An evaluation of chemical photoreactivity and the relationship to phototoxicity |
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Authors: | Mark H. Kleinman Mark D. Smith Edit Kurali Sarah Kleinpeter Kaina Jiang Yongxia Zhang Sonya A. Kennedy-Gabb Anthony M. Lynch Chris D. Geddes |
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Affiliation: | 1. GlaxoSmithKline, Upper Merion, 709 Swedeland Road UW2831, King of Prussia, PA 19406, USA;2. Institute of Fluorescence, University of Maryland Baltimore County, 701 East Pratt Street, Baltimore, MD 21202, USA;3. GlaxoSmithKline, Park Road, Ware, Hertfordshire SG12 0DP, UK;4. Institute of Fluorescence and Department of Chemistry and Biochemistry, University of Maryland Baltimore County, 701 East Pratt Street, Baltimore, MD 21202, USA |
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Abstract: | The existing regulatory guidance for photosafety testing of new drug products states that studies are warranted for those chemicals that both absorb light in the range of 290–700 nm, and that are either applied locally/topically, or “reach” (EMEA)/“significantly partition” (FDA) to the skin or eyes. The initial in vitro study recommended for the assessment of phototoxic potential is the 3T3 Neutral Red Uptake (NRU) Assay. The current study was undertaken to establish superior triggers for the initiation of biological photosafety testing. In this study, photophysical and photochemical parameters for 40 drug or drug-like molecules were studied. Principal Component Analysis (PCA), Partial Least Squares-Discriminant Analysis (PLS-DA), and a fivefold cross-validation PLS algorithm were used to evaluate the relationship between subsets of photophysical and photochemical parameters with the 3T3 NRU PIF/MPE (Photo Irritation Factor/Mean Photo Effect) results. The parameters most indicative of a 3T3 NRU positive PIF or MPE score were the extent of degradation in solution, the quantum yield of formation of singlet oxygen and the relative formation of superoxide anion. The results demonstrate that while absorption of light is critical to the induction of a light-induced process, it is the resultant events that may be used to predict the 3T3 NRU assay result. It is therefore proposed that the trigger for photosafety testing be revised to include a molecular basis for photoreactivity. From this limited investigation, estimated thresholds leading to 3T3 NRU positive results due to photodegradation, formation of singlet oxygen quantum yield or a relative superoxide anion formation value are proposed. |
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Keywords: | Phototoxicity 3T3 NRU Singlet oxygen Superoxide anion Photodegradation Photosafety testing Photoreactivity Photostability |
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