Sex-related differences in the gastrointestinal disposition of ivermectin in the rat: P-glycoprotein involvement and itraconazole modulation
Authors: Lifschitz, A.1; Ballent, M.1; Virkel, G.1; Sallovitz, J.2; Lanusse, C.1
Source: Journal of Pharmacy and Pharmacology, Volume 58, Number 8, August 2006 , pp. 1055-1062(8)
Publisher: Pharmaceutical Press
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Abstract:
Ivermectin (IVM), a macrocyclic lactone used as antiparasite agent, has been reported as a P-glycoprotein (P-gp) substrate. The participation of P-gp in the IVM excretion process has been previously demonstrated. Sex-related differences in the kinetic behaviour of some macrocyclic lactone compounds have been observed. The aim of this work was to characterize in-vivo the comparative gastrointestinal disposition of IVM in male and female rats. The sex-related influence on the itraconazole (ITZ) modulation of P-gp-mediated IVM intestinal transport was also assessed. Sixty Wistar rats (30 male, 30 female) received IVM alone or co-administered with ITZ. Rats were killed between 6 and 72 h after treatment and blood, gastrointestinal tissues and lumen contents were collected. IVM concentrations were determined by high performance liquid chromatography. Substantial sex-related differences in the IVM disposition kinetics were observed. Higher IVM systemic availability was observed in female rats. The ITZ-mediated modulation of the IVM disposition kinetics had a differential impact between male and female rats. Co-administration with ITZ resulted in a marked increase in the IVM concentrations in the wall tissue from different portions of the gastrointestinal tract of male rats. The presence of ITZ induced drastic sex-related changes on the P-gp-mediated IVM gastrointestinal disposition.Document Type: Research article
DOI: 10.1211/jpp.58.8.0005
Affiliations: 1: Laboratorio de Farmacología, Departamento de Fisiopatología, Facultad de Ciencias Veterinarias, Universidad Nacional del Centro, Tandil, Argentina; Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), (Argentina) 2: Laboratorio de Farmacología, Departamento de Fisiopatología, Facultad de Ciencias Veterinarias, Universidad Nacional del Centro, Tandil, Argentina
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