Equine veterinary journal2020; 53(1); 102-116; doi: 10.1111/evj.13260

Pharmacokinetics and anti-inflammatory effects of flunixin meglumine as a sole agent and in combination with phenylbutazone in exercised Thoroughbred horses.

Knych, HK
·
Arthur, RM
·
McKemie, DS
·
Baden, RW
·
Seminoff, K
·
Kass, PH

Abstract: Flunixin meglumine (FM) and phenylbutazone (PBZ) are potent anti-inflammatory agents and as such their potential to mask injuries that would otherwise keep a horse from training or racing is concerning. A common practice in racetrack medicine in the USA is to administer the two drugs within close proximity (24 hours apart) of each other, raising the concern of pharmacokinetic interactions and enhanced anti-inflammatory effects. Objective: Describe the pharmacokinetics and effects of PBZ on the clearance of FM when administered in close proximity as well as effects on inflammatory mediators. Methods: Two-way randomised balanced crossover experiment. Methods: Twelve Thoroughbred exercised horses received 500 mg FM IV alone or in combination with 2 g of IV PBZ 24 hours later. Blood and urine samples were collected prior to and for up to 120 hours post-drug administration. Whole blood samples were collected at various times and challenged with lipopolysaccharide or calcium ionophore to induce ex vivo synthesis of eicosanoids. Concentrations of FM, PBZ and eicosanoids were measured using LC-MS/MS and noncompartmental pharmacokinetic analysis performed on concentration data. Results: Flunixin meglumine clearance was significantly increased when horses received PBZ 24 hours post-administration (P = .03). No other differences in pharmacokinetic parameters were noted between groups. Thromboxane B2 was significantly suppressed, relative to baseline for 96 hours post-FM administration. Subsequent administration of PBZ prolonged the suppression. Prostaglandin E2 was decreased for 24 hours following administration of FM with subsequent administration of PBZ prolonging the suppression until 120 hours. PGF2alpha concentrations were decreased for up to 168 hours post-FM administration. FM administration significantly decreased 15-HETE. Conclusions: Small sample size and lack of a phenylbutazone-only treatment group. Conclusions: Administration of PBZ post-FM administration increased FM clearance. The anti-inflammatory effects of FM appear to be prolonged when PBZ is administered 24 hours post-administration.

Get Full Text

Publication Date: 2020-04-17 PubMed ID: 32145701DOI: 10.1111/evj.13260Google 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.

Facebook X LinkedIn Email Copy

Summary
Cite This
Publication
Affiliations
MeSH
Grants
References
Citations

Journal Article
Randomized Controlled Trial
Veterinary

Summary

This research summary has been generated with artificial intelligence and may contain errors and omissions. Refer to the original study to confirm details provided. Submit correction.

This research investigates the effects and interaction of two anti-inflammatory drugs, flunixin meglumine (FM) and phenylbutazone (PBZ), in racehorses. It suggests that the administration of PBZ after FM increases FM’s clearance from the body and enhances its anti-inflammatory action.

Study Design and Methodology

This study was structured as a two-way randomized balanced crossover experiment conducted on twelve Thoroughbred horses that had undergone exercise. Each horse received either FM alone or in combination with PBZ administered 24 hours later.
Blood and urine samples were taken before and up to 120 hours after the administration of these drugs to monitor their clearance from the body.
The blood samples were also challenged with lipopolysaccharide or calcium ionophore to study their effect on eicosanoid synthesis. Eicosanoids are biological compounds known to take part in inflammation and immunity responses.
The concentrations of FM, PBZ and eicosanoids were measured using Liquid Chromatography-Mass Spectrometry/Mass Spectrometry (LC-MS/MS), a technique used for identifying and quantifying small quantities of chemicals in samples. Noncompartmental pharmacokinetic analysis was performed to understand the distribution and elimination kinetics of the drugs.

Results

The clearance of FM increased significantly when horses received PBZ 24 hours after the administration of FM, indicating the potential pharmacokinetic interaction between these two drugs.
FM usage led to the suppression of Thromboxane B (an eicosanoid) relative to baseline for 96 hours. Furthermore, the administration of PBZ after FM administration extended this suppression period.
Prostaglandin E2 (another eicosanoid) levels decreased for 24 hours following administration of FM. The subsequent administration of PBZ prolonged this suppression until 120 hours.
Prostaglandin F (PGF) concentrations went down for up to 168 hours after administering FM.
Another finding was that FM administration decreased the levels of 15-HETE, an indicator of inflammation.

Conclusions

This study has some limitations, such as a small sample size and lack of a control group where only PBZ was administered.
Findings indicate that PBZ, when given post-administration of FM, increases the clearance of FM from the Thoroughbred horses’ bodies.
Furthermore, the results suggest that the anti-inflammatory action of FM is enhanced and prolonged when PBZ is administered 24 hours after FM.

