Ivermectin reduces secretion of meloxicam into milk by inhibition of ABCG2 transporter in sheep

Abstract

[EN] The ATP-binding cassette transporter G2 (ABCG2) is an efflux protein involved in the bioavailability and secretion into milk of several compounds including anti- inflammatory drugs. The aim of this work was to determine the effect in sheep of an ABCG2 inhibitor, such as the macrocyclic lactone ivermectin, on the secretion into milk of meloxicam, a non-steroidal anti-inflammatory drug widely used in veterinary medicine, and recently reported as an ABCG2 substrate in mice. In vitro meloxicam transport assays in ovine ABCG2-transduced cells have shown that meloxicam is a substrate of ovine ABCG2 and that ivermectin is an efficient inhibitor of in vitro transport of meloxicam mediated by ovine ABCG2. In addition, the role of ovine ABCG2 in secretion into milk of meloxicam was corroborated using Assaf lactating sheep coadministered with ivermectin. Animals were administered subcutaneously with meloxicam (0.5 mg/kg) with or without ivermectin (0.2 mg/kg). A significantly lower concentration of meloxicam in milk was detected when ivermectin was coadministered, revealing a major role of ABCG2 in the secretion into milk of meloxicam and a relevant drug-drug interaction affecting this process. These results will contribute to the understanding of the potential factors that modulate the transfer of anti-inflammatory drugs into milk, opening their potential use in lactating ruminants, and the effect of drug coadministration on the presence of milk residues of these compounds.