Pharmacokinetics and pharmacodynamics of ketoprofen enantiomers in the horse.
Abstract: Pharmacokinetic and pharmacodynamic parameters were established for enantiomers of the non-steroidal anti-inflammatory drug (NSAID) ketoprofen (KTP), each administered separately at a dose level of 1.1 mg/kg to a group of six New Forest geldings, in a three-period cross-over study using a tissue cage model of inflammation. For both S(+)-and R(-)-KTP, penetration into tissue cage fluid (transudate) and inflamed tissue cage fluid (exudate) was rapid, and clearances from exudate and transudate were much slower than from plasma. AUC values were, therefore, higher for exudate and, to a lesser degree, transudate than for plasma. Unidirectional chiral inversion of R(-)-to S(+)-KTP was demonstrated. Administration of both enantiomers produced marked, time-dependent inhibition of synthesis of serum thromboxane B2 and exudate prostaglandin E2, indicating non-selective inhibition of cyclo-oxygenase (COX) isoenzymes COX-1 and COX-2 respectively. Administration of both enantiomers also produced partial inhibition of beta-glucuronidase release into inflammatory exudate and of bradykinin-induced skin oedema. It is suggested that, although S(+)-KTP is generally regarded as the eutomer, R(-)-KTP was probably at least as active in inhibiting bradykinin swelling. Pharmacokinetic/pharmacodynamic (PK/PD) modelling of the data could not be undertaken following R(-)-KTP administration because of chiral inversion to S(+)-KTP, but pharmacodynamic parameters, Emax, EC50, N, keO and t1/2(keO). were determined for s(+)-KTP using the sigmoidal Emax equation. PK/DP modelling provided a novel means of comparing and quantifying several biological effects of KTP and of investigating its mechanisms of action.
Publication Date: 1996-12-01 PubMed ID: 8971676DOI: 10.1111/j.1365-2885.1996.tb00084.xGoogle Scholar: Lookup
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- Clinical Trial
- Controlled Clinical Trial
- Journal Article
- Research Support
- Non-U.S. Gov't
Summary
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The research investigates how different forms (enantiomers) of the anti-inflammatory drug, ketoprofen, behave in the bodies of horses, looking specifically at its movement, impact on inflammation, and transformation into other forms.
Study Design
- The study involved six New Forest geldings (castrated male horses) and employed a three-period cross-over study using a tissue cage model of inflammation.
- The two enantiomers of ketoprofen—S(+)-KTP and R(-)-KTP—were administered separately to the horses at a dose level of 1.1 mg/kg.
Results
- For both S(+)-KTP and R(-)-KTP, the absorption into tissue fluid (transudate) and inflamed tissue fluid (exudate) was rapid.
- Clearance from exudate and transudate was significantly slower than from the blood, resulting in higher Area Under the Curve (AUC) values in exudate and transudate than in plasma.
- The study observed a unidirectional chiral inversion of R(-)-to S(+)-KTP, indicating that the R(-)-KTP form of the drug can convert into the S(+)-KTP form in the body.
- The administration of both enantiomers resulted in a significant, time-dependent inhibition of the synthesis of serum thromboxane B2 and exudate prostaglandin E2. This indicated that the drug inhibits cyclo-oxygenase (COX) isoenzymes COX-1 and COX-2, enzymes involved in inflammatory processes.
- Both enantiomers also partially inhibited the release of a specific enzyme, beta-glucuronidase, into the inflammatory exudate, and reduced bradykinin-induced skin swelling.
Implications
- While the S(+)-KTP form is generally considered the eutomer (the more active or effective form), the research suggests that R(-)-KTP is probably just as effective at inhibiting bradykinin-induced swelling.
- Pharmacokinetic/pharmacodynamic (PK/PD) modeling was not possible following R(-)-KTP administration due to its conversion to S(+)-KTP, but they were able to measure pharmacodynamic parameters for S(+)-KTP.
- The study presents PK/PD modeling as a novel means of comparing and quantifying the various biological effects of ketoprofen, allowing for a better understanding of how it works.
Cite This Article
APA
Landoni MF, Lees P.
(1996).
Pharmacokinetics and pharmacodynamics of ketoprofen enantiomers in the horse.
J Vet Pharmacol Ther, 19(6), 466-474.
https://doi.org/10.1111/j.1365-2885.1996.tb00084.x Publication
Researcher Affiliations
- Department of Veterinary Basic Sciences, Royal Veterinary College, Hatfield, Herts, UK.
MeSH Terms
- Animals
- Anti-Inflammatory Agents, Non-Steroidal / administration & dosage
- Anti-Inflammatory Agents, Non-Steroidal / blood
- Anti-Inflammatory Agents, Non-Steroidal / metabolism
- Anti-Inflammatory Agents, Non-Steroidal / pharmacokinetics
- Anti-Inflammatory Agents, Non-Steroidal / pharmacology
- Bradykinin / toxicity
- Cross-Over Studies
- Dinoprostone / blood
- Dose-Response Relationship, Drug
- Edema / chemically induced
- Extracellular Space / metabolism
- Glucuronidase / metabolism
- Horses
- Injections, Intravenous / veterinary
- Ketoprofen / administration & dosage
- Ketoprofen / blood
- Ketoprofen / metabolism
- Ketoprofen / pharmacokinetics
- Ketoprofen / pharmacology
- Male
- Prostaglandin-Endoperoxide Synthases / blood
- Regression Analysis
- Software
- Stereoisomerism
- Thromboxane B2 / blood
Citations
This article has been cited 7 times.- Munn R, Whittem T, Woodward AP. The Surface Area to Volume Ratio Changes the Pharmacokinetic and Pharmacodynamic Parameters in the Subcutaneous Tissue Cage Model: As Illustrated by Carprofen in Sheep. Front Vet Sci 2022;9:905797.
- Nixon E, Chittenden JT, Baynes RE, Messenger KM. Pharmacokinetic/pharmacodynamic modeling of ketoprofen and flunixin at piglet castration and tail-docking. J Vet Pharmacol Ther 2022 Sep;45(5):450-466.
- Lemonnier LC, Thorin C, Meurice A, Dubus A, Touzot-Jourde G, Couroucé A, Leroux AA. Comparison of Flunixin Meglumine, Meloxicam and Ketoprofen on Mild Visceral Post-Operative Pain in Horses. Animals (Basel) 2022 Feb 21;12(4).
- Greene W, Mylniczenko ND, Storms T, Burns CM, Lewbart GA, Byrd L, Papich MG. Pharmacokinetics of Ketoprofen in Nile Tilapia (Oreochromis niloticus) and Rainbow Trout (Oncorhynchus mykiss). Front Vet Sci 2020;7:585324.
- Czub MP, Handing KB, Venkataramany BS, Cooper DR, Shabalin IG, Minor W. Albumin-Based Transport of Nonsteroidal Anti-Inflammatory Drugs in Mammalian Blood Plasma. J Med Chem 2020 Jul 9;63(13):6847-6862.
- Montoya L, Ambros L, Kreil V, Bonafine R, Albarellos G, Hallu R, Soraci A. A pharmacokinetic comparison of meloxicam and ketoprofen following oral administration to healthy dogs. Vet Res Commun 2004 Jul;28(5):415-28.
- Igarza L, Soraci A, Auza N, Zeballos H. Some pharmacokinetic parameters of R-(-)- and S-(+)-ketoprofen: the influence of age and differing physiological status in dairy cattle. Vet Res Commun 2004 Jan;28(1):81-7.
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