Chiral inversion of fenoprofen in horses and dogs: an in vivo-in vitro study.

The research paper is about the stereoselective disposition of the anti-inflammatory drug, fenoprofen (FPF), in horses and dogs which is driven by a chiral conversion that transforms R(-)FPF into S(+)FPF. The study establishes a direct correlation between FPF clearance pace and ligase activity.

Background of Study

• The research focuses on Fenoprofen (FPF), a chiral non-steroid anti-inflammatory drug which is distributed as a combination of its R(-) and S(+) enantiomers. Enantiomers are mirror image forms of a chiral molecule and are often used in pharmaceuticals because of their potential to increase efficacy and reduce side effects.
• The unusual characteristic of FPF is its chiral inversion, a process that converts R(-)FPF into S(+)FPF in the bodies of humans and animals. This chiral inversion is the reason behind its stereoselective disposition, or the preference of the body to process one form of the drug over the other.
• The first stage of this reaction creates an acyl-CoA thioester and is facilitated by an enzyme called an acyl-CoA ligase.

Methodology

• A stereospecific high performance liquid chromatography assay was utilized in this study to understand the ingestion and absorption of FPF enantiomers in four geldings and three male beagle dogs.
• These animals were administered with intravenous doses of mixed FPF, R(-)FPF, and S(+)FPF.
• The researchers also quantified acyl-CoA ligase activity in vitro on equine hepatic microsomes – small structures within cells – and used a high performance liquid chromatography method to measure thioester creation.

Findings

• The study discovered a one-way stereoinversion of the R(-) enantiomer into its optical antipode, explaining the distinct enantioselective conduct of FPF in horses and dogs.
• Results suggested that the clearance of R(-)FPF in these species is better correlated with ligase activity rather than with inversion rate, a finding which aligns with previous research done on rats and sheep.
• A highly significant linear relationship was demonstrated between R(-)FPF clearance and ligase activity, providing further understanding on how FPF engages with biological systems.

Conclusion

• The study concludes that in horses and dogs, as in previous research with rats and sheep, the R(-)FPF clearance is better associated with ligase activity than with inversion rate. It adds substance to the understanding of chiral enantiomers’ disposition, which could help in better predicting how a drug will behave in the body, leading to improved drug design and safer use.