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

Pharmaceutical Press

Lugar: Londres; Año: 2006 vol. 58 p. 1055 - 1062

0022-3573

  Ivermectin (IVM), a macrocyclic lactone used as antiparasite agent, has been reported as a P-glycoprotein (P-gp) substrate. The participation of P-gp on the IVM excretion process has been previously demonstrated. Sex-related differences on the kinetic behaviour of some macrocyclic lactone compounds have been observed. The aim of this work was to characterise in vivo the comparative gastrointestinal disposition of IVM in male and female rats. The sex-related influence on the itraconazole (ITZ) modulation of the P-gp-mediated IVM intestinal transport was also assessed..  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. Substantial sex-related differences were observed on the IVM disposition kinetics. Higher IVM systemic availability was observed in female animals. The ITZ-mediated modulation of the IVM disposition kinetics had a differential impact between male and female animals The co-administration with ITZ resulted in a marked increase of 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.