Photosensitization by fenofibrate. II. In vitro phototoxicity of the major metabolites.
Fenofibric acid, the major metabolite of fenofibrate, was found to be photolabile. Its irradiation in aqueous solution gave rise to two photoproducts, whose formation involves photodecarboxylation of the dissociated acid to an aryloxy-substituted carbanion, which is directly protonated or, alternatively, undergoes a Wittig rearrangement. A comparative in vitro phototoxicity study has been carried out on the anti-hyperlipoproteinemic drug fenofibrate, its metabolites and the photoproducts of fenofibric acid. Fenofibrate, fenofibric acid and its two photoproducts were found to be active when examined by the photohemolysis test and were able to photosensitize peroxidation of linoleic acid, as evidenced by the UV monitoring of dienic hydroperoxides. In summary, the major metabolite of fenofibrate (fenofibric acid), as well as its photoproducts, are phototoxic in vitro. This behavior can be attributed to the fact that the four compounds retain the benzophenone chromophore present in fenofibrate and is indicative of free radical-mediated photosensitization. In agreement with this rationalization, the metabolites with a reduced ketone functionality exhibit no detectable in vitro phototoxicity.
Miranda
M A
MA
Departamento de Química, Universidad Politécnica de Valencia, Spain.
Boscá
F
F
Vargas
F
F
Canudas
N
N
D011345:Fenofibrate / Q000009:adverse effects* / Q000378:metabolism / Q000528:radiation effects*; D006461:Hemolysis / Q000187:drug effects / Q000528:radiation effects; D006801:Humans; D066298:In Vitro Techniques; D010777:Photochemistry; D017319:Photosensitizing Agents / Q000009:adverse effects* / Q000737:chemistry / Q000378:metabolism
D017319:Photosensitizing Agents; D011345:Fenofibrate