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Home / Equine Research Bank / BMC Vet Res / Functional phenotyping of the CYP2D6 probe drug codeine in t...
BMC veterinary research2021; 17(1); 77; doi: 10.1186/s12917-021-02788-y

Functional phenotyping of the CYP2D6 probe drug codeine in the horse.

Abstract: In humans, the drug metabolizing enzyme CYP2D6 is highly polymorphic resulting in substantial differences in the metabolism of drugs including anti-arrhythmics, neuroleptics, and opioids. The objective of this study was to phenotype a population of 100 horses from five different breeds and assess differences in the metabolic activity of the equine CYP2D6 homolog using codeine as a probe drug. Administration of a probe drug is a common method used for patient phenotyping in human medicine, whereby the ratio of parent drug to metabolite (metabolic ratio, MR) can be used to compare relative enzyme function between individuals. A single oral dose of codeine (0.6 mg/kg) was administered and plasma concentrations of codeine and its metabolites were determined using liquid chromatography mass spectrometry. The MR of codeine O-demethylation [(codeine)/(morphine + morphine-3-glucuronide + morphine-6-glucuronide)] was determined using the area under the plasma concentration-time curve extrapolated from time zero to infinity (AUC) for each analyte and used to group horses into predicted phenotypes (high-, moderate-, and low-MR). Results: The MR of codeine O-demethylation ranged from 0.002 to 0.147 (median 0.018) among all horses. No significant difference in MR was observed between breeds, age, or sex. Of the 100 horses, 11 were classified as high-MR, 72 moderate-MR, and 17 low-MR. Codeine AUC and O-demethylation MR were significantly different (p < 0.05) between all three groups. The mean ± SD MR was 0.089 ± 0.027, 0.022 ± 0.011, and 0.0095 ± 0.001 for high-, moderate-, and low-MR groups, respectively. The AUC for the morphine metabolites morphine-3-glucuronide and morphine-6-glucuronide were significantly different between high-and low-MR groups (p < 0.004 and p < 0.006). Conclusions: The MR calculated from plasma following codeine administration allowed for classification of horses into metabolic phenotypes within a large population. The range of codeine metabolism observed among horses suggests the presence of genetic polymorphisms in CYP2D82 of which codeine is a known substrate. Additional studies including CYP2D82 genotyping of high- and low-MR individuals are necessary to determine the presence of CYP2D polymorphisms and their functional implications with respect to the metabolism of therapeutics.
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Publication Date: 2021-02-13 PubMed ID: 33581736PubMed Central: PMC7881596DOI: 10.1186/s12917-021-02788-yGoogle Scholar: Lookup
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  • Journal Article

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.

The research study aims to explore how different horses metabolize codeine, a drug that can be metabolized differently in different organisms due to genetic variations in the CYP2D6 enzyme.

Objective and Methodology of the Research

  • The objective of the study was to determine the different ways that a population of horses metabolizes the drug codeine, which is used as an indicator (probe) to determine how the horses will metabolize other drugs. The metabolism of codeine is monitored by the ratio of the drug to its metabolites. This ratio can then be compared between various horses to discern differences in their metabolism.
  • The researchers used a population of 100 horses from five different breeds for the study. The horses were given a single oral dose of codeine, and the concentration of codeine and its metabolites in their plasma was measured using a method called liquid chromatography mass spectrometry.
  • The ratio of codeine O-demethylation was calculated and used to categorize the horses into groups that had high, moderate, or low metabolic ratios.

Findings of the Research

  • The study found a wide range of metabolic ratios among the horses, from 0.002 to 0.147. This suggests varying levels of metabolic activity in the various horses, despite no significant differences being found in relation to breed, age, or sex.
  • Of the 100 horses studied, 11 were categorized as high metabolic ratio, 72 as moderate, and 17 as low. The area under the curve (AUC) and O-demethylation metabolic ratio for the three groups were found to differ significantly. The researchers calculated mean metabolic ratios for each group.
  • Significant differences were also found between the high and low metabolic ratio groups in the area under the curve (AUC) for certain metabolites of morphine.

Conclusions of the Research

  • The use of codeine as a probe drug allowed the researchers to categorize a large population of horses into metabolic phenotypes – classifications based on physical and biochemical characteristics.
  • The wide range of metabolic ratios observed suggest the presence of genetic variations in the CYP2D82 gene, which is known to metabolize codeine. Additional studies are recommended to further explore these genetic variations and to understand their implications for drug metabolism.

Cite This Article

APA
Gretler SR, Finno CJ, Kass PH, Knych HK. (2021). Functional phenotyping of the CYP2D6 probe drug codeine in the horse. BMC Vet Res, 17(1), 77. https://doi.org/10.1186/s12917-021-02788-y

Publication

BMC veterinary research
ISSN: 1746-6148
NlmUniqueID: 101249759
Country: England
Language: English
Volume: 17
Issue: 1
Pages: 77
PII: 77

Researcher Affiliations

Gretler, S R
  • K.L. Maddy Equine Analytical Pharmacology Laboratory, University of California-Davis, School of Veterinary Medicine, 620 West Health Science Drive, Davis, CA, 95616, USA.
Finno, C J
  • Department of Population Health and Reproduction, School of Veterinary Medicine, University of California, Davis, USA.
Kass, P H
  • Department of Population Health and Reproduction, School of Veterinary Medicine, University of California, Davis, USA.
Knych, H K
  • K.L. Maddy Equine Analytical Pharmacology Laboratory, University of California-Davis, School of Veterinary Medicine, 620 West Health Science Drive, Davis, CA, 95616, USA. hkknych@ucdavis.edu.
  • Department of Veterinary Molecular Biosciences, School of Veterinary Medicine, University of California, Davis, USA. hkknych@ucdavis.edu.

MeSH Terms

  • Animals
  • Codeine / analogs & derivatives
  • Codeine / blood
  • Codeine / metabolism
  • Codeine / pharmacokinetics
  • Cytochrome P-450 CYP2D6 / genetics
  • Cytochrome P-450 CYP2D6 / metabolism
  • Female
  • Horses
  • Male
  • Morphine Derivatives / metabolism
  • Phenotype
  • Polymorphism, Genetic

Conflict of Interest Statement

The authors have no competing interests.

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Citations

This article has been cited 4 times.
  1. Knych HK, Stucker K, Gretler SR, Kass PH, McKemie DS. Pharmacokinetics, adverse effects and effects on thermal nociception following administration of three doses of codeine to horses. BMC Vet Res 2022 May 25;18(1):196.
    doi: 10.1186/s12917-022-03299-0pubmed: 35614473google scholar: lookup
  2. Jonovski JC, Bacon EK, Velie BD. Towards precision pain management in veterinary practice: opportunities and barriers. Front Vet Sci 2025;12:1658765.
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  3. Bacon EK, Donnelly CG, Bellone RR, Haase B, Finno CJ, Velie BD. Preliminary investigation of potential links between pigmentation variants and opioid analgesic effectiveness in horses during cerebrospinal fluid centesis. BMC Vet Res 2024 Jul 12;20(1):311.
    doi: 10.1186/s12917-024-04139-zpubmed: 38997753google scholar: lookup
  4. Scantamburlo G, Nofziger C, Paulmichl M, Vanoni S. Genetic analysis of the equine orthologues for human CYP2D6: unraveling the complexity of the CYP2D family in horses. Front Vet Sci 2023;10:1188633.
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