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In Vivo Metabolite Formation and In Vitro Cytochrome P450-Mediated Metabolism of Vonoprazan in Horses.
Abstract: 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. 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. 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 ± SD C values were 39.2 ± 28.3 ng/mL for M-I and 1.67 ± 1.66 ng/mL for M-III. AUC increased dose-proportionally for both metabolites. In ELMs, M-I formation followed substrate inhibition kinetics, whereas M-III formation followed Michaelis-Menten kinetics. Among recombinant enzymes, CYP2D50 and CYP3A94 were the primary contributors to metabolite formation, exhibiting metabolite-specific kinetic profiles. 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-drug interaction potential and clinical use in this species.
Publication Date: 2026-08-18 PubMed ID: 42646320PubMed Central: PMC13515708DOI: 10.3390/metabo16080584Google Scholar: Lookup The Equine Research Bank provides access to a large database of publicly available scientific literature. Inclusion in the Research Bank does not imply endorsement of study methods or findings by Mad Barn.
- Journal Article
Summary
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Research Overview
- This study investigated how the drug vonoprazan is metabolized in horses, both in living animals and in laboratory settings, focusing on identifying the metabolites formed and the specific liver enzymes responsible.
- Understanding vonoprazan metabolism in horses is crucial because it has potential as a treatment for equine gastric ulcer syndrome, but its metabolic pathways in this species were previously unknown.
Background and Purpose
- Vonoprazan is a potassium-competitive acid blocker used to reduce stomach acid and treat ulcers.
- Equine gastric ulcer syndrome is a common condition in horses that causes discomfort and health issues.
- Before applying vonoprazan clinically in horses, it is necessary to understand how it is metabolized (broken down) in the horse’s body.
- The study aimed to identify the metabolites formed after oral administration of vonoprazan and to determine which horse liver enzymes are responsible for its breakdown.
Study Design and Methods
- Six healthy adult Thoroughbred horses were administered vonoprazan orally at two different doses (0.5 mg/kg and 1 mg/kg) using a randomized crossover design, allowing each horse to receive both doses in different periods.
- Blood plasma samples were collected to measure levels of vonoprazan and its metabolites.
- Metabolites focused on were vonoprazan-N-oxide (M-I) and vonoprazan-nitrone (M-III).
- Quantification of metabolites in plasma was performed using liquid chromatography-tandem mass spectrometry (LC-MS/MS), a precise analytical chemistry technique.
- Pharmacokinetic analysis (study of how the drug and metabolites move through the body) was conducted using non-compartmental methods.
- In vitro (test tube) studies used equine liver microsomes (ELMs) to mimic liver metabolism and recombinant equine cytochrome P450 (CYP450) enzymes to identify which specific enzymes metabolize vonoprazan.
- Enzyme kinetics, describing how enzyme activity changes with different drug concentrations, were analyzed using nonlinear regression models to distinguish between types of kinetics (substrate inhibition vs. Michaelis-Menten kinetics).
Key Findings: Metabolite Formation In Vivo
- Both metabolites, M-I and M-III, were detected in the plasma of horses after oral dosing, confirming that vonoprazan undergoes metabolic transformation.
- M-I (vonoprazan-N-oxide) had significantly higher plasma concentrations than M-III (vonoprazan-nitrone) at both doses, indicating it is the predominant metabolite circulating systemically.
- At the higher 1 mg/kg dose, the average plasma concentration for M-I was about 39.2 ng/mL, while for M-III it was much lower, about 1.67 ng/mL.
- The area under the curve (AUC), representing total drug exposure over time, increased proportionally with dose for both metabolites, showing predictable pharmacokinetics.
Key Findings: In Vitro Metabolism and Enzyme Kinetics
- Using equine liver microsomes, M-I formation exhibited substrate inhibition kinetics, meaning that at higher concentrations of vonoprazan, the metabolism to M-I is inhibited, a non-linear process.
- M-III formation displayed classic Michaelis-Menten kinetics, indicating a saturation effect at higher substrate concentrations with predictable enzyme activity.
- Two recombinant equine CYP450 enzymes—CYP2D50 and CYP3A94—were identified as the primary enzymes responsible for metabolite formation.
- CYP2D50 and CYP3A94 showed different enzyme kinetic profiles specific to each metabolite, indicating a specialized role in metabolizing vonoprazan.
Conclusions and Implications
- Vonoprazan undergoes hepatic (liver) oxidative metabolism in horses, predominantly forming the metabolite M-I circulating in plasma.
- The cytochrome P450 enzymes CYP2D50 and CYP3A94 are central to vonoprazan metabolism, highlighting their importance in processing this drug in horses.
- This knowledge provides a foundation for understanding potential drug-drug interactions involving vonoprazan in horses, as CYP enzymes are common sites for such interactions.
- The study supports further clinical development and prudent use of vonoprazan for treating equine gastric ulcers, with better insights into its metabolism aiding dosing and safety considerations.
Cite This Article
APA
Morales CJ, Mckemie DS, Neupane JB, Knych HK.
(2026).
In Vivo Metabolite Formation and In Vitro Cytochrome P450-Mediated Metabolism of Vonoprazan in Horses.
Metabolites, 16(8), 584.
https://doi.org/10.3390/metabo16080584 Publication
Researcher Affiliations
- K.L. Maddy Equine Analytical Chemistry Laboratory (Pharmacology Section), School of Veterinary Medicine, University of California, Davis, Davis, CA 95616, USA.
- K.L. Maddy Equine Analytical Chemistry Laboratory (Pharmacology Section), School of Veterinary Medicine, University of California, Davis, Davis, CA 95616, USA.
- K.L. Maddy Equine Analytical Chemistry Laboratory (Pharmacology Section), School of Veterinary Medicine, University of California, Davis, Davis, CA 95616, USA.
- K.L. Maddy Equine Analytical Chemistry Laboratory (Pharmacology Section), School of Veterinary Medicine, University of California, Davis, Davis, CA 95616, USA.
- Department of Molecular Biosciences, School of Veterinary Medicine, University of California, Davis, Davis, CA 95616, USA.
Grant Funding
- Center for Equine Health
Conflict of Interest Statement
The authors have no conflicts of interests.
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