{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2023,11,15]],"date-time":"2023-11-15T09:56:20Z","timestamp":1700042180674},"reference-count":34,"publisher":"American Veterinary Medical Association (AVMA)","issue":"8","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["ajvr"],"published-print":{"date-parts":[[2020,8]]},"abstract":"<jats:title>Abstract<\/jats:title>\n<jats:sec id=\"s001\">\n<jats:title>OBJECTIVE<\/jats:title>\n<jats:p>To determine the effects of coadministration of naltrexone, a human opioid abuse deterrent, on the pharmacokinetics and pharmacodynamics of a methadone-fluconazole combination administered orally to dogs.<\/jats:p>\n<\/jats:sec>\n<jats:sec id=\"s002\">\n<jats:title>ANIMALS<\/jats:title>\n<jats:p>12 healthy Beagles.<\/jats:p>\n<\/jats:sec>\n<jats:sec id=\"s003\">\n<jats:title>PROCEDURES<\/jats:title>\n<jats:p>Dogs (body weight, 10.7 to 13.9 kg) were randomly allocated to 2 groups in a parallel design study. All dogs received fluconazole (100 mg [7.19 to 9.35 mg\/kg], PO). Twelve hours later (time 0), dogs were administered methadone (10 mg [0.72 to 0.93 mg\/kg]) plus fluconazole (50 mg [3.62 to 4.22 mg\/kg]; methadone-fluconazole) or methadone (10 mg [0.72 to 0.93 mg\/kg]) plus fluconazole (50 mg [3.60 to 4.67 mg\/kg]) and naltrexone (2.5 mg [0.18 to 0.23 mg\/kg]; methadone-fluconazole-naltrexone), PO, in a gelatin capsule. Blood samples were collected for pharmacokinetic analysis, and rectal temperature and sedation were assessed to evaluate opioid effects at predetermined times up to 24 hours after treatment.<\/jats:p>\n<\/jats:sec>\n<jats:sec id=\"s004\">\n<jats:title>RESULTS<\/jats:title>\n<jats:p>Most dogs had slight sedation during the 12 hours after drug administration; 1 dog\/group had moderate sedation at 1 time point. Mean rectal temperatures decreased significantly from baseline (immediate pretreatment) values from 2 to \u2265 12 hours and 2 to \u2265 8 hours after methadone-fluconazole and methadone-fluconazole-naltrexone treatment, respectively. Geometric mean maximum observed concentration of methadone in plasma was 35.1 and 33.5 ng\/mL and geometric mean terminal half-life was 7.92 and 7.09 hours after methadone-fluconazole and methadone-fluconazole-naltrexone treatment, respectively. Naltrexone was sporadically detected in 1 dog. The active naltrexone metabolite, \u03b2-naltrexol, was not detected. The inactive metabolite, naltrexone glucuronide, was detected in all dogs administered methadone-fluconazole-naltrexone.<\/jats:p>\n<\/jats:sec>\n<jats:sec id=\"s005\">\n<jats:title>CONCLUSIONS AND CLINICAL RELEVANCE<\/jats:title>\n<jats:p>Opioid effects were detected after oral administration of methadone-fluconazole or methadone-fluconazole-naltrexone. Further studies assessing additional opioid effects, including antinociception, are needed.<\/jats:p>\n<\/jats:sec>","DOI":"10.2460\/ajvr.81.8.656","type":"journal-article","created":{"date-parts":[[2020,7,23]],"date-time":"2020-07-23T13:45:59Z","timestamp":1595511959000},"page":"656-664","source":"Crossref","is-referenced-by-count":3,"title":["Pharmacokinetics and pharmacodynamics of a novel analgesic with a deterrent to human opioid abuse (methadone-fluconazole-naltrexone) after oral administration in dogs"],"prefix":"10.2460","volume":"81","author":[{"given":"Butch","family":"KuKanich","sequence":"first","affiliation":[{"name":"1Department of Anatomy and Physiology, College of Veterinary Medicine, Kansas State University, Manhattan, KS 66506."},{"name":"3Institute of Computational Comparative Medicine, College of Veterinary Medicine, Kansas State University, Manhattan, KS 66506."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kate","family":"KuKanich","sequence":"additional","affiliation":[{"name":"2Department of Clinical Sciences, College of Veterinary Medicine, Kansas State University, Manhattan, KS 66506."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"David C.","family":"Rankin","sequence":"additional","affiliation":[{"name":"2Department of Clinical Sciences, College of Veterinary Medicine, Kansas State University, Manhattan, KS 66506."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Charles W.","family":"Locuson","sequence":"additional","affiliation":[{"name":"4Vanderbilt University Center for Neuroscience Drug Discovery, Cool Springs Life Science Center, Nashville, TN 37067"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hyun","family":"Joo","sequence":"additional","affiliation":[{"name":"1Department of Anatomy and Physiology, College of Veterinary Medicine, Kansas State University, Manhattan, KS 66506."},{"name":"3Institute of Computational Comparative Medicine, College of Veterinary Medicine, Kansas State University, Manhattan, KS 66506."}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1272","reference":[{"key":"ref1","series-title":"Vet Clin North Am Small Anim Pract","doi-asserted-by":"publisher","first-page":"1109","DOI":"10.1016\/j.cvsm.2013.04.007","article-title":"Outpatient oral analgesics in dogs and cats beyond nonsteroidal antiinflammatory drugs: an evidence-based approach","volume":"43","author":"KuKanich","year":"2013"},{"key":"ref2","series-title":"Vet Surg","doi-asserted-by":"publisher","first-page":"159","DOI":"10.1111\/j.1532-950X.1998.tb00114.x","article-title":"Comparison of plasma fentanyl concentrations by using three transdermal fentanyl patch sizes in dogs","volume":"27","author":"Egger","year":"1998"},{"key":"ref3","series-title":"Int J Legal Med","doi-asserted-by":"publisher","first-page":"147","DOI":"10.1007\/s00414-006-0137-3","article-title":"Fatal outcome in a child after ingestion of a transdermal fentanyl patch","volume":"121","author":"Teske","year":"2007"},{"key":"ref4","series-title":"Ann Pharmacother","doi-asserted-by":"publisher","first-page":"969","DOI":"10.1177\/106002809502901001","article-title":"Fentanyl remaining in a transdermal system following three days of continuous use","volume":"29","author":"Marquardt","year":"1995"},{"key":"ref5","series-title":"J Vet Pharmacol Ther","doi-asserted-by":"publisher","first-page":"461","DOI":"10.1111\/j.1365-2885.2005.00681.x","article-title":"The effects of inhibiting cytochrome P450 3A, P-glycoprotein, and gastric acid secretion on the oral bioavailability of methadone in dogs","volume":"28","author":"Kukanich","year":"2005"},{"key":"ref6","series-title":"Vet Anaesth Analg","doi-asserted-by":"publisher","first-page":"242","DOI":"10.1111\/j.1467-2995.2007.00369.x","article-title":"The disposition and behavioral effects of methadone in Greyhounds","volume":"35","author":"KuKanich","year":"2008"},{"key":"ref7","series-title":"Vet Anaesth Analg","doi-asserted-by":"publisher","first-page":"224","DOI":"10.1111\/j.1467-2995.2011.00602.x","article-title":"The effects of concurrent administration of cytochrome P-450 inhibitors on the pharmacokinetics of oral methadone in healthy dogs","volume":"38","author":"KuKanich","year":"2011"},{"key":"ref8","series-title":"Vet Anaesth Analg","doi-asserted-by":"publisher","first-page":"597","DOI":"10.1111\/vaa.12257","article-title":"KuKanich K. 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