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This is difficult to manage and often unresponsive to traditional analgesics. An important mechanism associated with maladaptive pain is central sensitization which results in part from increased NMDA (N-methyl-D-aspartate) receptor activation. Amantadine is an NMDA receptor antagonist that has been used in combination with opioids and NSAIDs in humans and dogs for the treatment of conditions associated with central sensitization. The goal of the current study was to describe the pharmacokinetics and physiological effects of amantadine in horses as a first step in assessing the utility of this drug in horses. Eight horses received a single intravenous administration of 5\u00a0mg\/kg and oral administrations of 3, 5, and 10\u00a0mg\/kg of amantadine in a randomized 4-way balanced crossover design. Blood samples were collected before drug administration and at predetermined time intervals for up to 96\u00a0h post-drug administration. Concentrations of amantadine were determined using liquid chromatography-tandem mass spectrometry and pharmacokinetic analysis was performed. Behavioral assessments (e.g., sedation, ataxia), locomotor activity, gastrointestinal borborygmi, and effects on heart rate were assessed.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      The C\n                      <jats:sub>max<\/jats:sub>\n                      and T\n                      <jats:sub>max<\/jats:sub>\n                      of amantadine were 208.7\u2009\u00b1\u200970.4, 347.9\u2009\u00b1\u200979.5, and 478.9\u2009\u00b1\u2009165.6 ng\/mL and 0.63 (0.16\u20130.75\u00a0h; median and range) 0.63 (0.16\u20131.0\u00a0h), and 1.0 (0.5\u20131.0\u00a0h) for 3, 5, and 10\u00a0mg\/kg, respectively. The terminal half-life was 3.90\u2009\u00b1\u20091.24 following IV administration of 5\u00a0mg\/kg, and 3.87\u2009\u00b1\u20092.17, 4.21\u2009\u00b1\u20091.41, and 4.87\u2009\u00b1\u20092.05\u00a0h following oral administration of 3, 5, and 10\u00a0mg\/kg, respectively. A 2-compartment population PK model best described concentration data. The absorption rate constant was 3.16 1\/h and the oral bioavailability was 23.2%. Transient signs, including ataxia and hypometria were observed in 5\/8 horses following IV administration.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>Amantadine administration to horses was well tolerated, supporting additional study. This study provides pharmacokinetic and limited safety data that can be used to guide pharmacodynamic studies to assess the therapeutic efficacy of this compound in horses.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1186\/s12917-026-05672-9","type":"journal-article","created":{"date-parts":[[2026,6,23]],"date-time":"2026-06-23T05:25:21Z","timestamp":1782192321000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Assessment of pharmacokinetic parameters, oral bioavailability, and physiological effects of amantadine in horses"],"prefix":"10.1186","volume":"22","author":[{"given":"Hannah L","family":"Riley","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Khursheed R","family":"Mama","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Megan E","family":"Jacobs","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniel S","family":"McKemie","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Philip H","family":"Kass","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Heather K","family":"Knych","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,6,23]]},"reference":[{"key":"5672_CR1","doi-asserted-by":"publisher","first-page":"1547764","DOI":"10.3389\/fpain.2025.1547764","volume":"6","author":"L Chiavaccini","year":"2025","unstructured":"Chiavaccini L, Reed RA, Spadavecchia C, Editorial. 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