{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,20]],"date-time":"2026-08-20T05:23:28Z","timestamp":1787203408136,"version":"build-2736575974"},"reference-count":23,"publisher":"MDPI AG","issue":"8","license":[{"start":{"date-parts":[[2026,8,18]],"date-time":"2026-08-18T00:00:00Z","timestamp":1787011200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100016749","name":"Center for Equine Health","doi-asserted-by":"crossref","id":[{"id":"10.13039\/100016749","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Metabolites"],"abstract":"<jats:p>Background\/Objectives: Vonoprazan is a potassium-competitive acid blocker with potential for the treatment of equine gastric ulcer syndrome. Vonoprazan metabolic pathways in horses have not been characterized. This study aimed to identify vonoprazan metabolites following oral administration and to determine the metabolic enzymes responsible for their metabolism using in vitro models. Methods: Six healthy adult Thoroughbred horses received vonoprazan (0.5 and 1 mg\/kg PO) in a randomized crossover design. Plasma concentrations of vonoprazan-N-oxide (M-I) and vonoprazan-nitrone (M-III) were quantified using a validated liquid chromatography-tandem mass spectrometry method, and a non-compartmental pharmacokinetic analysis was performed. In vitro metabolism was evaluated using equine liver microsomes (ELMs) and equine recombinant CYP450 (eq-rCYP) enzymes. Enzyme kinetics were characterized using nonlinear regression modeling. Results: Both metabolites were detected in plasma after oral administration. Systemic exposure to M-I was markedly greater than M-III at both doses. At 1 mg\/kg, mean \u00b1 SD Cmax values were 39.2 \u00b1 28.3 ng\/mL for M-I and 1.67 \u00b1 1.66 ng\/mL for M-III. AUC0\u2013\u221e increased dose-proportionally for both metabolites. In ELMs, M-I formation followed substrate inhibition kinetics, whereas M-III formation followed Michaelis\u2013Menten kinetics. Among recombinant enzymes, CYP2D50 and CYP3A94 were the primary contributors to metabolite formation, exhibiting metabolite-specific kinetic profiles. Conclusions: These findings demonstrate that vonoprazan undergoes hepatic oxidative metabolism in horses, with M-I as the predominant circulating metabolite. Equine recombinants CYP2D50 and CYP3A94 appear to play central roles in equine vonoprazan metabolism, providing foundation for future evaluation of drug\u2013drug interaction potential and clinical use in this species.<\/jats:p>","DOI":"10.3390\/metabo16080584","type":"journal-article","created":{"date-parts":[[2026,8,18]],"date-time":"2026-08-18T08:08:41Z","timestamp":1787040521000},"page":"584","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["In Vivo Metabolite Formation and In Vitro Cytochrome P450-Mediated Metabolism of Vonoprazan in Horses"],"prefix":"10.3390","volume":"16","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-6227-8572","authenticated-orcid":false,"given":"Camilo J.","family":"Morales","sequence":"first","affiliation":[{"name":"K.L. Maddy Equine Analytical Chemistry Laboratory (Pharmacology Section), School of Veterinary Medicine, University of California, Davis, Davis, CA 95616, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniel S.","family":"Mckemie","sequence":"additional","affiliation":[{"name":"K.L. Maddy Equine Analytical Chemistry Laboratory (Pharmacology Section), School of Veterinary Medicine, University of California, Davis, Davis, CA 95616, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jayanti Bhandari","family":"Neupane","sequence":"additional","affiliation":[{"name":"K.L. Maddy Equine Analytical Chemistry Laboratory (Pharmacology Section), School of Veterinary Medicine, University of California, Davis, Davis, CA 95616, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Heather K.","family":"Knych","sequence":"additional","affiliation":[{"name":"K.L. Maddy Equine Analytical Chemistry Laboratory (Pharmacology Section), School of Veterinary Medicine, University of California, Davis, Davis, CA 95616, USA"},{"name":"Department of Molecular Biosciences, School of Veterinary Medicine, University of California, Davis, Davis, CA 95616, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,8,18]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1288","DOI":"10.1111\/jvim.13578","article-title":"European College of Equine Internal Medicine Consensus Statement\u2014Equine Gastric Ulcer Syndrome in Adult Horses","volume":"29","author":"Sykes","year":"2015","journal-title":"J. Vet. Intern. Med."},{"key":"ref_2","doi-asserted-by":"crossref","unstructured":"Vokes, J., Lovett, A., and Sykes, B. (2023). Equine Gastric Ulcer Syndrome: An Update on Current Knowledge. 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