Phototoxicity associated with diclofenac: a photophysical, photochemical, and photobiological study on the drug and its photoproducts

Abstract

Diclofenac (1) is a photosensitizing nonsteroidal antiinflammatory drug. Its photodecomposition gives rise to chlorocarbazole 2a. This product undergoes photodehalogenation to 3a in a subsequent step. When the photobiological activities of 1, 2a, and 3a are compared by means of the photohemolysis test, it is clearly observed that chlorocarbazole 2a causes cell lysis with a markedly higher efficiency than the parent drug or the secondary photoproduct 3a. Laser flash photolysis studies suggest that photodehalogenation of 2a occurs from its excited triplet state via quenching by ground-state 2a and formation of an excimer. As a consequence, an aryl radical plus an N-centered carbazolyl radical are formed. These radical intermediates appear to be responsible for the observed photobiological effects of diclofenac, via hydrogen abstraction from the target biomolecules, which initiates a type-I photodynamic effect. The efficient peroxidation of model lipids, such as linoleic acid, photosensitized by 2a are in favor of this proposal. Thus, the photosensitizing properties of diclofenac appear to be associated with the photochemical and photobiological activity of its major photoproduct.