Involvement of p-glycoprotein on ivermectin disposition kinetics: in vitro and in vivo assessments

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

Simposio; 14th Biennal Symposium of American Academy of Veterinary Pharmacology and Therapeutics; 2005

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 to investigate the influence of the drug administration route on the IVM/P-GP interaction under in vivo conditions . 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) . 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. 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 .