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IN VITRO SCREEN FOR PHOTOTOXICITY OPTIMIZED DRUG DEVELOPMENT USING A HIGHLY DIFFERENTIATED SKIN MODEL.
Klausner, M., Neal, P., Kubilus, J.
MatTek Corporation, Ashland, MA.
Presented at the AAPS 2006 Biotechnology Conference, Boston, MA., June (2006).
Keywords: 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
Endpoints: MTT tissue viability assay, UVA irradiation
Materials Tested: 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
Summary:
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.
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EpiDerm Data Sheet
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EpiDerm Technical References
Dermal Phototoxicity (EpiDerm Application)
Skin Irritation (EpiDerm Application)
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