Cite This Article

APA

Knych HK, Arthur RM, McKemie DS, Baden RW, Seminoff K, Kass PH. (2020). Pharmacokinetics and anti-inflammatory effects of flunixin meglumine as a sole agent and in combination with phenylbutazone in exercised Thoroughbred horses. Equine Vet J, 53(1), 102-116. https://doi.org/10.1111/evj.13260

Publication

Equine veterinary journal

ISSN: 2042-3306

NlmUniqueID: 0173320

Country: United States

Language: English

Volume: 53

Issue: 1

Pages: 102-116

Researcher Affiliations

Knych, Heather K

K.L. Maddy Equine Analytical Pharmacology Laboratory, School of Veterinary Medicine, University of California, Davis, CA, USA.
Department of Veterinary Molecular Biosciences, School of Veterinary Medicine, University of California, Davis, CA, USA.

Arthur, Rick M

School of Veterinary Medicine, University of California, Davis, CA, USA.

McKemie, Daniel S

K.L. Maddy Equine Analytical Pharmacology Laboratory, School of Veterinary Medicine, University of California, Davis, CA, USA.

Baden, Russell W

K.L. Maddy Equine Analytical Pharmacology Laboratory, School of Veterinary Medicine, University of California, Davis, CA, USA.

Seminoff, Kelsey

K.L. Maddy Equine Analytical Pharmacology Laboratory, School of Veterinary Medicine, University of California, Davis, CA, USA.

Kass, Philip H

Department of Population Health and Reproduction, School of Veterinary Medicine, University of California, Davis, CA, USA.

MeSH Terms

Animals
Anti-Inflammatory Agents, Non-Steroidal / pharmacokinetics
Chromatography, Liquid / veterinary
Clonixin / analogs & derivatives
Clonixin / pharmacokinetics
Horses / metabolism
Phenylbutazone / pharmacokinetics
Tandem Mass Spectrometry / veterinary

