Photosensitizing Properties of Actarit, an Antirheumatic Drug

Abstract

The photobiological properties of 4-acetylaminophenylacetic acid (Actarit, ACT, MS-932, CAS 18699-02-0) were studied using in vitro phototoxicity assays: photohemolysis, photoperoxidation of linoleic acid and Candida sp phototoxicity test. ACT reduced nitro blue tetrazolium (NBT) when irradiated with λ ≥ 300 nm in deoxygenated aqueous buffer solution (pH 7.4). The photohemolysis rate and photoperoxidation of linoleic acid were inhibited significantly by reduced glutathione. ACT was phototoxic to Candida sp. The isolation and identification of the photodegradation products of ACT in phosphate buffered saline solution (pH 7.4) and methanol were studied under aerobic conditions. Four compounds were identified and two of them isolated and characterized by spectroscopic methods. A photodecarboxylation with the participation of oxygen via a type I mechanism was proposed for the photodegradation of ACT which undergoes direct electron transfer from the excited state of ACT carboxylate and homolytic rupture of the α-carbon bond. A photodynamic mechanism involving radicals and electron transfer reactions was suggested for the observed in vitro phototoxicity.

Key words

Actarit, in vitro studies, photohemolysis, photoperoxidation, phototoxicity - Antirheumatics - Candida sp - CAS 18699-02-0

• Literature

• 1 Nakagawa Y, Ogawa T, Omezu K, Shibata Y, Nishimura T, Sato S. Characterization of suppressor cells activated by 4-acetylaminophenylacetic acid (MS-932) in delayed type hypersensitivity. Int J Inmunother. 1990; 6: 149-156
• 2 Brew J, Bannister R The treatment of inflammatory bowel disease. 2006; WO2006046007.
• 3 Ekburibe N Methods and compositions employing 4-aminophenylacetic acid compound for the treatment of digestive and mucosal inflammatory conditions. 2005; WO200509448.
• 4 Miyamoto K, Yasuda Y Drug-containing photocrosslinked hyaluronic acid derivative gel. 2007; WO2007004675.
• 5 Brehm C, Klein T, Buhr W, Chiesa M, Palmer A, Zimmermann R et al. Mutual prodrug compounds for use as anti-inflammatory agents with gastrointestinal protective activity 2006 WO2006117316.
• 6 Fujisawa H, Nishimura T, Inoue Y, Ogaya S, Shibata Y, Naka-gawa Y et al. Antiinflammatory properties of the new antirheumatic agent 4-acetylaminophenylacetic acid. Arzneimittel-Forschung (Drug Research). 1990; 40: 693-697
• 7 Cosa G. Photodegradation and photosensitization in pharmaceutical products: assessing drug phototoxicity. Pure Appl Chem. 2004; 76 (2) 263-275
• 8 Stern R. Phototoxic reactions to piroxicam and other nonsteroidal anti-inflammatory agents. N Engl J Med. 1983; 309: 186-187
• 9 Ljunggren B. Propionic acid-derived non-steroidal anti-inflammatory drugs are phototoxic in vitro. Photodermatology. 1985; 2: 3-9
• 10 Canudas N, Zamora D, Villamizar JE, Fuentes J, Castelli C, Taddei A. Photosensitizing properties of 6-methoxy-2-naphthylacetic acid, the major metabolite of the phototoxic non-steroidal anti-inflammatory and analgesic drug Nabumetone. Pharmazie. 2005; 60 (8) 604-608
• 11 Kawada A, Hiruma M, Miura Y, Noguchi H, Akiyama M. Ishibashi A Photosensitivity due to actarit. Contact Dermatitis. 1997; 36: 175-
• 12 Tramontano A, Janda K, Lerner R. Antibody catalysis of bi-molecular amide formation. J Am Chem Soc. 1998; 110: 4835-4837
• 13 Canudas N, Moulinier J, Zamora D, Sanchez A. Photobio-logical properties of Nabumetone (4-[6-methoxy-2-napht-haleny]-2-butanone) a novel non-steroidal anti-inflammatory and analgesic agent. Pharmazie. 2000; 55 (4) 282-285
• 14 Mori Y, Sakagushi Y, Hayashi H. Spin effects on decay dynamics of charge-separated states generated by photoinduced electron transfer in zinc porphyrin-naphthalene diimide dyads. J Physical Chemistry A. 2002; 106 (18) 4453-4467
• 15 Lewis E, Adamek T, Vinning L, White R. Metabolites of a blocked chloramphenicol producer. J Natural Products. 2003; 66 (l) 62-66
• 16 Cho B, Kang S, Kim M, Ryu S, An D. Solvent free reduction of aldehydes and ketones using solid acid-activated sodium borohydride. Tetrahedron. 2006; 62 (34) 8164-8168
• 17 Daniels FA. simple microbiological method for demonstrating phototoxic compounds. J Invest Dermatol. 1965; 44: 259-267
• 18 Knudsen EA. The Candida phototoxicity test. The sensitivity of different strains and species of Candida, standardization attempts and analysis of the dose response curves for 5- and 8-methoxypsoralen. Photodermatology. 1985; 2: 80-85
• 19 Giuffrida S, De Guidi G, Sortino S, Chimelli R, Constanzo G, Condorelli A. Molecular mechanism of drug photosensitization. Part 6: Photohaemolysis sensitized by tolmetin. J Photochem Photobiol. B Biol. 1995; 29: 125-133
• 20 Miranda MA. Phototoxicity of drugs. In Castell JV. editor Alternative in vitro models to animal experimentation in pharmaco-toxicology. Barcelona: Farmaindustria; 1992. p 239-240
• 21 Moore D, Chappuis P. A comparative study of photochemistry of the non-steroidal anti-inflammatory drugs naproxen benoxaprofen and indomethacin. Photochem Photobiol. 1988; 47 (2) 173-180
• 22 Constanzo L, De Guidi G, Condorelli G, Gambia A, Fama A. Molecular mechanism of Naproxen photosensitization in red blood cells. J Photochem Photobiol B Biol. 1989; 3: 223-225
• 23 Boscá F, Miranda MA, Vano L. Vargas E New photodegradation pathways of Naproxen a phototoxic non-steroidal anti-inflammatory drug. J Photochem Photobiol A:Chem. 1990; 54: 131-134
• 24 Encinas S, Boscá F, Miranda MA. Phototoxicity associated with Diclofenac:a photophysical, photochemical and photobiological study on the drug and its photoproducts. Chem Res Toxicol. 1998; 11: 946-952
• 25 Castell J, Gomez-L M, Miranda MA, Morera I. Photolytic degradation of Ibuprofen. Toxicity of the isolated photoproducts on fibroblasts and erythrocytes. Photochem Photobiol. 1987; 46 (6) 991-996
• 26 Boscâ F, Miranda MA, Garganico G, Mauleón D. Photochemical and photobiological properties of ketoprofen associated with the benzophenone chromophore. Photochem Photobiol. 1994; 60: 96-101
• 27 Kavli G, Volden G. The Candida test for phototoxicity. Photodermatology. 1984; 1: 204-207