Atorvastatin calcium (ATV) is one of the most frequently prescribed drugs worldwide. Among the
adverse effects observed for this lipid-lowering agent, clinical cases of cutaneous adverse reactions have
been reported and associated with photosensitivity disorders. Previous work dealing with ATV
photochemistry has shown that exposure to natural sunlight in aqueous solution leads to photoproducts
resulting from oxidation of the pyrrole ring and from cyclization to a phenanthrene derivative. Laser
flash photolysis of ATV, at both 266 and 308 nm, led to a transient spectrum with two maxima at λ )
360 and λ ) 580 nm (τ ) 41 μs), which was assigned to the primary intermediate of the stilbene-like
photocyclization. On the basis of the absence of a triplet-triplet absorption, the role of the parent drug
as singlet oxygen photosensitizer can be discarded. By contrast, a stable phenanthrene-like photoproduct
would be a good candidate to play this role. Laser flash photolysis of this compound showed a triplet-triplet
transient absorption at λmax ) 460 nm with a lifetime of 26 μs, which was efficiently quenched by
oxygen (kq ) 3 ((0.2) × 109 M-1 s-1). Its potential to photosensitize formation of singlet oxygen was
confirmed by spin trapping experiments, through conversion of TEMP to the stable free radical TEMPO.
The photoreactivity of the phenanthrene-like photoproduct was investigated using Trp as a marker. The
disappearance of the amino acid fluorescence (λmax ) 340 nm) after increasing irradiation times at 355
nm was taken as a measurement of photodynamic oxidation. To confirm the involvement of a type II mechanism, the same experiment was also performed in D2O; this resulted in a significant enhancement of the reaction rate. On the basis of the obtained photophysical and photochemical results, the phototoxicity of atorvastatin can be attributed to singlet oxygen formation with the phenanthrene-like photoproduct as
a photosensitizer
