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Evidence for polymorphism in the cytochrome P450 2D50 gene in horses
Author(s) -
Corado C. R.,
McKemie D. S.,
Young A.,
Knych H. K.
Publication year - 2016
Publication title -
journal of veterinary pharmacology and therapeutics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.527
H-Index - 60
eISSN - 1365-2885
pISSN - 0140-7783
DOI - 10.1111/jvp.12269
Subject(s) - single nucleotide polymorphism , cyp2d6 , biology , tramadol , gene , genetics , polymorphism (computer science) , drug metabolism , pharmacology , genotype , drug , analgesic
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. CYP 2D6, the human orthologue to equine CYP 2D50, is a drug‐metabolizing enzyme that is highly polymorphic in humans leading to widely differing levels of metabolic activity. As CYP 2D6 is highly polymorphic, in this study it was hypothesized that the gene coding for the equine orthologue, CYP 2D50, may also be prone to polymorphism. Blood samples were collected from 150 horses, the CYP 2D50 gene was cloned and sequenced; and full‐length sequences were analyzed for single nucleotide polymorphisms ( SNP s), 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 CYP 2D50 to metabolize tramadol to O ‐desmethyltramadol was confirmed. Sequencing of CYP 2D50 identified 126 exonic SNP s, 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 CYP 2D50 gene in horses.