Effects of triclabendazole on secretion of danofloxacin and moxidectin into the milk of sheep: Role of triclabendazole metabolites as inhibitors of the ruminant ABCG2 transporter

Barrera, Borja; González-Lobato, Lucía; Otero, Jon A.; Real, Rebeca; Prieto, J. E.; Álvarez, Ana Bernardo; Merino, Gracia

doi:10.1016/j.tvjl.2013.07.033

Cited by 22 publications

(22 citation statements)

References 27 publications

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“…A comparable interaction was described by Barrera et al. () demonstrating the inhibitory effects of triclabendazole metabolites on BCRP. This inhibitory activity was found to modulate the excretion of danofloxacin and moxidectin (both BCRP substrates) into the milk of lactating ewes.…”

Section: Transporter Polymorphismssupporting

confidence: 84%

See 1 more Smart Citation

Population variability in animal health: Influence on dose–exposure–response relationships: Part I: Drug metabolism and transporter systems

Martinez

Court

Fink‐Gremmels

et al. 2018

Vet Pharm & Therapeutics

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There is an increasing effort to understand the many sources of population variability that can influence drug absorption, metabolism, disposition, and clearance in veterinary species. This growing interest reflects the recognition that this diversity can influence dose-exposure-response relationships and can affect the drug residues present in the edible tissues of food-producing animals. To appreciate the pharmacokinetic diversity that may exist across a population of potential drug product recipients, both endogenous and exogenous variables need to be considered. The American Academy of Veterinary Pharmacology and Therapeutics hosted a 1-day session during the 2017 Biennial meeting to explore the sources of population variability recognized to impact veterinary medicine. The following review highlights the information shared during that session. In Part I of this workshop report, we consider sources of population variability associated with drug metabolism and membrane transport. Part II of this report highlights the use of modeling and simulation to support an appreciation of the variability in dose-exposure-response relationships.

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Section: Transporter Polymorphismssupporting

confidence: 84%

“…Co-administration of triclabendazole (due to its flukicidal activity) and broad-spectrum endectocides such the macrocyclic lactones is a common practice in ruminants. A comparable interaction was described by Barrera et al (2013)…”

Section: Drugs and Toxins Acting As Modulators Of Bcrp Activitysupporting

confidence: 69%

Population variability in animal health: Influence on dose–exposure–response relationships: Part I: Drug metabolism and transporter systems

Martinez

Court

Fink‐Gremmels

et al. 2018

Vet Pharm & Therapeutics

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“…The secretion rate of the antimicrobial danofloxacin into milk was reduced by the presence of the anthelmintic ivermectin (Real et al., ) or the natural isoflavones genistein and daidzein (Perez et al., ). The coadministration of the halogenated BZD triclabendazole with either moxidectin or danofloxacin to sheep reduced moxidectin but not danofloxacin levels in milk (Barrera et al., ).…”

Section: Discussionmentioning

confidence: 99%

“…Drug‐drug interactions leading to inhibition of mammary BCRP could influence drug secretion into milk and consequently the accumulation of drug residues in milk and milk‐derived products. For instance, the coadministration of triclabendazole and moxidectin to sheep results in significantly reduced levels of the BCRP substrate moxidectin in milk (Barrera et al., ). In this context, the main goal of this study was to evaluate the potential in vivo drug‐drug interactions after the coadministration of MNP and oxfendazole (OFZ), which could affect the milk excretion patterns of those anthelmintics in dairy cows.…”

Section: Introductionmentioning

confidence: 99%

Pharmacokinetic assessment of the monepantel plus oxfendazole combined administration in dairy cows

