Effect of CYP2D Genetic Polymorphisms on Drug Metabolism in the Horse

Results of this study support the presence of polymorphisms in the CYP2D50 gene that appear to have functional implications with respect to metabolism of drugs that are substrates for this enzyme. Authors’ address: K.L. Maddy Equine Analytical Chemistry Laboratory, School of Veterinary Medicine, University of California, Davis 95616; e-mail: hkknych@ucdavis.edu.

1. Introduction

Metabolism is an essential factor in the clearance of many drugs and, as such, plays a major role in the establishment of dosing regimens and withdrawal times. CYP2D6, the human ortholog to equine CYP2D50, is a drug-metabolizing enzyme that is highly polymorphic in humans, leading to widely differing levels of metabolic activity. In horses, it has been proposed that the CYP2D50 gene may be prone to polymorphism.

2. Materials and Methods

Blood samples were obtained from 150 horses, the CYP2D50 gene cloned, sequenced, and full-length sequences analyzed for single nucleotide polymorphisms (SNPs), deletions, or insertions. Pharmacokinetic data was collected from a subset of horses following administration of a single oral dose of tramadol or dextromethorphan and probit analysis was used to calculate metabolic ratios and correlate results of the genotyping studies with those of the phenotyping studies.

3. Results and Discussion

Alignment of the full-length sequences from over one hundred horses showed a distribution into three distinct haplotypes, which may correspond to phenotypes previously described in the human. A number of SNPs were discovered which may interfere with protein function, as determined by SIFT analysis of the protein sequence. Furthermore, probit analysis of the metabolic ratio of 2 CYP2D probe drugs administered to a subset of the horses revealed what appears to be poor, extensive, and ultrarapid metabolizers.

Acknowledgments

Conflict of Interest

This study was funded by the Grayson-Jockey Club.