Sex-related differences in the gastrointestinal disposition of ivermectin in the rat: P-glycoprotein involvement and itraconazole modulation

LIFSCHITZ, A.; BALLENT, M.; VIRKEL, G.; SALLOVITZ, J.; LANUSSE, C.

JOURNAL OF PHARMACY AND PHARMACOLOGY

Ingente Connect

Año: 2006 vol. 58 p. 1055 - 1062

0022-3573

ABSTRACT Ivermectin (IVM), a macrocyclic lactone used as antiparasite agent, has been reported as a P-gp substrate. The possible participation of P-gp on the IVM excretion process was suggested. Sex-related differences on the kinetic behaviour of some macrocyclic lactone compounds have been observed. The aim of this work was to study in-vivo the involvement of P-glycoprotein on the IVM gastrointestinal disposition and to evaluate gender-related differences on IVM tissue disposition kinetics using itraconazole (ITZ) as a P-gp modulator agent. Sixty (60) Wistar (30 male, 30 female) rats received IVM alone or co-administered with ITZ. Rats were sacrificed between 6 and 72 h post-treatment and blood, gastrointestinal tissues and lumen contents were collected. IVM concentrations were determined by HPLC. The co-administration with ITZ resulted in a marked enhancement of IVM concentrations in the wall tissue of different portions of the gastrointestinal tract of male rats. Substantial sex-related difference were observed on the IVM disposition kinetics. The ITZ-mediated modulation of the IVM disposition kinetics had a differential impact between male and female animals. The ITZ-mediated modulation of P-gp activity accounted for drastic changes on the IVM disposition kinetics, which resulted markedly different according to the sex of the experimental animals.