IN VITRO SCREEN FOR PHOTOTOXICITY OPTIMIZED DRUG DEVELOPMENT USING A HIGHLY DIFFERENTIATED SKIN MODEL.

This study by MatTek Corp. scientists demonstrated that MatTek’s EpiDerm human skin tissue equivalent can be used to determine the phototoxicity of systemically administered drugs, significantly improving the drug development process. PURPOSE: Both topically applied and systemically administered medications can induce photosensitivity. Photosensitivity includes both photo-allergic (immunologically mediated) reactions, and phototoxic effects, which occur following an initial exposure to a drug and sunlight. The majority of medications causing photosensitivity are systemic phototoxicants and phototoxicity is much more common than photo-allergy. In the development of new drugs, determining whether a new candidate is phototoxic is essential. Current in vitro methods result in a high percentage of false positives thereby eliminating good candidates from further development. In the current work, MatTek scientists investigated whether the 3-dimensional, highly differentiated EpiDerm skin model (EPI-200) could predict phototoxicity of systemically administered drugs. METHODS: Fourteen known phototoxins, including fibrates, non-steroidal anti-inflammatory drugs (NSAIDs), tetracyclines, quinolones, psoralens, and histamine receptor antagonists, and 2 non-phototoxins were used in this study. EpiDerm EPI-200 tissues (n=2) were cultured for 3 hours in the presence of at least three concentrations of drug ranging from 0-200 mg%. The tissues were rinsed, placed in phosphate buffered saline, and exposed to a non-toxic dose of UVA (10 J/cm^2) using a solar simulator. After irradiation, the tissues were again rinsed, cultured (37ºC, 5% CO2) for an additional 18 hours in fresh medium, and evaluated for viability using the MTT assay. The viability of parallel non-irradiated, drug-exposed tissues (n=2) was also evaluated. RESULTS: For tissues exposed to the phototoxic drugs, the viability of the irradiated tissues decreased by 33-75% more than the non-irradiated, drug exposed tissues, indicating phototoxicity. The assay was sensitive (14 of 14 phototoxins detected) and specific (2 of 2 negatives correctly identified). CONCLUSIONS: The EpiDerm skin model will have utility in determining the phototoxicity of systemically administered drugs. Such an assay system will significantly improve the drug development process.

Drug development, EPI-200, EpiDerm, Fibrates, Histamine receptor antagonist, Histamine receptor antagonists, Irradiation, Non-steroidal anti-inflammatory drugs (NSAIDs), Opmitized drug development, Photo-allegeric, Photo-toxicity protocol, Photosensitivity, Phototoxic, Phototoxicants, Phototoxicity, Psoralens, Quinolones, Skin irritation, Systemically administered drugs, Tetracyclines, UVA

5-methoxy psoralen (5-MOP), 8-methoxy psoralen (8-MOP), Acetic acid, Carprofen, Chlorpromazine, Ciprofloxacin, Dimethylsulfoxide (DMSO), Doxycycline, Fenofibrate, Fibrates, Fleroxacin, Histamine receptor antagonists, Ketoprofen, Nalidixic acid, Non-steroidal anti-inflammatory drugs (NSAIDs), Norfloxacin, Ofloxacin, Promethazine, Psoralens, Quinolones, Tetracycline