Photochemical toxicity of drugs intended for ocular use

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Abstract

The present investigation was undertaken to evaluate the possible ocular phototoxicity of drugs used in ophthalmic formulations. Sulphacetamide, ketoconazole, voriconazole, diclofenac, and ketorolac were assessed in the concentrations available in the market for their ocular use. The suitable models viz Hen’s Egg Test Chorioallantoic Membrane (HET-CAM) test, Isolated Chicken Eye (ICE) test, and Red Blood Cell (RBC) haemolysis test as recommended by ECVAM, ICCVAM, and OECD guidelines were performed. Results of HET-CAM and ICE tests suggest that sulphacetamide is moderately toxic in the presence of light/UV-A and very slightly irritant without irradiation. Ketoconazole and voriconazole were found slightly irritant in presence of light/UV-A and non-irritant in dark. Diclofenac and ketorolac demonstrated slight irritancy in the light and were found to be non-irritant in dark. The results suggest that some of the drugs have potential toxic effect in the presence of light. The extent of phototoxicity might get extended when used for longer time. The recommendation is that these drugs should be stored and used in the dark for a specified time and be labelled with specific instructions for patients, especially for those working longer in the sunlight.

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  • 1. Organisation for Economic Cooperation and Development (OECD). Guidelines for the Testing of Chemicals No. 405: Acute Eye Irritation/Corrosion. Paris: OECD; 2002.

  • 2. Furrer P Mayer JM Gurny R. Ocular tolerance of preservatives and alternatives. Eur J Pharm Biopharm 2002;53:263-80. doi: 10.1016/S0939-6411(01)00246-6

  • 3. Benavides T Martínez V Mitjans M Infante MR Moran C Clapés P Clothier R Vinardell MP. Assessment of the potential irritation and photoirritation of novel amino acidbased surfactants by in vitro methods as alternative to the animal tests. Toxicology 2004;201:87-93. doi: 10.1016/j. tox.2004.04.003

  • 4. ICCVAM Test Method Evaluation Report: Appendix G-ICCVAM Recommended HET-CAM Test Method Protocol 2006 [displayed 2 May 2014]. Available at http://ntp.niehs.nih.gov/iccvam/docs/ocutox_docs/oteval/appg-508.pdf

  • 5. ICCVAM-Recommended Protocol for Using the Isolated Chicken Eye (ICE) Test Method Protocol 2012 [displayed 2 May 2014]. Availalble at http://ntp.niehs.nih.gov/iccvam/docs/protocols/iceprotocol16jul12v2-508.pdf

  • 6. Organisation for Economic Cooperation and Development (OECD). Guidelines for the Testing of Chemicals No 438: Isolated Chicken Eye Test Method for Identifying Ocular Corrosives and Severe Irritants. Paris: OECD; 2009.

  • 7. Velpandian T Bankoti R Humayun S Ravi AK Kumari SS Biswas NR. Comparative evaluation of possible ocular photochemical toxicity of fluoroquinolones meant for ocular use in experimental models. Indian J Exp Biol 2006;44:387-91. PMID: 16708892

  • 8. INVITTOX Protocol No 37 European Centre for the Validation of Alternative Methods RBC Test System Ispra: ECVAM DB-ALM; 2010.

  • 9. Editors. Artifacts of light. Nat Meth. 2013;10:1135. doi: 10.1038/nmeth.2760

  • 10. Ahmad T Ahmed I. Multicomponent spectrophotometric assay of sulphacetamide and photodegradation products. Pak J Pharm Sci 1990;3:29-39. PMID:16414659

  • 11. Miyazaki T Yomota C Okada S. Depolymerization of hyaluronate by the phototoxic drugs phenothiazines and sulphacetamide. Colloid Polymer Sci 2000;278:84-9. doi: 10.1007/s003960050014

  • 12. Jordan L. Holtzman. Role of reactive oxygen and metabolite binding in drug toxicity. Life Sci 1982;30:1-9. doi: 10.1016/0024-3205(82)90629-4

  • 13. Mhaske RA Sahasrabudhe S. Identification of Major Degradation Products of Ketoconazole. Sci Pharm 2011;79:817-36. doi: 10.3797/scipharm.1107-18

  • 14. Mohamed KN. Severe photodermatitis during ketoconazole therapy. Clin Exp Derm 1988;13:54. PMID: 3208444

  • 15. Murayama N Imai N Nakane T Shimizu M Yamazaki H. Roles of CYP3A4 and CYP2C19 in methyl hydroxylated and N-oxidized metabolite formation from voriconazole a new antifungal agent in human liver microsomes. Biochem Pharmacol 2007;73:2020-6. doi: 10.1111/j.1365-2125.2009.03534.x

  • 16. Vogna D Marotta R Napolitano A Andreozzi R d’Ischia M. Advanced oxidation of the pharmaceutical drug diclofenac with UV/H2O2 and ozone. Water Res 2004;38:414-22. doi: 10.1016/j.watres.2003.09.028

  • 17. Roberts JE. Ocular phototoxicity. J Photochem Photobiol B 2001;64:136-43. doi: 10.1016/S1011-1344(01)00196-8

  • 18. Motten AG Chignell CF. Spectroscopic studies of cutaneous photosensitizing agents-III. Spin trapping of photolysis products from sulphanilamide analogs. Photochem Photobiol 1983;37:17-26. PMID: 6300940

  • 19. Staub I Flores L Gosmann G Pohlmann A Fröehlich PE Schapoval EES Bergold AM. Photostability studies of ketoconazole: isolation and structural elucidation of the main photodegradation products. Latin Am J Pharm 2010;29:1100-6.

  • 20. Adams AIH Grace G Paulo HS Ana MB. LC stability studies of voriconazole and structural elucidation of its major degradation product. Chromatographia 2009;69(Supplement):115-22. doi: 10.1365/s10337-009-1082-3

  • 21. Epaulard O Saint-Raymond C Villier C Charles J Roch N Beani JC Leccia MT. Multiple aggressive squamous cell carcinomas associated with prolonged voriconazole therapy in four immunocompromised patients. Clin Microbiol Infect 2010;16:1362-4. doi: 10.1111/j.1469-0691.2009.03124.x

  • 22. Scholz I Oberwittler H Riedel KD Burhenne J Weiss J Haefeli WE Mikus G. Pharmacokinetics metabolism and bioavailability of the triazole antifungal agent voriconazole in relation to CYP2C19 genotype. Br J Clin Pharmacol 2009;68:906-15. doi: 10.1111/j.1365-2125.2009.03534.x

  • 23. Encinas S Bosca F Miranda MA. Phototoxicity associated with diclofenac: a photophysical photochemical and photobiological study on the drug and its photoproducts. Chem Res Toxicol 1988;11:946-52. doi: 10.1021/tx9800708

  • 24. Leo G Hi-Shi C Johanson D. Light degradation of ketorolac tromethamine. Int J Pharmaceutics 1988;41:105-13. doi:10.1016/0378-5173(88)90142-1.

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