{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,17]],"date-time":"2025-10-17T00:34:17Z","timestamp":1760661257610,"version":"build-2065373602"},"reference-count":28,"publisher":"Wiley","issue":"3","license":[{"start":{"date-parts":[[2025,3,4]],"date-time":"2025-03-04T00:00:00Z","timestamp":1741046400000},"content-version":"vor","delay-in-days":3,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":["analyticalsciencejournals.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Labelled Comp Radiopharmac"],"published-print":{"date-parts":[[2025,3]]},"abstract":"<jats:title>ABSTRACT<\/jats:title><jats:p>Bupivacaine is a local anesthetic widely used in equine and human medicine. Use of bupivacaine in performance horses is regulated because its ability to block pain means that it can be misused for advantage in performance horses. In racing regulation, bupivacaine is classified by the Association of Racing Commissioners International (ARCI) as a Class 2 Penalty Class A Foreign substance, the detection of which can lead to significant penalties. In horses, bupivacaine is metabolized by Phase\u2010I hydroxylation to yield 3\u2010hydroxybupivacaine, which is then glucuronidated to yield the Phase\u2010II metabolite bupivacaine\u20103\u2010hydroxyglucuronide, which is excreted at relatively high concentrations in equine urine. Standard regulatory procedure during urinalysis is to perform an enzymatic hydrolysis, thereby enabling subsequent detection of 3\u2010hydroxybupivacaine, the primary analyte used for bupivacaine regulation in urine samples from competition horses. We now report on the synthesis of 3\u2010hydroxybupivacaine and deuterated 3\u2010hydroxybupivacaine from piperidine\u20102\u2010carboxylic acid in six successive steps with moderate yield. The compounds were characterized by <jats:sup>1<\/jats:sup>H and <jats:sup>13<\/jats:sup>C NMR and their purity ascertained by HPLC\u2010MS. The deuterated bupivacaine and 3\u2010hydroxybupivacaine were further confirmed by HRMS. The synthesis of these compounds provides certified reference standards and stable isotope\u2010labeled internal standards for drug testing in competitive equine sports including horse racing.<\/jats:p>","DOI":"10.1002\/jlcr.4132","type":"journal-article","created":{"date-parts":[[2025,3,12]],"date-time":"2025-03-12T00:18:33Z","timestamp":1741738713000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Synthesis and Characterization of 3\u2010Hydroxybupivacaine and Deuterated 3\u2010Hydroxybupivacaine for Use in Equine Medication Regulation"],"prefix":"10.1002","volume":"68","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-3076-264X","authenticated-orcid":false,"given":"Adedamola\u00a0S.","family":"Arojojoye","sequence":"first","affiliation":[{"name":"Department of Chemistry University of Kentucky  Lexington Kentucky USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9977-3633","authenticated-orcid":false,"given":"Justin","family":"Holmes","sequence":"additional","affiliation":[{"name":"Department of Chemistry University of Kentucky  Lexington Kentucky USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Miles\u00a0P.","family":"Buchart","sequence":"additional","affiliation":[{"name":"The Department of Veterinary Science and the Maxwell H. Gluck Equine Research Center, Martin\u2010Gatton College of Agriculture, Food and Environment and the Department of Toxicology and Cancer Biology University of Kentucky  Lexington Kentucky USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4947-7283","authenticated-orcid":false,"given":"Samuel\u00a0G.","family":"Awuah","sequence":"additional","affiliation":[{"name":"Department of Chemistry University of Kentucky  Lexington Kentucky USA"},{"name":"Center for Pharmaceutical Research and Innovation, College of Pharmacy and Department of Pharmaceutical Sciences, College of Pharmacy University of Kentucky  Lexington Kentucky USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Rodney","family":"Eisenberg","sequence":"additional","affiliation":[{"name":"Frontier BioPharm, LLC  Richmond Kentucky USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6234-3197","authenticated-orcid":false,"given":"Clara\u00a0K.","family":"Fenger","sequence":"additional","affiliation":[{"name":"Equine Integrated Medicine  Georgetown Kentucky USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0009-0004-1967-5451","authenticated-orcid":false,"given":"George\u00a0A.","family":"Maylin","sequence":"additional","affiliation":[{"name":"New York Drug Testing and Research Program  Ithaca New York USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8506-3147","authenticated-orcid":false,"given":"Thomas","family":"Tobin","sequence":"additional","affiliation":[{"name":"The Department of Veterinary Science and the Maxwell H. Gluck Equine Research Center, Martin\u2010Gatton College of Agriculture, Food and Environment and the Department of Toxicology and Cancer Biology University of Kentucky  Lexington Kentucky USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2025,3,4]]},"reference":[{"volume-title":"Guideline M10 on Bioanalytical Method Validation","year":"2019","author":"ICH Draft","key":"e_1_2_6_2_1"},{"key":"e_1_2_6_3_1","doi-asserted-by":"publisher","DOI":"10.1021\/tx800139z"},{"key":"e_1_2_6_4_1","doi-asserted-by":"publisher","DOI":"10.1002\/bmc.2757"},{"key":"e_1_2_6_5_1","doi-asserted-by":"publisher","DOI":"10.1520\/JFS13007J"},{"key":"e_1_2_6_6_1","doi-asserted-by":"publisher","DOI":"10.1093\/anatox\/35.5.302"},{"key":"e_1_2_6_7_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jchromb.2009.01.020"},{"key":"e_1_2_6_8_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jchromb.2012.02.021"},{"key":"e_1_2_6_9_1","doi-asserted-by":"publisher","DOI":"10.1002\/dta.3357"},{"key":"e_1_2_6_10_1","first-page":"346","volume-title":"Principles of Pharmacology for Athletic Trainers","author":"Thomas C.","year":"2024"},{"key":"e_1_2_6_11_1","doi-asserted-by":"publisher","DOI":"10.1002\/rcm.6648"},{"key":"e_1_2_6_12_1","doi-asserted-by":"publisher","DOI":"10.1002\/9781119421375.ch48"},{"key":"e_1_2_6_13_1","doi-asserted-by":"publisher","DOI":"10.1002\/dta.2999"},{"volume-title":"Unnatural Ability: The History of Performance\u2010Enhancing Drugs in Thoroughbred Racing","year":"2023","author":"Toby M. 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