Assessment of 8-Methosypsoralen, Lomefloxacin, Sparfloxacin, and Pirfenidone phototoxicity in Long-Evans Rats

Abstract

Phototoxicity has a strong impact on drug development. Although several animal models have been developed to quantitatively assess human risks, none have been validated for standardized use. In this study, we validated an in vivo phototoxicity model using Long-Evans (LE) rats treated with 4 well-known phototoxic drugs, namely 8-methoxypsoralen, lomefloxacin, sparfloxacin, and pirfenidone. Daily macroscopic observations of skin and eyes, ophthalmological examinations 4 days after dosing, and blood sampling for toxicokinetics (TKs) were performed after exposure of treated animals to ultraviolet, and dose-dependent eye and/or skin reactions were noted for all compounds. Margins of safety were calculated when possible and correlated well with known relative phototoxicity of the 4 compounds. We conclude that the present in vivo phototoxicity assay using LE rats with TK analysis can be used to quantitatively predict the risk of pharmaceutical phototoxicity in humans.

Phototoxicity: Its Mechanism and Animal Alternative Test Methods

“…A wide spectrum of organic chemicals, especially drugs possess a concern of phototoxicity probably because of the common existence of UV-absorbing benzene or heterocyclic rings as chromophores in their structures (6 , 7) . Examples can be readily found in various classes of drugs (8) ; antibiotics (quinolones (9) , tetracyclines and sulfonamides), antihistamines, anti-malarial drugs (quinine, chloroquine), anti-cancer agents (5-fluorouracil, vinblastine, vemurafenib (10) and dacarbazine), cardiac drugs (amiodarone, nifedipine, quinidine and diltiazem), diuretics (furosemide, thiazides and hydrochlorothiazide), anti-diabetics (sulfonylurea and glyburide), non-steroidal anti-inflammatory drugs (naproxen, piroxicam, diclofenac, celecoxib (11) and ketoprofen), anti-fibrotic drug (piferindone (12 , 13) ) and psychiatric drugs (phenothiazines, tricyclic antidepressants and imipramine). Dermatological drugs also have a concern of phototoxicity but a certain class of drugs capitalize phototoxic responses as their mode of pharmacological action as can be exemplified by photodynamic therapy like 5-aminolevulinic acid and 8-methoxy psoralen (7) .…”

Experimental Testing of an in Vivo Method of Phototoxicity Evaluation

“…Кожную реакцию оценивали через 30 мин, 24 ч после облучения и далее ежедневно на протяжении двух недель [19]. Кожная реакция оценивалась по наличию эритемы, отека и других повреждений кожного покрова по следующей шкале [20]: «+» -наличие слабо выраженной эритемы и/или эдемы; «++» -наличие эритемы и/или эдемы и/или трещин кожного покрова умеренной степени выраженности;…”

“…В проведенном исследовании кроме эритемы и эдемы было отмечено развитие трещин и изъязвлений кожного покрова. Реакция кожи должна оцениваться через различные промежутки времени после облучения, наиболее часто используются периоды 0,5; 24; 48 и 72 ч [20][21][22][23]. Но для ряда веществ, особенно тех, которые медленно проникают в кожу, иногда необходим более длительный период наблюдения (до 5 суток) как описано в рекомендациях по оценке фототоксических свойств в руководстве под редакцией h. vogel [19].…”

Multi-site study of an <i>in vivo</i> phototoxicity evaluation in Sprague-Dawley rats: skin site and sex differences in sensitivity to drug-induced phototoxicity

“…This protocol focused on the effects of skin site (ventral skin, dorsal skin, or auricle) and sex on sensitivity to lomefloxacin-induced phototoxicity. We selected lomefloxacin as the reference drug for use in this multi-site study as it is an established phototoxic drug in both humans and animals (Oliveira et al, 2000;Adachi et al, 2015;Shimoda et al, 1993). Study conditions in each facility conformed to the ICH S10 guideline.…”