In vivo and ex vivo assessment of the interaction between ivermectin and danofloxacin in sheep

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

The Veterinary Journal

ELSEVIER SCI LTD

Lugar: Amsterdam; Año: 2012 p. 422 - 427

1090-0233

The impact of an efflux pumps-related interaction between ivermectin (IVM) 29 and danofloxacin (DFX) on their ex vivo intestinal transport and in vivo dispositionand danofloxacin (DFX) on their ex vivo intestinal transport and in vivo disposition 30 kinetics was assessed in sheep. Corriedale male sheep (n=6) received IVM (0.2 mg/Kg)kinetics was assessed in sheep. Corriedale male sheep (n=6) received IVM (0.2 mg/Kg) 31 by subcutaneous (SC) injection (Group A). Animals in Group B received DFXby subcutaneous (SC) injection (Group A). Animals in Group B received DFX 32 subcutaneously (6 mg/Kg, twice every 48 h) and those in Group C were co33subcutaneously (6 mg/Kg, twice every 48 h) and those in Group C were co33 administered with IVM+DFX at the indicated individual dose rates. IVM and DFX 34 plasma concentrations were measured by HPLC using fluorescence detection. The explasma concentrations were measured by HPLC using fluorescence detection. The ex 35 vivo intestinal drug transport activity was measured by the use of the Ussing chambervivo intestinal drug transport activity was measured by the use of the Ussing chamber 36 technique. IVM plasma concentrations tended to increase in the presence of DFX duringtechnique. IVM plasma concentrations tended to increase in the presence of DFX during 37 the first six days post-administration. Besides, IVM increased significantly DFXthe first six days post-administration. Besides, IVM increased significantly DFX 38 systemic exposure (AUC values 32-35% higher) and prolonged its elimination half-lifesystemic exposure (AUC values 32-35% higher) and prolonged its elimination half-life 39 (40 to 52% longer). The rhodamine 123, a P-gp substrate, efflux transport in sheep(40 to 52% longer). The rhodamine 123, a P-gp substrate, efflux transport in sheep 40 intestine was significantly decreased after incubation with IVM. However, nointestine was significantly decreased after incubation with IVM. However, no 41 significant changes on transport activity were observed in the presence of DFX. Thesignificant changes on transport activity were observed in the presence of DFX. The 42 data from the current work seem to demonstrate that IVM but not DFX has a markeddata from the current work seem to demonstrate that IVM but not DFX has a marked 43 inhibitory effect on P-gp activity. Additionally, the evaluation of the interaction of DFXinhibitory effect on P-gp activity. Additionally, the evaluation of the interaction of DFX 44 with the breast cancer resistance protein (BCRP) showed that pantoprazole and IVMwith the breast cancer resistance protein (BCRP) showed that pantoprazole and IVM 45 significantly decreased DFX secretion in the rat intestine. Although the IVM-inducedsignificantly decreased DFX secretion in the rat intestine. Although the IVM-induced 46 reduction on DFX efflux transport observed in sheep intestine suggests that BCRPreduction on DFX efflux transport observed in sheep intestine suggests that BCRP 47 activity may be involved on DFX intestinal secretion, the involvement of P-gp can notactivity may be involved on DFX intestinal secretion, the involvement of P-gp can not 48 be ruled out.be ruled out.