{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,29]],"date-time":"2026-09-29T12:09:26Z","timestamp":1790683766174,"version":"4.1.0"},"reference-count":47,"publisher":"Wiley","license":[{"start":{"date-parts":[[2026,9,29]],"date-time":"2026-09-29T00:00:00Z","timestamp":1790640000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"},{"start":{"date-parts":[[2026,9,29]],"date-time":"2026-09-29T00:00:00Z","timestamp":1790640000000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Vet Pharm &amp; Therapeutics"],"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:p>\n                    Veterinary drug residues in milk represent an important food safety concern, particularly under conditions of co\u2010administration where transporter\u2010mediated drug\u2013drug interactions may alter residue profiles. Marbofloxacin, a fluoroquinolone antimicrobial, is actively secreted into milk through the ATP\u2010binding cassette transporter ABCG2 (BCRP), whereas ivermectin has been reported to interact with ABC transporters. The present study integrated\n                    <jats:italic>in silico<\/jats:italic>\n                    and in\u00a0vivo approaches to investigate whether ivermectin may influence marbofloxacin secretion into sheep milk through transporter\u2010mediated mechanisms. A homology model of ovine ABCG2 was constructed using the human cryo\u2010electron microscopy structure as a template. Molecular docking and molecular dynamics simulations were subsequently performed to evaluate ligand\u2013transporter interactions and complex stability. Docking analysis demonstrated that ivermectin exhibited a broader and more favorable interaction profile within the ABCG2 transmembrane cavity compared with marbofloxacin, with partial overlap at residues associated with substrate recognition, particularly within the Asp129\u2010Asp130 region. Molecular dynamics simulations confirmed stable accommodation of ivermectin within the transporter throughout the simulation period without structural destabilization of the protein. The in\u00a0vivo component included lactating dairy ewes receiving marbofloxacin alone or in combination with ivermectin under routine field conditions. Milk samples collected at the predicted peak milk concentration were analyzed using a validated HPLC\u2013PDA\/MS method. Marbofloxacin was detected in all milk samples with high analytical specificity. Ewes treated with ivermectin exhibited significantly lower marbofloxacin concentrations in milk compared with animals receiving marbofloxacin alone, while significant within\u2010animal variability between udder halves was also observed.\n                  <\/jats:p>","DOI":"10.1111\/jvp.70113","type":"journal-article","created":{"date-parts":[[2026,9,29]],"date-time":"2026-09-29T11:48:38Z","timestamp":1790682518000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Deciphering Transporter\u2010Mediated Drug Interactions Affecting Marbofloxacin Residues in Sheep Milk: From In Silico Predictions to In\u00a0Vivo Validation"],"prefix":"10.1111","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-6918-830X","authenticated-orcid":false,"given":"Konstantinos V.","family":"Arsenopoulos","sequence":"first","affiliation":[{"name":"Department of Veterinary Medicine School of Veterinary Medicine, University of Nicosia  Nicosia Cyprus"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2785-145X","authenticated-orcid":false,"given":"Evroula","family":"Hapeshis","sequence":"additional","affiliation":[{"name":"Department of Health Sciences, School of Life and Health Sciences University of Nicosia  Nicosia