Photodegradation and in vitro phototoxicity of fenofibrate, a photosensitizing anti-hyperlipoproteinemic drug.
The phototoxic anti-hyperlipoproteinemic drug fenofibrate was found to be photolabile under aerobic and anaerobic conditions. Irradiation under argon of a methanol solution of this drug produced the photoproducts isopropyl 4-(1-[4-chlorophenyl]-1,2-dihydroxy)ethylphenoxyisobutyrate, 1,2-bis(4-chlorophenyl)-1,2bis (4-[isopropoxycarbonylisopropoxy]phenyl)ethane-1,2-diol and 4-(4-chlorobenzoyl)phenol, while under oxygen the photoproducts were 4-chloroperbenzoic acid, methyl 4-chlorobenzoate, 4-chlorobenzoic acid and singlet oxygen, as evidenced by trapping with 2,5-dimethylfuran. These results can be rationalized through hydrogen abstraction by excited fenofibrate, to afford a free radical as key intermediate. Biologically active antioxidants such as glutathione and cysteine efficiently reduced 4-chloroperbenzoic acid to 4-chlorobenzoic acid. The involvement of an electron transfer mechanism is suggested by detection (UV-vis spectrophotometry) of the radical cation TMP+. during the oxidation of tetramethylphenylenediamine (TMP) with 4-chloroperbenzoic acid. Fenofibrate was phototoxic in vitro when examined by the photohemolysis test, both under oxygen and argon atmosphere, although the photohemolysis rate was markedly lower under anaerobic conditions. The photoproducts 4-(1-[4-chlorophenyl]-1,2-dihydroxy)ethylphenoxyisobutyrate and 4-chloroperbenzoic acid induced hemolysis in the dark; however, this effect was quantitatively less important than photohemolysis by fenofibrate. On the other hand, fenofibrate photosensitized peroxidation of linoleic acid, monitored by the UV detection of dienic hydroperoxides. Based on the inhibition of this process upon addition of butylated hydroxyanisole, a radical chain (type I) mechanism appears to operate. In summary, fenofibrate is phototoxic in vitro. This behavior can be explained through the involvement of free radicals, singlet oxygen and stable photoproducts.
Vargas
F
F
Centro de Química, Instituto Venezolano de Investigaciones Cieníficas I.V.I.C., Caracas, Spain.
Canudas
N
N
Miranda
M A
MA
Boscá
F
F
D004912:Erythrocytes / Q000187:drug effects / Q000502:physiology; D011345:Fenofibrate / Q000737:chemistry* / Q000528:radiation effects / Q000633:toxicity*; D006461:Hemolysis / Q000187:drug effects*; D006801:Humans; D019787:Linoleic Acid; D008041:Linoleic Acids / Q000737:chemistry; D015227:Lipid Peroxidation; D010782:Photolysis; D017319:Photosensitizing Agents / Q000737:chemistry* / Q000633:toxicity; D013053:Spectrophotometry
D008041:Linoleic Acids; D017319:Photosensitizing Agents; D019787:Linoleic Acid; D011345:Fenofibrate