Population pharmacokinetics and clinical evaluation of intravenous acetaminophen and its metabolites in Andalusian horses.
Abstract: To date, no intravenous pharmacokinetics (PK) studies have assessed acetaminophen or its major metabolites (acetaminophen-glucuronide and acetaminophen-sulphate) in horses. The influence of sex on acetaminophen metabolism in horses is unclear, and Monte Carlo simulations have not been applied to explore potential clinical applications. This study aimed to determine the intravenous PK and safety of acetaminophen in Andalusian horses at 10 and 20 mg/kg, evaluate sex as a covariate, and simulate clinical regimens. Twenty mares and twenty stallions received intravenous acetaminophen, and plasma concentrations were analysed by LC-MS/MS and modelled using non-linear mixed-effects models (MonolixSuite®). Safety was evaluated via clinical examinations and by haematological and biochemical profiles 24 h after administration. Two constant-rate infusion (CRI) regimens were examined in PK simulations that did not involve surgery: a short-duration, high-dose infusion (3 h) for peri-operative scenarios (short-infusion group at 3.33, 6.66, and 10.0 mg/kg/h) and a longer-duration, lower-dose infusion (8 h) for post-operative analgesia scenarios (long-infusion group at 1.25, 2.50, and 3.75 mg/kg/h). After modelling, glucuronide and sulphate levels were 2.1 and 4.53 times higher, respectively, than acetaminophen levels. Half-lives were 3.5, 5.6, and 3.2 h for acetaminophen, glucuronide, and sulphate, respectively. Clearance was influenced by sex (mares: 0.47 L/h/kg; stallions: 0.35 L/h/kg). No adverse effects were observed. Steady-state concentrations observed in the CRI simulations ranged from 1.75-5.21 µg/mL (short-infusion group) and 0.62-2.02 µg/mL (long-infusion group). Acetaminophen exhibited sex-dependent PK variability and high-level formation of metabolites. These findings support further clinical evaluation of acetaminophen CRIs in equine analgesia.
Copyright © 2025 Elsevier Ltd. All rights reserved.
Publication Date: 2025-04-24 PubMed ID: 40286979DOI: 10.1016/j.tvjl.2025.106357Google Scholar: Lookup
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Summary
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The research investigates the effects and safety of intravenous acetaminophen and its primary metabolites in Andalusian horses, also looking into the influence of gender on acetaminophen metabolism. Potential uses of acetaminophen in medical regimens for horses are also considered via simulation.
Study Description and Methodology
- The study aimed at understanding the intravenous pharmacokinetics (the movement of drugs within the body) and safety of acetaminophen in Andalusian horses.
- Further, it explored the influence of sex on acetaminophen metabolism and used Monte Carlo simulations to observe potential clinical applications.
- Two groups of twenty horses, mares and stallions, were administered with intravenous acetaminophen, after which their plasma concentration was analyzed and modeled.
Clinical Examination and Safety Handling Procedures
- Horses were subjected to clinical examinations and were given hematological and biochemical profiles 24 hours after administration to assess the safety of acetaminophen administration.
- No adverse effects were observed on the horses, indicating the safety of acetaminophen administration.
Key Study Findings
- After providing acetaminophen, the glucuronide and sulphate (key metabolites of acetaminophen) levels were observed to be significantly higher than acetaminophen levels.
- The clearance of the drug was influenced by the sex of the horse. The clearance rate in mares was found to be higher (0.47 L/h/kg) than that in stallions (0.35 L/h/kg), thereby suggesting a sex-dependent pharmacokinetic variability.
- Furthermore, acetaminophen exhibited high levels of metabolite formation.
Study Implications
- The study results suggest that further clinical evaluation of acetaminophen is required, especially constant-rate infusions for equine analgesia.
- These findings are particularly relevant for the veterinary field as it gives deeper insights into potential uses of acetaminophen in the medical regimen of horses.
Cite This Article
APA
Granados MM, Medina-Bautista F, Navarrete-Calvo R, Argüelles D, Domínguez-Pérez JM, Priego-Capote F, Muñoz-Rascón P, Serrano-Rodríguez JM.
(2025).
Population pharmacokinetics and clinical evaluation of intravenous acetaminophen and its metabolites in Andalusian horses.
Vet J, 312, 106357.
https://doi.org/10.1016/j.tvjl.2025.106357 Publication
Researcher Affiliations
- Veterinary Clinical Hospital, University of Cordoba, Córdoba, Spain; Department of Animal Medicine and Surgery, Veterinary Faculty, University of Cordoba, Córdoba, Spain.
- Veterinary Clinical Hospital, University of Cordoba, Córdoba, Spain; Department of Animal Medicine and Surgery, Veterinary Faculty, University of Cordoba, Córdoba, Spain.
- Veterinary Clinical Hospital, University of Cordoba, Córdoba, Spain; Department of Animal Medicine and Surgery, Veterinary Faculty, University of Cordoba, Córdoba, Spain. Electronic address: v92nacar@uco.es.
- Veterinary Clinical Hospital, University of Cordoba, Córdoba, Spain; Department of Animal Medicine and Surgery, Veterinary Faculty, University of Cordoba, Córdoba, Spain.
- Veterinary Clinical Hospital, University of Cordoba, Córdoba, Spain; Department of Animal Medicine and Surgery, Veterinary Faculty, University of Cordoba, Córdoba, Spain.
- Department of Analytical Chemistry, University of Córdoba, Córdoba, Spain.
- Pharmacology Area, Department of Nursing, Pharmacology and Physiotherapy, Veterinary Faculty, University of Córdoba, Córdoba, Spain.
- Pharmacology Area, Department of Nursing, Pharmacology and Physiotherapy, Veterinary Faculty, University of Córdoba, Córdoba, Spain.
Conflict of Interest Statement
Declaration of Competing Interest None of the authors of this manuscript has any financial or personal relationships that could inappropriately influence or bias the content of the paper.
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