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Plasma concentrations and therapeutic efficacy of phenylbutazone and flunixin meglumine in the horse: pharmacokinetic/pharmacodynamic modelling.
Abstract: The purpose of the present study was to establish in the horse the relationship between plasma concentration profiles of phenylbutazone (PBZ) and flunixin meglumine (FM) and their pharmacological effects in order to build a predictive pharmacokinetic/pharmacodynamic (PK/PD) model. In five horses, an experimental arthritis was induced by injecting Freund's adjuvant into a carpal joint. PBZ (4 mg/kg) and FM (1 mg/kg) were injected by the intravenous route as a single intravenous dose in two different trials. Five pharmacodynamic end-points were regularly measured after test article injection using standardized procedures: local skin temperature, stride length, the rest angle flexion and the maximal carpal flexion of the injured leg and circumference of the inflamed joint. Plasma drug concentrations and pharmacodynamic data were analysed according to an integrated PK/PD model; for the stride length, the PBZ EC50, i.e. the plasma concentration for which half the maximum effect could be obtained, was 3.6 +/- 2.2 micrograms/ml and the maximum potential effect was 10.7 +/- 9.4% above the control value. For FM, the corresponding values were 0.93 +/- 0.35 micrograms/ml and 16.3 +/- 4.6%. EC50 values for rest angle flexion and local skin temperature were similar to that obtained for stride length. Maximal carpal flexion was an unreliable end-point, and circumference of the joint did not display significant response to the drugs. Using these experimental parameters, a dose-effect relationship was simulated for both drugs; it was shown for PBZ that the model predicts an absence of effect for a 1 mg/kg dose and a maximum effect at about 2 mg/kg; at higher PBZ doses, the maximum effect was not modified, but its duration was increased from 8 h with a 2 mg/kg dose to about 24 h with an 8 mg/kg dose. For FM the model predicts that a dose of 0.5 mg/kg will be without significant effect, whereas a 1 mg/kg dose allows a nearly maximal effect with a return to the control value after a delay of 16 h. A 2 mg/kg dose allows the effect to be maintained for 24 h. It is concluded that PK/PD is a tool of potential value for the preclinical screening of a dosage regimen.
Publication Date: 1994-12-01 PubMed ID: 7707492DOI: 10.1111/j.1365-2885.1994.tb00278.xGoogle 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.
- Comparative Study
- Journal Article
Summary
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This research was aimed at mapping the relationship between concentrations of phenylbutazone and flunixin meglumine in horse plasma and their therapeutic effects. Through this, a forecast model indicating the concentration of medicine and their therapeutic effect was built.
Research Methodology
- The study is premised on artificial arthritis induced by Freund’s adjuvant into the carpal joint of five horses.
- Each horse was then intravenously injected separately with a single dose of phenylbutazone (PBZ) and flunixin meglumine (FM).
- After administering these drugs, five pharmacodynamic endpoints were measured regularly. These measurements consisted of local skin temperature, stride length, angles of rest and maximal flexion of the carpal joint, and the circumference of the inflamed joint.
- Plasma drug concentrations were monitored alongside pharmacodynamic data by deploying an integrated PK/PD model.
Key Findings
- The results indicate that flunixin meglumine was more effective at lower concentrations than phenylbutazone. It was established that phenylbutazone’s EC50 (the plasma concentration where half the maximum effect can be achieved) was 3.6 +/- 2.2 micrograms/ml, while flunixin meglumine’s was 0.93 +/- 0.35 micrograms/ml.
- The same model was unable to establish a significant impact of either drug on the circumference of the inflamed joint. Likewise, maximal carpal flexion proved to be an unreliable endpoint.
- In a simulation of dose-effect relationship, it was discovered that phenylbutazone had no effect at a dose of 1 mg/kg, but its maximum effect was reached at about 2 mg/kg.
- For flunixin meglumine, a dose of 0.5 mg/kg showed no significant effect, but nearly maximum effect was achieved with a dose of 1 mg/kg. Doubling the dosage to 2 mg/kg could maintain the effect for 24 hours.
- The study is premised on artificial arthritis induced by Freund’s adjuvant into the carpal joint of five horses.
- Each horse was then intravenously injected separately with a single dose of phenylbutazone (PBZ) and flunixin meglumine (FM).
- After administering these drugs, five pharmacodynamic endpoints were measured regularly. These measurements consisted of local skin temperature, stride length, angles of rest and maximal flexion of the carpal joint, and the circumference of the inflamed joint.
- Plasma drug concentrations were monitored alongside pharmacodynamic data by deploying an integrated PK/PD model.
Key Findings
- The results indicate that flunixin meglumine was more effective at lower concentrations than phenylbutazone. It was established that phenylbutazone’s EC50 (the plasma concentration where half the maximum effect can be achieved) was 3.6 +/- 2.2 micrograms/ml, while flunixin meglumine’s was 0.93 +/- 0.35 micrograms/ml.
