes-Noriega
authors.forename: Helgi
authors.initials: H
authors.lastname: Jung-Cook
mesh_terms: D020003:1-Octanol / Q000737:chemistry; D000818:Animals; D000871:Anthelmintics / Q000737:chemistry* / Q000493:pharmacokinetics*; D001562:Benzimidazoles / Q000737:chemistry* / Q000493:pharmacokinetics*; D018938:Caco-2 Cells; D006801:Humans; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D012995:Solubility; D013450:Sulfones / Q000378:metabolism; D013454:Sulfoxides / Q000378:metabolism; D014867:Water / Q000737:chemistry
chemical_list: D000871:Anthelmintics; D001562:Benzimidazoles; D013450:Sulfones; D013454:Sulfoxides; D014867:Water; D020003:1-Octanol