Search

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 vitro meloxicam transport assays in ovine ABCG2-transduced cells have shown that ivermectin is an efficient inhibitor of in vitro transport of meloxicam mediated by ovine ABCG2, with a 75% inhibition in the transport ratio (24.85 ± 4.62 in controls vs 6.31 ± 1.37 in presence of ivermectin). 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). No difference in plasma pharmacokinetic parameters was found between treatments. In the case of milk, a significant reduction in the area under concentration-time curve (AUC) (3.92 ± 0.66 vs 2.26 ± 1.52 μg·h/mL) and the AUC milk-to-plasma ratio (0.17 ± 0.03 vs 0.09 ± 0.06) was reported for ivermectin-treated animals compared to controls., Competing Interests: Declaration of Competing Interest None., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Therapeutic outcome results of the coadministration of several drugs in veterinary medicine is affected by, among others, the relationship between drugs and ATP-binding cassette (ABC) transporters, such as ABCG2. ABCG2 is an efflux protein involved in the bioavailability and milk secretion of drugs. The aim of this work was to determine the role of eprinomectin, a macrocyclic lactone (ML) member of avermectin class, as inhibitor of ABCG2. The experiments were carried out through in vitro inhibition assays based on mitoxantrone accumulation and transport assays in ovine ABCG2 transduced cells using the antimicrobial drug danofloxacin and the anti-inflammatory drug meloxicam, both widely used in veterinary medicine and well known ABCG2 substrates. The inhibition results obtained showed that eprinomectin was an efficient in vitro ABCG2 inhibitor, tested in mitoxantrone accumulation assays. In addition, this ML decreased ovine ABCG2-mediated transport of danofloxacin and meloxicam. To evaluate the role of eprinomectin in systemic exposure of drugs, pharmacokinetic assays based on subcutaneous coadministration of eprinomectin with danofloxacin (1.25 mg/kg) or meloxicam (0.5 mg/kg) in sheep were performed obtaining a significant increase of systemic exposure of these drugs. Especially relevant was the increase of the systemic concentration of meloxicam, since coadministration with eprinomectin increased significantly the plasma concentration of meloxicam, obtaining an increase of AUC (0-72 h) value of more than 40%., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

After oral co-administration of two dosages of netobimin (7.5 and 20 mg kg-1 with fenbendazole (1.1 mg kg-1) to Merino sheep, the AUC0-infinity of albendazole sulphoxide at the lower dosage of netobimin, was significantly increased (75.5 per cent) from control value (34.43 +/- 7.91 versus 60.33 +/- 11.93 microg h ml-1). The pharmacokinetic parameters MRT and T1/2 were also increased: 18.96 +/- 2.54 vs 26.44 +/- 4.69 h and 10.31 +/- 1.72 vs 22.28 +/- 6.75 h respectively. No data corresponding to the higher dosage of netobimin (20 mg kg-1) were statistically different from control values. It is concluded that fenbendazole increases the bioavailability of albendazole sulphoxide in sheep at the 7.5 mg kg-1 dosage, and this may produce a potentiated anthelmintic action., (Copyright 1999 W.B. Saunders Company Ltd.)