Ex vivo and in vivo evaluation of intestinal drug transport interactions in sheep

Abstract

Although less frequent compared to drug interactions involving the cytochrome P450 system, clinically significant ATP binding cassette (ABC) transporter‐mediated drug interactions have been reported. The aims of this study were: 1) to understand the basis of the transport‐ mediated interaction between the antimicrobial danofloxacin (DFX) and the antiparasitic compound ivermectin (IVM), performing ex vivo transport assays with an Ussing Chambers system. 2) to evaluate the in vivo disposition kinetics of both compounds given either separately or co‐administered to sheep. The effects of IVM and DFX on Rhodamine 123 (Rho 123) intestinal transport was ex vivo assessed. Rho 123 concentrations were measured by spectrofluorometry. The apparent permeability coefficients/per unit of membrane surface area (Peff) (cm/s) were estimated. Corriedale sheep (in vivo trial) received either IVM (subcutaneously, 0.2 mg/kg) (Group A), danofloxacin (DFX) (subcutaneously, 6 mg/kg, twice every 48 h) (Group B) or the co‐administration of IVM+DFX (Group C). Plasma concentrations of both molecules were measured by HPLC. No significant changes to the IVM disposition were observed after its co‐administration with DFX. However, IVM significantly enhanced the DFX systemic exposure (32 to 35 %) and extending its elimination half‐life (40 to 52 %) (P< 0.05) in co‐ administered animals. Although, DFX did not affect Rho‐123 transport, IVM markedly decreased Rho‐123 efflux transport in sheep intestine mounted in the Ussing Chambers. The involvement of the transporters P‐glycoprotein and/or BCRP on the described DFX‐IVM interaction will be discussed as well as the clinical relevance of intestinal transport‐mediated interactions between drugs commonly used in veterinary therapeutics.