EXPERIMENTAL TESTING OF AN IN VIVO METHOD OF PHOTOTOXICITY EVALUATION

At present all new medicinal products and cosmetics that absorb medium-wavelength UVB, long-wavelength UVA, or visible light in the range 290–700 nm need to be tested for potential phototoxicity. phototoxicity is evaluated by both in vitro and in vivo methods. There are guidelines for in vitro phototoxicity evaluation, however, there are no formally validated protocols for in vivo phototoxicity evaluation. The purpose of this study was to test an economically viable and informative method for in vivo evaluation of tetracycline and ketorolac phototoxicity using outbred rats. Two medicinal products potentially capable of causing clinically established phototoxic reactions were used in this study: tetracycline (tablets, 200 mg/kg and 300 mg/kg) and ketorolac (gel, 13.4 mg/kg, 26.8 mg/kg and 40.3 mg/kg). The medicines were administered in both single and multiple doses. Ultraviolet irradiator OUFK-03 (OOO «Solnyshko», Russia) was used as a light source. The UV exposure (5 J/cm2 and 15 J/cm²) was performed once 1 h after medicine administration. The skin reaction was evaluated 30 minutes and 24 hours after irradiation and then daily for 2 weeks. As a result, the following optimal parameters were determined for in vivo evaluation of phototoxic reactions caused by the medicines: radiation intensity — 15 J/cm² for single systemic administration and 5 J/cm² for single topical (dermal) administration; recommended period of skin reaction evaluation for outbred rats is not less than 7 days.

1. Tappeiner H, Raab O. Ueber die Wirkung Fluorescierender Stoffe auf Infusorien nach Versuchen von O. Raab. Munch Med Wochenschr. 1900;47:5.

2. Ive FA, Magnus IA, Warin RP, Jones EW. «Actinic Reticuloid»; a Chronic Dermatosis Associated with Severe Photosensitivity and the Histological Resemblance to Lymphoma. Br J Dermatol. 1969;81(7):469–85

3. Note for Guidance on Photosafety Testing. London, UK: The European Agency for the Evaluation of Medicinal Product; 2002. Available from: http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2009/09/WC500003353.pdf

4. Guidance for Industry Photosafety Testing. Rockville, MD: Center for Drug Evaluation and Research Food and Drug Administration; 2003. Available from: https://ntp.niehs.nih.gov/iccvam/suppdocs/feddocs/fda/fda-3640fnl.pdf

5. Guidance on Photosafety Evaluation of Pharmaceuticals. Geneva, Switzerland: ICH Harmonised Tripartite Guideline; 2013. Available from: http://www.ich.org/fileadmin/Public_Web_Site/ICH_Products/Guidelines/Safety/S10/S10_Step_4.pdf

6. OECD Guidelines for the Testing of Chemicals, Test No. 432: In Vitro 3T3 NRU Phototoxicity Test. OECD. Organization for Economic Cooperation and Development; 2004. Available from: https://ntp.niehs.nih.gov/iccvam/suppdocs/feddocs/oecd/oecdtg432-508.pdf

7. Interstate Standard GOST 32372–2013. Testing of Chemical of Health Hazard. In Vitro 3T3 NRU Phototoxicity Test. Moscow: Standartinform; 2014 (In Russ.)

8. GOST R 56701–2015. Medicines for Medical Applications. Guidance on Nonclinical Safety Studies for the Conduct of Human Clinical Trials and Marketing Authorization for Pharmaceuticals. Moscow: Standartinform; 2016 (In Russ.)

9. Guidance on Evaluation of Medicines. V. 1. Мoscow: Grif i K; 2014 (In Russ.)

10. Wlodek C, Narayan S. A Reminder about Photo-onycholysis Induced by Tetracycline, and the First Report of a Case Induced by Lymecycline. Clin Exp Dermatol. 2014;39(6):746–7.

11. Vassileva SG, Mateev G, Parish LC. Antimicrobial Photosensitive Reactions. Arch Intern Med. 1998;158(18):1993–2000.

12. Smith EL, al Raddadi A, al Ghamdi F, Kutbi S. Tetracycline Phototoxicity. Br J Dermatol. 1995;132(2):316–7.

13. Hasan T, Khan AU. Phototoxicity of the Tetracyclines: Photosensitized Emission of Singlet Delta Dioxygen. Proceedings of the National Academy of Sciences of the United States of America 1986;83(13):4604–6.

14. Monteiro AF, Rato M, Martins C. Drug-induced Photosensitivity: Photoallergic and Phototoxic Reactions. Clin Dermatol. 2016;34(5):571–81.

15. Kaidbey KH, Mitchell FN. Photosensitizing Potential of Certain Nonsteroidal Anti-inflammatory Agents. Arch Dermatol. 1989;125(6):783–6.

16. Bagheri H, Lhiaubet V, Montastruc JL, Chouini-Lalanne N. Photosensitivity to Ketoprofen: Mechanisms and Pharmacoepidemiological Data. Drug Saf. 2000;22(5):339–49.

17. Sahu RK, Singh B, Saraf SA, Kaithwas G, Kishor K. Photochemical Toxicity of Drugs Intended for Ocular Use. Arh Hig Rada Toksikol. 2014;65(2):157–67.

18. Agwuh KN, MacGowan A. Pharmacokinetics and Pharmacodynamics of the Tetracyclines Including Glycylcyclines. J Antimicrob Chemother. 2006;58(2):256–65.

19. Vogel HG. Drug Discovery and Evaluation: Pharmacological Assays. Springer Science & Business Media; 2002.

20. Adachi T, Satou Y, Satou H, Shibata H, Miwa S, Iwase Y, et al. Assessment of 8-Methosypsoralen, Lomefloxacin, Sparfloxacin, and Pirfenidone Phototoxicity in Long-Evans Rats. Int J Toxicol. 2015;34(1):16–23.

21. Matsumoto N, Akimoto A, Kawashima H, Kim S. Comparative Study of Skin Phototoxicity with Three Drugs by an in vivo Mouse Model. J Toxicol Sci. 2010;35(1):97–100

22. Owen K. Comparative Grepafloxacin Phototoxicity in Mouse Skin. J Antimicrob Chemother. 1998;42(2):261–4.

23. Wagai N, Yamaguchi F, Tawara K, Onodera T. Studies on Experimental Conditions for Detecting Phototoxic Potentials of Drugs in Balb/c Mice. J Toxicol Sci. 1989;14(3):197–204.