P-glycoprotein involvement on ivermectin disposition kinetics: influence of gender and administration route

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

Mar del Plata

Congreso; XXXVII Reunión Anual de la Asociación Argentina de Farmacología Experimental (SAFE); 2005

Ivermectin (IVM) is a substrate of the drug transporter P-glycoprotein (P-gp). The goals of the studies reported here were: a) to characterize a gender influence on the P-gp-mediated intestinal secretion of IVM (Phase I), and b) to evaluate the effect of the IVM administration route on the IVM/P-gp interaction in sheep (Phase II).  Wistar (30 male, 30 female) rats received IVM (200 µg/kg) alone or co-administered with itraconazole (ITZ) (5 mg) (a P-gp inhibitor agent). Rats were sacrificed (between 6 and 72 h pt). Blood, gastrointestinal tissues and lumen contents were collected (Phase I). In Phase II, twenty-four (24) female sheep were divided in four experimental groups, which received IVM (50 µg/kg) by intravenous (IV) and intraruminal (IR) routes either alone or co-administered with ITZ. Plasma was collected up to 15 days and IVM concentrations measured by HPLC. ITZ induced a marked enhancement on IVM plasma Cmax and gastrointestinal tissues concentrations, which resulted higher in male ( 112 to 307 %) than in female (19-102 %) rats. The route of administration affected the IVM-P-gp interaction. ITZ did not change the IVM plasma disposition after the IV treatment. However, a markedly higher IVM systemic availability was observed in the presence of ITZ after the IR administration of the antiparasitic drug compared to the treatment without the P-gp-modulator agent.