Comparative ex vivo interaction of ivermectin, moxidectin and closantel with intestinal ABC transporters.

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

Congreso; 12th International Congress of the European Association for Veterinary Pharmacology and Toxicology; 2012

Introduction: Transport proteins play an important role in the intestinal secretion of different drug molecules widely used in veterinary therapeutics. An active intestinal efflux of different antiparasitic compounds has been described (Laffont et al., 2002; Ballent et al., 2006; Lespine et al., 2007). Although P-gp seems to be the main efflux transporter involved on the kinetic behaviour of different antiparasitic drugs, the tissue distribution of the breast cancer resistance protein (BCRP) overlaps extensively with the P-gp tissue location/function, suggesting a similar role in substrate transport. The aim of the study was to assess the ex vivo interaction of different antiparasitic drugs such as ivermectin (IVM), moxidectin (MXD) and closantel (CLS) with P-gp and BCRP in rat intestine.   Material and Methods: The Ussing chamber technique was used to undertake the intestine transport studies. The ileal segment obtained from male Wistar rats was opened along the mesenteric border and the resulting flat sheets were mounted into the Ussing chamber system. Either rhodamine 123 (Rho 123) (5 µM) a P-gp substrate, or danofloxacin (DFX) (50 µM), a BCRP substrate, were added in both mucosal (M) and serosal (S) compartments. For inhibition studies, IVM, MXD and CLS were added at equimolar concentrations. Additionally, PSC833 and pantoprazole (PTZ) were used as specific P-gp and BCRP inhibitors, respectively. The amounts of Rho 123 and DFX permeated were determined by spectrofluorometric detection. The apparent permeability coefficients per unit of membrane surface area (Peff) (cm/s) and the efflux ratio were calculated. Results: The efflux transport of Rho 123 and DFX in rat intestine was corroborated. The efflux ratio values were 2.91 (Rho 123) and 4.38 (DFX). The Peff S-M (secretion) of Rho 123 was significantly reduced (P<0.05) by IVM and PSC833, whereas no differences were observed for MXD and CLS. On the other hand, the efflux of the BCRP substrate DFX was significantly reduced by IVM (1.24) as well as MXD (1.67), CLS (1.82) and PTZ (2.10), suggesting an inhibition of the active secretion process. Discussion: These preliminary results demonstrated the usefulness of this experimental approach for testing the intestinal transport mechanisms involved in the absorption/excretion processes for widely used antiparasitic drugs. As the functional architecture of the intestinal mucosa remains intact, ex vivo studies with the Ussing chamber system results a useful tool for direct correlation with in vivo occurring drug-drug interactions. The patterns of interaction between different antiparasitic drugs and intestinal efflux transporters were assessed in the ileal tissue of rat. The anthelmintic molecules under study showed a differential inhibitory effect on P-gp and BCRP-mediated intestinal transport, which may have a therapeutic relevance.