Cyprus"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2564-5203","authenticated-orcid":false,"given":"Elias","family":"Papadopoulos","sequence":"additional","affiliation":[{"name":"Laboratory of Parasitology and Parasitic Diseases, School of Veterinary Medicine, Faculty of Health Sciences Aristotle University of Thessaloniki  Thessaloniki Greece"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8356-0868","authenticated-orcid":false,"given":"Manos C.","family":"Vlasiou","sequence":"additional","affiliation":[{"name":"Department of Veterinary Medicine School of Veterinary Medicine, University of Nicosia  Nicosia Cyprus"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,9,29]]},"reference":[{"issue":"2","key":"e_1_2_11_2_1","doi-asserted-by":"crossref","DOI":"10.3390\/pathogens10020232","article-title":"Will Fly Repellency Using Deltamethrin Reduce Intramammary Infections, Stress and Fatigue Indicators of Dairy Ewes Under Intensive Management?","volume":"10","author":"Arsenopoulos K. V.","year":"2021","journal-title":"Pathogens"},{"issue":"1","key":"e_1_2_11_3_1","doi-asserted-by":"crossref","first-page":"235","DOI":"10.1093\/nar\/28.1.235","article-title":"The Protein Data Bank","volume":"28","author":"Berman H. M.","year":"2000","journal-title":"Nucleic Acids Research"},{"key":"e_1_2_11_4_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.rvsc.2022.10.019"},{"issue":"16","key":"e_1_2_11_5_1","first-page":"3271","article-title":"A Liquid Chromatography\u2013Tandem Mass Spectrometry Method for the Detection of Antimicrobial Agents From Seven Classes in Calf Milk Replacers: Validation and Application","volume":"64","author":"Chiesa L. M.","year":"2016","journal-title":"Journal of Agricultural and Food Chemistry"},{"key":"e_1_2_11_6_1","first-page":"84","article-title":"The Performance of Analytical Methods for Residues of Pharmacologically Active Substances Used in Food\u2010Producing Animals and on the Interpretation of Results","volume":"23","author":"Commission Implementing Regulation (EU)","year":"2021","journal-title":"Official Journal of the European Union, L180"},{"issue":"4","key":"e_1_2_11_7_1","doi-asserted-by":"crossref","first-page":"337","DOI":"10.1016\/S0304-4017(03)00008-6","article-title":"Enhancement of Moxidectin Bioavailability in Lamb by a Natural Flavonoid: Involvement of P\u2010Glycoprotein","volume":"112","author":"Dupuy J.","year":"2003","journal-title":"Veterinary Parasitology"},{"key":"e_1_2_11_8_1","volume-title":"Marbofloxacin: Summary Report (2) (EMEA\/MRL\/693\/99\u2010FINAL)","author":"European Medicines Agency","year":"2000"},{"key":"e_1_2_11_9_1","unstructured":"European Medicines Agency.2026.\u201cMaximum Residue Limits (MRL).\u201dhttps:\/\/www.ema.europa.eu\/en\/veterinary\u2010regulatory\u2010overview\/research\u2010development\u2010veterinary\u2010medicines\/maximum\u2010residue\u2010limits\u2010mrl."},{"issue":"10","key":"e_1_2_11_10_1","doi-asserted-by":"crossref","DOI":"10.3390\/nu11102372","article-title":"Transporters in the Mammary Gland\u2010Contribution to Presence of Nutrients and Drugs Into Milk","volume":"11","author":"Garc\u00eda\u2010Lino A. M.","year":"2019","journal-title":"Nutrients"},{"issue":"5","key":"e_1_2_11_11_1","doi-asserted-by":"crossref","first-page":"700","DOI":"10.1124\/dmd.115.068940","article-title":"ABCG2 Transporter in the Mammary Gland Mediates Veterinary Drug Secretion Across the Blood\u2013Milk Barrier Into Milk of Dairy Cows","volume":"44","author":"Garc\u00eda\u2010Lino A. M.","year":"2016","journal-title":"Drug Metabolism and Disposition"},{"key":"e_1_2_11_12_1","article-title":"Rapid Determination of 103 Common Veterinary Drug Residues in Milk and Dairy Products by Ultra\u2010High Performance Liquid Chromatography\u2010Tandem Mass Spectrometry","volume":"384","author":"Guo