Photoisomerization of fluvoxamine generates an isomer that has reduced activity on the 5-hydroxytryptamine transporter and does not affect cell proliferation
Introduction
The interaction of ultraviolet (UV) light with pharmacologically active molecules often results in molecular alterations that may significantly modify and/or reduce the biological activity of drugs and lead to unwanted effects, such as phototoxicity (Beijersbergen van Henegouwen, 1997). Since light therapy has also been used in treating depression (Lam et al., 2000), it would be useful to have a better understanding of possible interaction between light and antidepressants. For instance, Wang et al. (1992) investigated the potential phototoxicity of various antidepressants and proposed that there might be an increased risk for light damage to the lens and retina if patients are treated concurrently with antidepressants and light therapy.
Phototoxic reactions have been observed with a number of compounds acting on the central nervous system (CNS), e.g., antipsychotics, anxiolytics, and antidepressants Harth and Rapoport, 1996, Glass et al., 1998. Viola et al. (2000) also found that two antidepressants, amitriptyline and imipramine, were moderately phototoxic to various substrates (3T3 murine fibroblasts, lipids). On the other side, it is known that the phototoxic effects of drugs are not limited to the organs directly exposed to light (for instance, skin and eyes). Thus, UV–visible radiation is able to penetrate the skin to different extent, depending on its wavelength and skin type. This radiation can reach capillaries and the circulating blood, causing systemic phototoxicity (Parrish, 1982).
Fluvoxamine is a selective inhibitor of neuronal serotonin (5-hydroxytryptamine, 5-HT) re-uptake, and has clinically established antidepressant/anxiolytic activity Edwards and Anderson, 1999, Figgitt and McClellan, 2000. There are no reports of phototoxicity in the clinical use of fluvoxamine, but the presence in its molecule of a CN double bond implies the existence of two different geometric isomers, E (trans) and Z (cis) (Fig. 1), of which only the former is marketed as a drug. It appears that trans to cis transformation does not occur during metabolism of fluvoxamine in vivo (Ruijten et al., 1984), but photoisomerization of CN double bonds under suitable wavelengths is a well-known event (Turro, 1965; Fig. 1).
In this work, we established that UVB light (wavelength range 290–320 nm) is indeed capable of transforming fluvoxamine from trans- into cis-isomer and we characterized some of the biological effects of fluvoxamine and its photoproduct.
Section snippets
Compounds
Fluvoxamine maleate, (E)-5-methoxy-1-[4-(trifluoromethyl)phenyl]1-pentanone O-(2-aminoethyl)oxime maleic acid salt, was a kind gift by Solvay (Solvay Pharmaceutical, Weesp, The Netherlands). Fluoxetine hydrochloride was obtained from Eli Lilly & Co. (Indianapolis, IN, USA). Desipramine, pargyline, phentolamine, and prazosin were purchased from Sigma (St. Louis, MO, USA). All other reagents and solvents were of analytical grade.
Animals
Adult male Sprague–Dawley rats (200–250 g) were obtained from
Photostability of fluvoxamine
Fig. 2 shows how the UV absorption spectrum of fluvoxamine (1×10−5 M in water) changes as a function of the UVB (ultraviolet light, class B, wavelength range 290–320 nm) dose administered. The absorption band at 245 nm disappears, and the presence of two isosbestic points at 218 and 224 nm suggests that a single photoproduct forms in response to irradiation.
Photolysis of a 1×10−2 M solution was also followed by reverse-phase HPLC. In the chromatogram, in addition to the peak of the original
Discussion
Our present findings confirmed that fluvoxamine is photounstable and that UVB irradiation of a fluvoxamine solution gives rise to a single photoproduct. The [1H]- and [13C]-NMR spectra, as well as the mass spectrum of this product, indicate that it has the same general formula of fluvoxamine. However, despite this similarity, the UV absorption spectrum and the chromatographic behavior of the photoproduct differed significantly from fluvoxamine. This difference suggests structural diversity that
Acknowledgements
This work was supported by the 2000 NARSAD Independent Investigator Award to H. Manev, and by the Ministero dell'Istruzione, dell'Università e della Ricerca (Rome) (Project: Mechanisms of photoinduced processes in organized systems).
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