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Journal of veterinary pharmacology and therapeutics2014; 38(1); 24-34; doi: 10.1111/jvp.12139

Pharmacokinetic and pharmacodynamic analysis comparing diverse effects of detomidine, medetomidine, and dexmedetomidine in the horse: a population analysis.

Abstract: The present study characterizes the pharmacokinetic (PK) and pharmacodynamic (PD) relationships of the α2-adrenergic receptor agonists detomidine (DET), medetomidine (MED) and dexmedetomidine (DEX) in parallel groups of horses from in vivo data after single bolus doses. Head height (HH), heart rate (HR), and blood glucose concentrations were measured over 6 h. Compartmental PK and minimal physiologically based PK (mPBPK) models were applied and incorporated into basic and extended indirect response models (IRM). Population PK/PD analysis was conducted using the Monolix software implementing the stochastic approximation expectation maximization algorithm. Marked reductions in HH and HR were found. The drug concentrations required to obtain inhibition at half-maximal effect (IC50 ) were approximately four times larger for DET than MED and DEX for both HH and HR. These effects were not gender dependent. Medetomidine had a greater influence on the increase in glucose concentration than DEX. The developed models demonstrate the use of mechanistic and mPBPK/PD models for the analysis of clinically obtainable in vivo data.
© 2014 John Wiley & Sons Ltd.
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Publication Date: 2014-07-29 PubMed ID: 25073816PubMed Central: PMC4286451DOI: 10.1111/jvp.12139Google Scholar: Lookup
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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 study evaluates how three drugs—detomidine, medetomidine, and dexmedetomidine—relate to the pharmacokinetic (how the body affects a drug) and pharmacodynamic (how a drug affects the body) profiles in horses, by comparing effects on heart rate, blood glucose levels, and head height. The research found that the concentration required to achieve half of the maximal response is significantly larger for detomidine compared to medetomidine and dexmedetomidine, and that medetomidine has a more profound impact on elevated blood glucose levels.

Overview of Drugs and Their Effects

  • The drugs being examined, detomidine, medetomidine, and dexmedetomidine, are all α2-adrenergic receptor agonists, meaning they interact with specific types of receptors in the body.
  • The researchers looked at the effect of these drugs on horses’ head height (HH), heart rate (HR), and blood glucose concentrations, measuring these parameters over a 6 hour period following a single bolus dose of the drug.

Methods of Analysis

  • The team used compartmental and minimal physiologically based pharmacokinetic (mPBPK) models, which allow for the representation of drug distribution and elimination in the body, both physically and kinetically.
  • The pharmacokinetic parameters were incorporated into basic and extended indirect response models (IRM) to understand the response of the body to the drug, at different dose levels and over time.
  • Population pharmacokinetic/pharmacodynamic (PK/PD) analysis was performed using the Monolix software, a commonly used tool for population PK/PD analysis.

Findings of the Study

  • Significant decreases in HH and HR were observed, indicating a profound impact of the drugs on the cardiovascular system and an apparent sedative effect.
  • The concentration of detomidine required to induce half of the maximal effect (known as IC50) was found to be around four times larger than that of medetomidine and dexmedetomidine.
  • The effect of these drugs on heart rate and head height was not affected by the gender of the horse.
  • Medetomidine was found to have a stronger impact on increasing blood glucose concentration than dexmedetomidine.

Model Use and Clinical Application

  • This study demonstrates how mechanistic and mPBPK/PD models can be used to analyze clinical data that can be obtained in vivo.
  • They offer valuable insight into drug behavior, potential therapeutic applications, and possible side effects in horses.

Cite This Article

APA
Grimsrud KN, Ait-Oudhia S, Durbin-Johnson BP, Rocke DM, Mama KR, Rezende ML, Stanley SD, Jusko WJ. (2014). Pharmacokinetic and pharmacodynamic analysis comparing diverse effects of detomidine, medetomidine, and dexmedetomidine in the horse: a population analysis. J Vet Pharmacol Ther, 38(1), 24-34. https://doi.org/10.1111/jvp.12139

Publication

Journal of veterinary pharmacology and therapeutics
ISSN: 1365-2885
NlmUniqueID: 7910920
Country: England
Language: English
Volume: 38
Issue: 1
Pages: 24-34

Researcher Affiliations

Grimsrud, K N
  • Campus Veterinary Services, School of Veterinary Medicine, University of California, Davis, CA, USA.
Ait-Oudhia, S
    Durbin-Johnson, B P
      Rocke, D M
        Mama, K R
          Rezende, M L
            Stanley, S D
              Jusko, W J

                MeSH Terms

                • Adrenergic alpha-2 Receptor Antagonists / administration & dosage
                • Adrenergic alpha-2 Receptor Antagonists / blood
                • Adrenergic alpha-2 Receptor Antagonists / pharmacokinetics
                • Adrenergic alpha-2 Receptor Antagonists / pharmacology
                • Animals
                • Dexmedetomidine / administration & dosage
                • Dexmedetomidine / blood
                • Dexmedetomidine / pharmacokinetics
                • Dexmedetomidine / pharmacology
                • Dose-Response Relationship, Drug
                • Female
                • Horses / blood
                • Horses / metabolism
                • Imidazoles / administration & dosage
                • Imidazoles / blood
                • Imidazoles / pharmacokinetics
                • Imidazoles / pharmacology
                • Male
                • Medetomidine / administration & dosage
                • Medetomidine / blood
                • Medetomidine / pharmacokinetics
                • Medetomidine / pharmacology
                • Models, Biological

                Grant Funding

                • R01 GM057980 / NIGMS NIH HHS
                • UL1 TR000002 / NCATS NIH HHS
                • UL1 TR 000002 / NCATS NIH HHS
                • GM57980 / NIGMS NIH HHS

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                Citations

                This article has been cited 6 times.
                1. Abass M, Ibrahim H, Salci H, Hamed MA. Evaluation of the effect of different sedative doses of dexmedetomidine on the intestinal motility in clinically healthy donkeys (Equus asinus). BMC Vet Res 2022 Jul 14;18(1):274.
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                3. Kritchevsky JE, Muir GS, Leschke DHZ, Hodgson JK, Hess EK, Bertin FR. Blood glucose and insulin concentrations after alpha-2-agonists administration in horses with and without insulin dysregulation. J Vet Intern Med 2020 Mar;34(2):902-908.
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