Evidence for polymorphism in the cytochrome P450 2D50 gene in horses

C. R. Corado, D. S. Mckemie, A. Young, Heather K Knych

Research output: Contribution to journalArticle

8 Citations (Scopus)

Abstract

Metabolism is an essential factor in the clearance of many drugs and as such plays a major role in the establishment of dosage regimens and withdrawal times. CYP2D6, the human orthologue to equine CYP2D50, is a drug-metabolizing enzyme that is highly polymorphic in humans leading to widely differing levels of metabolic activity. As CYP2D6 is highly polymorphic, in this study it was hypothesized that the gene coding for the equine orthologue, CYP2D50, may also be prone to polymorphism. Blood samples were collected from 150 horses, the CYP2D50 gene was cloned and sequenced; and full-length sequences were analyzed for single nucleotide polymorphisms (SNPs), deletions, or insertions. Pharmacokinetic data were collected from a subset of horses following the administration of a single oral dose of tramadol and probit analysis used to calculate metabolic ratios. Prior to drug administration, the ability of recombinant CYP2D50 to metabolize tramadol to O-desmethyltramadol was confirmed. Sequencing of CYP2D50 identified 126 exonic SNPs, with 31 of those appearing in multiple horses. Oral administration of tramadol to a subset of these horses revealed variable metabolic ratios (tramadol: O-desmethyltramadol) in individual horses and separation into three metabolic groups. While a limited number of horses of primarily a single breed were studied, the variability in tramadol metabolism to O-desmethyltramadol between horses and preliminary evidence of what appears to be poor, extensive, and ultra-rapid metabolizers supports further study of the potential for genetic polymorphisms in the CYP2D50 gene in horses.

Original languageEnglish (US)
Pages (from-to)245-254
Number of pages10
JournalJournal of Veterinary Pharmacology and Therapeutics
Volume39
Issue number3
DOIs
StatePublished - Jun 1 2016

Fingerprint

cytochrome P-450
Cytochrome P-450 Enzyme System
Horses
genetic polymorphism
horses
Tramadol
Genes
genes
Cytochrome P-450 CYP2D6
drugs
single nucleotide polymorphism
Single Nucleotide Polymorphism
Pharmaceutical Preparations
probit analysis
metabolism
Genetic Polymorphisms
dosage
oral administration
pharmacokinetics
Oral Administration

ASJC Scopus subject areas

  • Pharmacology
  • veterinary(all)

Cite this

Evidence for polymorphism in the cytochrome P450 2D50 gene in horses. / Corado, C. R.; Mckemie, D. S.; Young, A.; Knych, Heather K.

In: Journal of Veterinary Pharmacology and Therapeutics, Vol. 39, No. 3, 01.06.2016, p. 245-254.

Research output: Contribution to journalArticle

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