Title:Comparative In vitro Metabolism of Enflicoxib in Dogs, Rats, and Humans:
Main Metabolites and Proposed Metabolic Pathways
Volume: 14
Issue: 3
Author(s): Josep Solà, Àngel Menargues, Josep Homedes*, Marta Salichs, Maria Teresa Serafini and Gregorio Encina
Affiliation:
- Ecuphar
Veterinaria S.L.U. (Animalcare Group PLC), Barcelona, Spain
Keywords:
Enflicoxib, metabolism, CYP, COX-2, dog, rat, humans.
Abstract: Background: Enflicoxib is a non-steroidal anti-inflammatory drug of the coxib family
characterized by a long-lasting pharmacological activity that has been attributed to its active
metabolite E-6132.
Objectives: The aim of this work was to explore enflicoxib biotransformation In vitro in humans,
rats and dogs, and to determine its metabolic pathways.
Methods: Different In vitro test systems were used, including hepatocytes and liver and non-hepatic
microsomes. The samples were incubated with enflicoxib and/or any of its metabolites at 37°C
for different times depending on the test system. The analyses were performed by liquid chromatography
coupled with either radioactivity detection or high-resolution mass spectrometry.
Results: Enflicoxib was efficiently metabolized by cytochrome P-450 into three main phase I
metabolites: M8, E-6132, and M7. The non-active hydroxy-pyrazoline metabolite M8 accounted
for most of the fraction metabolized in all the three species. The active pyrazol metabolite E-6132
showed a slow formation rate, especially in dogs, whereas metabolite M7 was a secondary metabolite
formed by oxidation of M8. In hepatocytes, diverse phase II metabolite conjugates were
formed, including enflicoxib glucuronide, M8 glucuronide, E-6132 glucuronide, M7 glucuronide,
and M7 sulfate. Metabolite E-6132 was most probably eliminated by a unique glucuronidation reaction
at a very low rate.
Conclusion: The phase I metabolism of enflicoxib was qualitatively very similar among rats, humans
and dogs. The low formation and glucuronidation rates of the active enflicoxib metabolite
E-6132 in dogs are postulated as key factors underlying the mechanism of its long-lasting pharmacokinetics
and enflicoxib's overall sustained efficacy.