X.","year":"2022","journal-title":"Food Chemistry"},{"key":"e_1_2_11_13_1","doi-asserted-by":"crossref","DOI":"10.1038\/s41598-025-32613-7","article-title":"Sustainable HPLC Method for Simultaneous Determination of Cefazolin, Sulfadimidine and Marbofloxacin Residues in Milk","volume":"16","author":"Hammad S. F.","year":"2026","journal-title":"Scientific Reports"},{"issue":"7","key":"e_1_2_11_14_1","doi-asserted-by":"crossref","first-page":"2103","DOI":"10.3168\/jds.S0022-0302(94)77153-8","article-title":"Physiology of Mastitis and Factors Affecting Somatic Cell Counts","volume":"77","author":"Harmon R. J.","year":"1994","journal-title":"Journal of Dairy Science"},{"issue":"1","key":"e_1_2_11_15_1","doi-asserted-by":"crossref","DOI":"10.1186\/1471-2105-12-S1-S33","article-title":"iGEMDOCK: A Graphical Environment of Enhancing GEMDOCK Using Pharmacological Interactions and Post\u2010Screening Analysis","volume":"12","author":"Hsu K. C.","year":"2011","journal-title":"BMC Bioinformatics"},{"issue":"4","key":"e_1_2_11_16_1","doi-asserted-by":"crossref","first-page":"333","DOI":"10.1038\/s41594-018-0049-1","article-title":"Structural Basis of Small\u2010Molecule Inhibition of Human Multidrug Transporter ABCG2","volume":"25","author":"Jackson S. 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L.","year":"1974"},{"key":"e_1_2_11_21_1","article-title":"Antibiotics in Milk: Validation of Analytical Methodologies for Ensuring Food Safety","volume":"164","author":"Leite M.","year":"2025","journal-title":"International Dairy Journal"},{"issue":"1","key":"e_1_2_11_22_1","doi-asserted-by":"crossref","first-page":"46","DOI":"10.3168\/jds.S0022-0302(04)73140-9","article-title":"Changes in Milk Composition as Affected by Subclinical Mastitis in Sheep","volume":"87","author":"Leitner G.","year":"2004","journal-title":"Journal of Dairy Science"},{"key":"e_1_2_11_23_1","first-page":"58","article-title":"P\u2010Glycoproteins and Other Multidrug Resistance Transporters in the Pharmacology of Anthelmintics: Prospects for Reversing Transport\u2010Dependent Anthelmintic Resistance","volume":"2","author":"Lespine A.","year":"2012","journal-title":"International Journal for Parasitology: Drugs and Drug Resistance"},{"key":"e_1_2_11_24_1","first-page":"126","article-title":"Pharmacokinetics, Milk Penetration and PK\/PD Analysis by Monte Carlo Simulation of Marbofloxacin in Lactating Goats After Intravenous and Intramuscular Administration","volume":"113","author":"Lorenzutti A. M.","year":"2017","journal-title":"Research in Veterinary Science"},{"issue":"11","key":"e_1_2_11_25_1","doi-asserted-by":"crossref","first-page":"3098","DOI":"10.3390\/ani11113098","article-title":"PK\/PD Analysis by Nonlinear Mixed\u2010Effects Modeling of a Marbofloxacin Dose Regimen for Treatment of Goat Mastitis Produced by Coagulase\u2010Negative Staphylococci","volume":"11","author":"Lorenzutti A. 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A.","year":"2016","journal-title":"Journal of Dairy Science"},{"issue":"4","key":"e_1_2_11_36_1","first-page":"601","article-title":"The Gain\u2010Of\u2010Function Y581S Polymorphism of the ABCG2 Transporter Increases Secretion Into Milk of Danofloxacin at the Therapeutic Dose for Mastitis Treatment","volume":"9","author":"Otero J. 