Involvement of P-glycoprotein on ivermectin kinetic behaviour in sheep: itraconazole-mediated changes on gastrointestinal disposition

Abstract

Different pharmacological approaches have been used in an attempt to increased drug systemic availability of anthelmintic drugs. The comparative effect of the itraconazole (ITZ)-mediated modulation of P-glycoprotein (P-gp) activity on the in vivo kinetic behaviour of ivermectin (IVM) administered by intravenous (IV) and intraruminal (IR) routes to sheep was assessed in the current work. Corriedale sheep received IVM (50 µg/kg) by the intravenous (IV) route either alone (Group A) or co-administered with the P-gp modulator ITZ (100 mg orally three times every 12 h) (Group B). Animals in Groups C and D were intraruminally (IR) treated with IVM (50 µg/kg) alone or co-administered with ITZ (100 mg orally three times every 12 h), respectively. Jugular blood and gastrointestinal tissue samples (only of the IVM IR treated animals) were collected. The samples were analyzed by HPLC using fluorescence detection. The plasma disposition of IVM given intravenously was unaffected by the presence of ITZ. However, the co-administration with ITZ resulted in markedly higher IVM plasma concentration profiles compared to the control group. Likewise, the presence of ITZ enhanced the IVM concentration profiles in the gastrointestinal mucosal tissues. An ITZ-induced reduction on the P-gp efflux activity at the intestinal lining may have accounted for the greater absorption and enhanced systemic availability observed for IVM in the intraruminally-treated animals.