- The same model was unable to establish a significant impact of either drug on the circumference of the inflamed joint. Likewise, maximal carpal flexion proved to be an unreliable endpoint.
- In a simulation of dose-effect relationship, it was discovered that phenylbutazone had no effect at a dose of 1 mg/kg, but its maximum effect was reached at about 2 mg/kg.
- For flunixin meglumine, a dose of 0.5 mg/kg showed no significant effect, but nearly maximum effect was achieved with a dose of 1 mg/kg. Doubling the dosage to 2 mg/kg could maintain the effect for 24 hours.
- The results indicate that flunixin meglumine was more effective at lower concentrations than phenylbutazone. It was established that phenylbutazone’s EC50 (the plasma concentration where half the maximum effect can be achieved) was 3.6 +/- 2.2 micrograms/ml, while flunixin meglumine’s was 0.93 +/- 0.35 micrograms/ml.
- The same model was unable to establish a significant impact of either drug on the circumference of the inflamed joint. Likewise, maximal carpal flexion proved to be an unreliable endpoint.
- In a simulation of dose-effect relationship, it was discovered that phenylbutazone had no effect at a dose of 1 mg/kg, but its maximum effect was reached at about 2 mg/kg.
- For flunixin meglumine, a dose of 0.5 mg/kg showed no significant effect, but nearly maximum effect was achieved with a dose of 1 mg/kg. Doubling the dosage to 2 mg/kg could maintain the effect for 24 hours.
These findings suggest that pharmacokinetic/pharmacodynamic modelling can serve as a useful tool in determining dosage regimen in preclinical screenings. Thus, this practice can help to maximize the therapeutic benefits of phenylbutazone and flunixin meglumine in horses, reducing unnecessary drug loading and minimizing potential adverse effects.
Cite This Article
APA
Toutain PL, Autefage A, Legrand C, Alvinerie M.
(1994).
Plasma concentrations and therapeutic efficacy of phenylbutazone and flunixin meglumine in the horse: pharmacokinetic/pharmacodynamic modelling.
J Vet Pharmacol Ther, 17(6), 459-469.
https://doi.org/10.1111/j.1365-2885.1994.tb00278.x Publication
Researcher Affiliations
- Ecole Nationale Vétérinaire, Unité Associée INRA/ENVT de Physiopathologie et Toxicologie expérimentakes, Toulouse, France.
MeSH Terms
- Animals
- Arthritis, Experimental / drug therapy
- Clonixin / administration & dosage
- Clonixin / analogs & derivatives
- Clonixin / pharmacokinetics
- Dose-Response Relationship, Drug
- Female
- Horses / blood
- Horses / metabolism
- Male
- Models, Biological
- Phenylbutazone / administration & dosage
- Phenylbutazone / pharmacokinetics
- Skin Temperature
Citations
This article has been cited 21 times.- Kuroda T, Knych HK, Noble GK, Minamijima Y, Leung GN, Nomura M, Mizobe F, Ishikawa Y, Kusano K, Toutain PL. A Meta-Analysis of International Flunixin Pharmacokinetics in Horses: Toward Regulatory Harmonization and Individualized Detection Times Using Bayesian Paradigm. Drug Test Anal 2026 Jan;18(1):32-50.
- Ozdemir Kutahya Z, Aslan Akyol B, Mamuk S, Piner Benli P, Gokbulut C. Comparison of Intravenous and Oral Meloxicam Pharmacokinetics in Female and Male Saanen Goats. Vet Sci 2025 Jul 23;12(8).
- Whitfield-Cargile CM, Chung HC, Coleman MC, Cohen ND, Chamoun-Emanuelli AM, Ivanov I, Goldsby JS, Davidson LA, Gaynanova I, Ni Y, Chapkin RS. Integrated analysis of gut metabolome, microbiome, and exfoliome data in an equine model of intestinal injury. Microbiome 2024 Apr 15;12(1):74.
- O'Brien M, Mochel JP, Kersh K, Wang C, Troy J. Phenylbutazone concentrations in synovial fluid following administration via intravenous regional limb perfusion in the forelimbs of six adult horses. Front Vet Sci 2023;10:1236976.
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- Trindade PHE, Taffarel MO, Luna SPL. Spontaneous Behaviors of Post-Orchiectomy Pain in Horses Regardless of the Effects of Time of Day, Anesthesia, and Analgesia. Animals (Basel) 2021 May 31;11(6).
- Whitfield-Cargile CM, Coleman MC, Cohen ND, Chamoun-Emanuelli AM, DeSolis CN, Tetrault T, Sowinski R, Bradbery A, Much M. Effects of phenylbutazone alone or in combination with a nutritional therapeutic on gastric ulcers, intestinal permeability, and fecal microbiota in horses. J Vet Intern Med 2021 Mar;35(2):1121-1130.
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