Grant Funding

Racing Medication and Testing Consortium
California Horse Racing Board

References

This article includes 34 references

Knych HK, Arthur RM, McKemie DS, Chapman N. Pharmacokinetics and effects on thromboxane B2 production following intravenous administration of flunixin meglumine to exercised thoroughbred horses.. J Vet Pharmacol Ther 2015;38:313-20.
EHSLC. https://www.ehslc.com/detection-times.
Miners JO, Birkett DJ. Cytochrome P4502C9: an enzyme of major importance in human drug metabolism.. Br J Clin Pharmacol 1998;45:525-38.
Takigawa T, Tainaka H, Mihara K, Ogata H. Inhibition of S-warfarin metabolism by nonsteroidal antiinflammatory drugs in human liver microsomes in vitro.. Biol Pharm Bull 1998;21:541-3.
Zweers-Zeilmaker WM, Horbach GJ, Witkamp RF. Differential inhibitory effects of phenytoin, diclofenac, phenylbutazone and a series of sulfonam ides on hepatic cytochrom e P4502C activity in vitro, and correlation with som e m olecular descriptors in the dwarf goat (Caprus hircus aegagrus).. Xenobiotica 1997;27:769-80.
Semrad SD, Sams RA, Harris ON, Ashcraft SM. Effects of concurrent administration of phenylbutazone and flunixin meglumine on pharmacokinetic variables and in vitro generation of thromboxane B2 in mares.. Am J Vet Res 1993;54:1901-5.
Mangal D, Uboh CE, Soma LR, Liu Y. Inhibitory effect of triamcinolone acetonide on synthesis of inflammatory mediators in the equine.. Eur J Pharmacol 2014;736:1-9.
Mangal D, Uboh CE, Soma LR. Analysis of bioactive eicosanoids in equine plasma by stable isotope dilution reversed-phase liquid chromatography/multiple reaction monitoring mass spectrometry.. Rapid Commun Mass Spectrom 2011;25:585-98.
Knych HK, Arthur RM, McKemie DS, Seminoff K, Hamamoto-Hardman B, Kass PH. Phenylbutazone blood and urine concentrations, pharmacokinetics, and effects on biomarkers of inflammation in horses following intravenous and oral administration of clinical doses.. Drug Test Anal 2019;11:792-803.
Young JM, Panah S, Satchawatcharaphong C, Cheung PS. Human whole blood assays for inhibition of prostaglandin G/H synthases-1 and -2 using A23187 and lipopolysaccharide stimulation of thromboxane B2 production.. Inflamm Res 1996;45:246-53.
Knych HK, Arthur RM, Mitchell MM, Holser I, Poppenga R, Smith LL. Pharmacokinetics and selected pharmacodynamics of cobalt following a single intravenous administration to horses.. Drug Test Anal 2015;7:619-25.
Huang S-M. Clinical Drug Interaction Studies-Study Design, Data Analysis, and Clinical Implications Guidance for Industry DRAFT GUIDANCE.. 2009.
Fda and Cder. Bioanalytical Method Validation Guidance for Industry Biopharmaceutics Bioanalytical Method Validation Guidance for Industry Biopharmaceutics Contains Nonbinding Recommendations.. 2018.
Foreman JH, Ruemmler R. Phenylbutazone and flunixin meglumine used singly or in combination in experimental lameness in horses.. Equine Vet J 2011;43:12-7.
Tobin T, Chay S, Kamerling S, Woods WE, Weckman TJ, Blake JW. Phenylbutazone in the horse: a review.. J Vet Pharmacol Ther 1986;9:1-25.
Soma LR, Behrend E, Rudy J, Sweeney RW. Disposition and excretion of flunixin meglumine in horses.. Am J Vet Res 1988;49:1894-8.
Knych HK, Stanley SD, Seminoff KN, McKemie DS, Kass PH. Pharmacokinetics of methocarbamol and phenylbutazone in exercised Thoroughbred horses.. J Vet Pharmacol Ther 2016;39:469-77.
Lees P, Higgins AJ, Mawhinney IC, Reid DS. Absorption of phenylbutazone from a paste formulation administered orally to the horse.. Res Vet Sci 1986;41:200-6.
Maitho TE, Lees P, Taylor JB. Absorption and pharmacokinetics of phenylbutazone in Welsh Mountain ponies.. J Vet Pharmacol Ther 1986;9:26-39.
Lees P, Ewins CP, Taylor JBO, Sedgwick AD. Serum thromboxane in the horse and its inhibition by aspirin, phenylbutazone and flunixin.. Br Vet J 1987;143:462-76.
Cuniberti B, Odore R, Barbero R, Cagnardi P, Badino P, Girardi C. In vitro and ex vivo pharmacodynamics of selected non-steroidal anti-inflammatory drugs in equine whole blood.. Vet J 2012;191:327-33.
Brideau C, Van Staden C, Chan CC. In vitro effects of cyclooxygenase inhibitors in whole blood of horses, dogs, and cats.. Am J Vet Res 2001;62:1755-60.
Higgs GA, Moncada S, Salmon JA, Seager K. The source of thromboxane and prostaglandins in experimental inflammation.. Br J Pharmacol 1983;79:863-8.
Brock TG, McNish RW, Peters-Golden M. Arachidonic acid is preferentially metabolized by cyclooxygenase-2 to prostacyclin and prostaglandin E2.. J Biol Chem 1999;274:11660-6.
Ricciotti E, FitzGerald GA. Prostaglandins and inflammation.. Arterioscler Thromb Vasc Biol 2011;31:986-1000.
Young JM, Panah S, Satchawatcharaphong C, Cheung PS. Human whole blood assays for inhibition of prostaglandin G/H synthases-1 and-2 using A23187 and lipopolysaccharide stimulation of thromboxane B2 production.. 1996.
Sugimoto Y. Failure of parturition in mice lacking the prostaglandin F receptor.. Science 1997;277:681-3.
Dahlén SE, Hansson G, Hedqvist P, Björck T, Granström E, Dahlén B. Allergen challenge of lung tissue from asthmatics elicits bronchial contraction that correlates with the release of leukotrienes C4, D4, and E4.. Proc Natl Acad Sci USA 1983;80:1712-6.
Drazen JM, Lilly CM, Sperling R, Rubin P, Israel E. Role of cysteinyl leukotrienes in spontaneous asthmatic responses.. Adv Prostaglandin Thromboxane Leukot Res 1994;22:251-62.
Chen Y, Hu Y, Zhang H, Peng C, Li S. Loss of the Alox5 gene impairs leukemia stem cells and prevents chronic myeloid leukemia.. Nat Genet 2009;41:783-92.
Sanchez-Borges M, Capriles-Hulett A, Caballero-Fonseca F. NSAID-induced urticaria and angioedema.. Am J Clin Dermatol 2002;3:599-607.
Kühn H, O’Donnell VB. Inflammation and immune regulation by 12/15-lipoxygenases.. Prog Lipid Res 2006;45:334-56.
Brinckmann R, Schnurr K, Heydeck D, Rosenbach T, Kolde G, Kühn H. Membrane translocation of 15-lipoxygenase in hematopoietic cells is calcium-dependent and activates the oxygenase activity of the enzyme.. Blood 1998;91:64-74.
Dobrian AD, Lieb DC, Cole BK, Taylor-Fishwick DA, Chakrabarti SK, Nadler JL. Functional and pathological roles of the 12- and 15-lipoxygenases.. Prog Lipid Res 2011;50:115-31.