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The photolysis of amiodarone (AM) and its major metabolite mono‐N‐desethylamiodarone (DEA), has been studied by absorption spectroscopy, electron spin resonance spectroscopy (spin trapping) and oxygraph measurements. Changes in the absorption spectrum of both AM and DEA upon UV irradiation indicate that both drugs undergo deiodination. Spin trapping experiments with 2‐methyl‐2‐nitrosopropane (MNP), α‐phenyl‐N‐tert‐butyl‐nitrone (PBN) and 5.5‐dimethyl‐1‐pyrroline‐N‐oxide (DMPO) suggest the formation of an aryl radical from AM during UV irradiation. Amiodarone also undergoes photoionization. Under aerobic conditions the photoelectron is scavenged by oxygen to give superoxide, which is trapped by DMPO. Oxygraph measurements further confirmed the consumption of oxygen and the generation of superoxide during the irradiation of aqueous solutions of AM. Deiodination, photoionization and superoxide formation were all observed at wavelengths as low as 335 nm, suggesting that some or all of these processes may be involved in AM‐induced photosensitivity. The aryl radical derived from AM during UV irradiation abstracted a hydrogen atom from suitable donors (ethanol, glutathione, cysteine, linoleic acid). Reaction of the dienyl radical derived from linoleic acid would yield the corresponding peroxy radical thereby initiating lipid peroxidation. This would explain the deposition of lipofuscin, a pigment formed from the products of lipid peroxidation, in the skin of patients receiving AM.

Abstract— Irradiation of daunomycin (or adriamycin) and the spin trap 5,5‐dimethyl‐l‐pyrroline‐1‐oxide (DMPO) at 490 nm in the presence or in the absence of air generated the hydroxyl radical adduct (DMPO‐OH). The observed DMPO‐OH signal was not affected by the addition of hydroxyl radical scavengers (ethanol, formate), suggesting that direct trapping of the hydroxyl radical was not involved. The DMPO‐OH signal was insensitive to superoxide dismutase and catalase, which ruled out the possibility of superoxide or H2O2 involvement. These findings demonstrate that daunomycin (or adriamycin) does not generate hydroxyl radicals or superoxide radical anions when subjected to 490‐nm excitation. However, when daunomycin (or adriamycin) was irradiated at 310 nm DMPO adducts derived from two carbon‐centered radicals, superoxide and the hydroxyl radical were detected. The superoxide adduct of DMPO was abolished by the addition of SOD, providing unequivocal evidence for the generation of the superoxide anion radical. The daunomycin semiquinone radical, observed upon 310‐nm irradiation of daunomycin in the absence of DMPO, appears to be the precursor of the superoxide radical anion. One of the carbon‐centered radicals trapped by DMPO exhibited a unique set of hyperfine parameters and was identified as an acyl radical. This suggests that the known photochemical deacylation of daunomycin occurs via a homolytic cleavage mechanism. The free radicals generated photolytically from adriamycin and daunomycin may be involved in the etiology of the skin ulceration and inflammation caused by these drugs. A knowledge of the dependence of these photogenerated radicals on the wavelength of excitation may be important in the development of adriamycin and daunomycin for photodynamic therapy.

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