Pharmacokinetics of enflicoxib in dogs: Effects of prandial state and repeated administration

Homedes, Josep; Salichs, Marta; Solá, Josep; Menargues, Angel; Cendros, J. M.; Encina, Gregorio

doi:10.1111/jvp.12995

Cited by 10 publications

(23 citation statements)

References 23 publications

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“…When tested for in vivo genotoxic potential, enflicoxib was shown to lack genotoxic activity, either clastogenic or aneugenic, as evidenced by the lack of induction of MN in mouse bone marrow erythrocytes, after single dose oral administration of up to 2000 mg/kg dosages. The peak (Cmax) systemic exposure to enflicoxib achieved in mice after oral administration of a 2000 mg/kg dose, as determined in an independent pharmacokinetic study (unpublished results), was approximately 15-times the highest exposure achieved in the target animal species under therapeutic conditions [27].…”

Section: Discussionmentioning

confidence: 93%

Evaluation of the Genotoxic Potential of the Selective COX-2 Inhibitor Enflicoxib in a Battery of in vitro and in vivo Genotoxicity Assays

Guzmán¹,

Homedes²,

Salichs³

2022

Drug Res (Stuttg)

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Aim Enflicoxib, a selective COX-2 inhibitor approved for the treatment of pain and inflammation associated with osteoarthritis in dogs (Daxocox® [Ecuphar/Animalcare Group]) was assessed for its genotoxic potential in a battery of in vitro and in vivo genotoxicity assays. These comprised a bacterial reverse mutation assay (Ames test), an in vitro human lymphocyte chromosome aberration assay and an in vivo mouse bone marrow micronucleus assay. Methods Relevant vehicle and positive control cultures and animals were included in all assays. In the Ames test, enflicoxib was tested at concentrations of up to 5000 μg/plate. Signs of cytotoxicity were observed at the highest tested concentrations for several of the bacterial strains, both in absence and presence of S9. In human lymphocytes, enflicoxib was assessed for the induction of chromosomal aberrations when exposed at concentrations of up to 62.5 (3 hours) and 29.6 µg/mL (20 hours) in the absence of S9, and up to 66.7 µg/mL (3 hours) in presence of S9. Signs of cell toxicity, evidenced as a decrease in the mitotic index, were observed at these concentrations. In the mouse micronucleus assay, enflicoxib dose levels of up to 2000 mg/kg were administered (single dose) to male and female animals, and bone marrow samples were taken 24 and 48 hours (high-dose animals only) after administration. Results Enflicoxib was shown to lack genotoxic activity in the conducted assays. Conclusions The administration of enflicoxib as a therapeutic analgesic agent would not pose a genotoxic risk to animals or humans.

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Section: Discussionmentioning

confidence: 93%

Evaluation of the Genotoxic Potential of the Selective COX-2 Inhibitor Enflicoxib in a Battery of in vitro and in vivo Genotoxicity Assays

Guzmán¹,

Homedes²,

Salichs³

2022

Drug Res (Stuttg)

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“…The results from in vitro studies using isolated cyclooxygenase enzymes and in vivo in inflammation models in rats have proven that pyrazol metabolite is largely more active and COX‐2 selective than the parent compound (Wagemakers et al, 2009 ). In addition, the pyrazol metabolite shows marked, saturable binding to red blood cells, plasma concentrations at therapeutic levels being considerably lower than those at whole blood, and the opposite expected at very high circulating concentrations (Homedes et al, 2021 ). Moreover, the pyrazol metabolite shows slow rates of formation and elimination together with a high volume of distribution in vivo.…”

Section: Introductionmentioning

confidence: 99%

“…Moreover, the pyrazol metabolite shows slow rates of formation and elimination together with a high volume of distribution in vivo. Consequently, the circulating levels of the pyrazol metabolite become sustained over time after administration and are considered the basis for the long‐lasting therapeutic efficacy of enflicoxib (Homedes et al, 2021 ).…”

