Dextromethorphan and debrisoquine metabolism and polymorphism of the gene for cytochrome P450 isozyme 2D50 in Thoroughbreds.

This study examines genetic variations that influence the body’s response to certain drugs within a sample of racehorses. The researchers found significant variation in how individual horses metabolized two tested drugs, possibly due to specific genetic differences in the enzyme that processes these substances.

Objective of the Study

This research was carried out to examine the variations or polymorphisms of the gene responsible for the production of cytochrome P450 isozyme 2D50 (CYP2D50), an enzyme involved in processing different drugs in horses. It also aimed to assess how these variations might influence the disposition of two probe drugs, dextromethorphan and debrisoquine, in the animal’s system.

Procedure

• A total of 23 healthy horses (22 Thoroughbreds and 1 Standardbred) were included in the study.
• Single-nucleotide polymorphisms (SNPs), which are variations at a single position in a DNA sequence, in the CYP2D50 gene were first identified.
• The horses were then administered either dextromethorphan orally or debrisoquine through a nasogastric tube, and the disposition of these probe drugs was determined.
• By analyzing data from the area under the plasma concentration-versus-time curve, the metabolic ratios of plasma dextromethorphan and total dextrorphan, as well as 4-hydroxydebrisoquine concentrations, were calculated.
• Horses were categorized into the phenotypes of poor, extensive, and ultrarapid metabolizers, based on the pharmacokinetic data. The relationships between SNPs and metabolism categories were also examined.

Results and Conclusion

• The gene sequencing identified 51 SNPs, including 27 nonsynonymous SNPs, which are expected to impact on protein structure.
• Varied disposition of the two drugs was observed among the horses, signifying that drug metabolism rates could be influenced by the gene polymorphisms.
• Based on the metabolic ratios, 1 horse was categorised as a poor metabolizer, 18 as extensive metabolizers and 3 as ultrarapid metabolizers of the probe drugs.
• The study concluded that the cytochrome P450 isozyme 2D50 (CYP2D50) gene is indeed polymorphic in horses and this variation has a strong potential to influence drug metabolism.
• However, to fully understand the functional implications of these polymorphisms in CYP2D50, additional research with a larger sample size and a variety of horse breeds would be necessary.