Ballent

Viviani

Imperiale

et al. 2017

Vet Pharm & Therapeutics

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Monepantel (MNP) is a novel anthelmintic compound launched into the veterinary pharmaceutical market. MNP is not licenced for use in dairy animals due to the prolonged elimination of its metabolite monepantel sulphone (MNPSO ) into milk. The goal of this study was to evaluate the presence of potential in vivo drug-drug interactions affecting the pattern of milk excretion after the coadministration of the anthelmintics MNP and oxfendazole (OFZ) to lactating dairy cows. The concentrations of both parent drugs and their metabolites were measured in plasma and milk samples by HPLC. MNPSO was the main metabolite recovered from plasma and milk after oral administration of MNP. A high distribution of MNPSO into milk was observed. The milk-to-plasma ratio (M/P ratio) for this metabolite was equal to 6.75. Conversely, the M/P ratio of OFZ was 1.26. Plasma concentration profiles of MNP and MNPSO were not modified in the presence of OFZ. The pattern of MNPSO excretion into milk was also unchanged in animals receiving MNP plus OFZ. The percentage of the total administered dose recovered from milk was 0.09 ± 0.04% (MNP) and 2.79 ± 1.54% (MNPSO ) after the administration of MNP alone and 0.06 ± 0.04% (MNP) and 2.34 ± 1.38% (MNPSO ) after the combined treatment. The presence of MNP did not alter the plasma and milk disposition kinetics of OFZ. The concentrations of the metabolite fenbendazole sulphone tended to be slightly higher in the coadministered group. Although from a pharmacodynamic point of view the coadministration of MNP and OFZ may be a useful tool, the presence of OFZ did not modify the in vivo pharmacokinetic behaviour of MNP and therefore did not result in reduced milk concentrations of MNPSO .

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“…In vivo reduced secretion into sheep milk of ABCG2 substrates such as antibiotics and endectocides has been reported with the coadministration of ABCG2 inhibitors (Real, Egido, et al 2011;Barrera et al 2013;Pérez et al 2013). However, as a previous step towards in vivo assays, in vitro tools are essential to characterise the ruminant ABCG2-mediated transcellular transport including identification of substrates and drug interactions.…”

Section: Introductionmentioning

confidence: 95%

Novelin vitrosystems for prediction of veterinary drug residues in ovine milk and dairy products

González-Lobato

Real

Herrero

et al. 2014

Food Additives & Contaminants: Part A

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A new in vitro tool was developed for the identification of veterinary substrates of the main drug transporter in the mammary gland. These drugs have a much higher chance of being concentrated into ovine milk and thus should be detectable in dairy products. Complementarily, a cell model for the identification of compounds that can inhibit the secretion of drugs into ovine milk, and thus reduce milk residues, was also generated. The ATP-binding cassette transporter G2 (ABCG2) is responsible for the concentration of its substrates into milk. The need to predict potential drug residues in ruminant milk has prompted the development of in vitro cell models over-expressing ABCG2 for these species to detect veterinary drugs that interact with this transporter. Using these models, several substrates for bovine and caprine ABCG2 have been found, and differences in activity between species have been reported. However, despite being of great toxicological relevance, no suitable in vitro model to predict substrates of ovine ABCG2 was available. New MDCKII and MEF3.8 cell models over-expressing ovine ABCG2 were generated for the identification of substrates and inhibitors of ovine ABCG2. Five widely used veterinary antibiotics (marbofloxacin, orbifloxacin, sarafloxacin, danofloxacin and difloxacin) were discovered as new substrates of ovine ABCG2. These results were confirmed for the bovine transporter and its Y581S variant using previously generated cell models. In addition, the avermectin doramectin was described as a new inhibitor of ruminant ABCG2. This new rapid assay to identify veterinary drugs that can be concentrated into ovine milk will potentially improve detection and monitoring of veterinary drug residues in ovine milk and dairy products.

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Effects of triclabendazole on secretion of danofloxacin and moxidectin into the milk of sheep: Role of triclabendazole metabolites as inhibitors of the ruminant ABCG2 transporter

Cited by 22 publications

References 27 publications

Population variability in animal health: Influence on dose–exposure–response relationships: Part I: Drug metabolism and transporter systems

Population variability in animal health: Influence on dose–exposure–response relationships: Part I: Drug metabolism and transporter systems

Pharmacokinetic assessment of the monepantel plus oxfendazole combined administration in dairy cows

Novelin vitrosystems for prediction of veterinary drug residues in ovine milk and dairy products

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