Section: Introductionmentioning

confidence: 99%

“…Both the hydroxylated pyrazoline and the pyrazol metabolites are effectively formed from both enflicoxib enantiomers through the action of cytochrome P450 enzyme system (Pretel et al, 2001 ). The latter displays no chirality, while the hydroxylated pyrazoline metabolite contains two chiral centres and is considered as the major enflicoxib metabolite accounting for a relevant fraction of the AUC of the drug‐related material in vivo (more than half of the enflicoxib's AUC with very similar elimination slope, Homedes et al, 2021 ). However, neither the isomeric nature of M8 formed in vivo, nor its pharmacological activity have been studied to date.…”

Section: Introductionmentioning

confidence: 99%

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Selective inhibition of cyclooxygenase‐2 by enflicoxib, its enantiomers and its main metabolites in vitro in canine blood

Solá

Menargues

Homedes³

et al. 2022

Vet Pharm & Therapeutics

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Enflicoxib is approved for the treatment of pain and inflammation in canine osteoarthritis. The objective of this work was to assess the mechanistic basis of enflicoxib therapy investigating the COX inhibitory activity of enflicoxib (racemate), its enantiomers and its main metabolites using the canine whole blood assay. The (R)‐(+)‐Enflicoxib enantiomer and metabolite M8 (hydroxylated pyrazoline) did not induce significant COX inhibition. Enflicoxib and its (S)‐(‐)‐Enflicoxib enantiomer inhibited COX‐1 and COX‐2 with variable degree of preferential isoform inhibition, but no significant therapeutic effect is anticipated in vivo. The pyrazol metabolite showed the highest COX‐2 inhibition and was the most selective (IC50 COX‐1/ COX‐2 ratio: 19.45). As the pyrazol metabolite shows saturable binding to red blood cells, its in vivo concentrations in plasma are lower than in whole blood. Accordingly, when applying the red blood cell partitioning, the respective IC50 and IC80 for COX‐2 inhibition decreased from 2.8 µM (1129 ng/ml) and 13.4 µM (5404 ng/ml) to 0.2 µM (80.7 ng/ml) and 1.2 µM (484 ng/ml) and the selectivity ratio increased to close to 55. The corrected pyrazol metabolite IC50 and IC80 are well within the plasma levels described in treated dogs.

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“…( 1B )) was identified earlier, which also exerts a potent and selective inhibitory effect on COX-2 [ 3 ]. Following enflicoxib administration to dogs, the E-6132 metabolite shows a longer half-life and higher volume of distribution than the parent compound and is believed to account for most of the long-lasting pharmacological activity of enflicoxib [ 1 , 7 , 8 ]. Besides E-6132, the chemical structure of another phase I metabolite (M8) has also been identified, which corresponds to a hydroxylated pyrazoline derivative of enflicoxib [ 9 ] Fig.…”

Section: Introductionmentioning

confidence: 99%

Comparative In vitro Metabolism of Enflicoxib in Dogs, Rats, and Humans: Main Metabolites and Proposed Metabolic Pathways

Solá

Menargues

Homedes³

et al. 2021

DML

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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. Objective: The aim of this work was to explore enflicoxib biotransformation in vitro in humans, rats and dogs, and to determine its metabolic pathways. Method: 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.

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Pharmacokinetics of enflicoxib in dogs: Effects of prandial state and repeated administration

Cited by 10 publications

References 23 publications

Evaluation of the Genotoxic Potential of the Selective COX-2 Inhibitor Enflicoxib in a Battery of in vitro and in vivo Genotoxicity Assays

Evaluation of the Genotoxic Potential of the Selective COX-2 Inhibitor Enflicoxib in a Battery of in vitro and in vivo Genotoxicity Assays

Selective inhibition of cyclooxygenase‐2 by enflicoxib, its enantiomers and its main metabolites in vitro in canine blood

Comparative In vitro Metabolism of Enflicoxib in Dogs, Rats, and Humans: Main Metabolites and Proposed Metabolic Pathways

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