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P.","year":"2021","journal-title":"Archives of Toxicology"},{"issue":"15","key":"e_1_2_11_39_1","doi-asserted-by":"crossref","first-page":"376","DOI":"10.1136\/vr.103964","article-title":"Susceptibility and PK\/PD Relationships of \n                     Staphylococcus aureus\n                   Strains Isolated From the Milk of Sheep and Goats With Clinical Mastitis to Five Veterinary Fluoroquinolones","volume":"180","author":"Serrano\u2010Rodr\u00edguez J. M.","year":"2017","journal-title":"Veterinary Record"},{"issue":"5","key":"e_1_2_11_40_1","doi-asserted-by":"crossref","first-page":"3241","DOI":"10.3168\/jds.2024-25194","article-title":"Pharmacokinetic\/Pharmacodynamic Modeling in Plasma and Milk and Monte Carlo Simulations of Marbofloxacin Against Staphylococcus aureus and \n                     Mycoplasma agalactiae\n                   in Lactating Sheep","volume":"108","author":"Serrano\u2010Rodr\u00edguez J. M.","year":"2025","journal-title":"Journal of Dairy Science"},{"issue":"9","key":"e_1_2_11_41_1","doi-asserted-by":"crossref","first-page":"511","DOI":"10.1111\/j.1439-0442.1997.tb01137.x","article-title":"Pharmacokinetics and Penetration of Marbofloxacin From Blood Into the Milk of Cows and Ewes","volume":"44","author":"Shem\u2010Tov M.","year":"1997","journal-title":"Zentralblatt Fur Veterinarmedizin Reihe A"},{"issue":"1","key":"e_1_2_11_42_1","doi-asserted-by":"crossref","first-page":"131","DOI":"10.1007\/s10911-013-9309-1","article-title":"The Role of Tight Junctions in Mammary Gland Function","volume":"19","author":"Stelwagen K.","year":"2014","journal-title":"Journal of Mammary Gland Biology and Neoplasia"},{"issue":"7659","key":"e_1_2_11_43_1","doi-asserted-by":"crossref","first-page":"504","DOI":"10.1038\/nature22345","article-title":"Structure of the Human Multidrug Transporter ABCG2","volume":"546","author":"Taylor N. M. 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E.","year":"2006","journal-title":"Trends in Pharmacological Sciences"},{"issue":"1","key":"e_1_2_11_46_1","doi-asserted-by":"crossref","first-page":"14","DOI":"10.1016\/j.addr.2008.08.007","article-title":"Physiological and Pharmacological Roles of ABCG2\/BCRP: Recent Findings in Abcg2 Knockout Mice","volume":"61","author":"Vlaming M. L. H.","year":"2009","journal-title":"Advanced Drug Delivery Reviews"},{"issue":"1","key":"e_1_2_11_47_1","first-page":"59","article-title":"Pharmacokinetic Behaviour of Marbofloxacin After Intravenous and Intramuscular Administration in Adult Goats","volume":"161","author":"Waxman S.","year":"2001","journal-title":"Veterinary Journal"},{"issue":"6","key":"e_1_2_11_48_1","doi-asserted-by":"crossref","first-page":"6376","DOI":"10.3168\/jds.2020-20029","article-title":"Invited Review: The Role of the Blood\u2010Milk Barrier and Its Manipulation for the Efficacy of the Mammary Immune Response and Milk Production","volume":"104","author":"Wellnitz O.","year":"2021","journal-title":"Journal of Dairy Science"}],"container-title":["Journal of Veterinary Pharmacology and Therapeutics"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1111\/jvp.70113","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/full-xml\/10.1111\/jvp.70113","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1111\/jvp.70113","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,9,29]],"date-time":"2026-09-29T11:48:46Z","timestamp":1790682526000},"score":1,"resource":{"primary":{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/10.1111\/jvp.70113"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,9,29]]},"references-count":47,"alternative-id":["10.1111\/jvp.70113"],"URL":"https:\/\/doi.org\/10.1111\/jvp.70113","archive":["Portico"],"relation":{},"ISSN":["0140-7783","1365-2885"],"issn-type":[{"value":"0140-7783","type":"print"},{"value":"1365-2885","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,9,29]]},"assertion":[{"value":"2026-05-19","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-09-22","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-09-29","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"jvp.70113"}}