In vitro and in vivo assesment on the involement of P-glycoprotein on ivermectin disposition kinetics

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

Washington DC, USA

Congreso; 14 th Biennal Symposium Veterinary Pharmacology, AAVPT; 2005

Ivermectin (IVM), a potent antiparasitic drug widely used in veterinary medicine, has been reported as a substrate of drug transport P-Glycoprotein (P-GP). The aims of these studies were: 1) to characterize “in vitro” the P-GP-mediated intestinal secretion of IVM using the everted intestinal sacs technique (PHASE I) and 2) to evaluate "in vivo" the influence of sex on the interaction between IVM and P-GP (PHASE II). In PHASE I, 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 or absence of itraconazole (ITZ), a P-GP inhibitor (10 µM). In PHASE II, sixty (60) Wistar male (n=30) and female (n=30) 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 wall tissues and lumen contents were collected. IVM concentrations were measured by HPLC with fluorescent detection. IVM accumulation in ileal tissue (>84%) and serosal transfer (>63%) were greater after the incubation of the intestinal sacs in the presence of ITZ. The effects on modulation of P-GP activity were markedly greater in male rats. The enhancement of IVM peak plasma and tissue concentrations after the co-administration with ITZ was 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.