INVOLVEMENT OF P-glycoprotein ON IVERMECTIN INTESTINAL SECRETION

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

Nueva Zelanda

Congreso; Congreso de la Asociación Mundial de Parasitología Veterinaria WAAVP; 2005

WAAVP

Ivermectin (IVM), a potent antiparasitic drug widely used in veterinary medicine, has been reported as a substrate of the drug transport P-Glycoprotein (P-GP). The aims of the studies reported here were: 1) to characterize “in vitro” the P-GP-mediated intestinal secretion of IVM using the everted intestinal sacs technique (Phase I), 2) to evaluate "in vivo" the sex influence on the interaction between IVM and P-GP and on the resultant IVM gastrointestinal disposition  (Phase II), and 3) to investigate the influence of the drug administration route on the IVM/P-GP interaction under in vivo conditions (Phase III). Ileum from male Wistar rats was used to prepare everted intestinal sacs, which were incubated over 60 min with  IVM (3 µM) in the presence/ absence of itraconazole (ITZ), a P-GP inhibitor (10 µM) (Phase I). In Phase II, sixty (60) Wistar (30 male, 30 female) rats received IVM (200 µg/kg) alone or co-administered with ITZ (5 mg). Rats were sacrificed (between 6 and 72 h pt) and blood, gastrointestinal tissues and lumen contents were collected. In Phase III, twenty-four (24) female sheep were divided in four experimental groups, which received IVM (200µg/kg) either alone or co-administered with ITZ by both the intravenous and oral routes. IVM concentrations were measured by HPLC with fluorescent detection. IVM accumulation at the ileal tissue (>84%) and IVM serosal transfer (>63%) were significantly greater after incubation of the intestinal sacs in the presence of ITZ. The ITZ-induced changes to P-GP activity and IVM disposition kinetics (enhanced systemic availability) were markedly greater in male rats. The presence of ITZ accounted for increased IVM peak plasma and tissue concentrations, which were significantly higher in male (171%) compared to female rats (48%). Overall, these preliminary results confirm the involvement of P-GP on the intestinal secretion of IVM and suggest gender differences on expression/activity of this drug transport protein.