An evaluation of chemical photoreactivity and the relationship to phototoxicity.
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.
Kleinman
Mark H
MH
GlaxoSmithKline, King of Prussia, PA 19406, USA. mark.h.kleinman@gsk.com
Smith
Mark D
MD
Kurali
Edit
E
Kleinpeter
Sarah
S
Jiang
Kaina
K
Zhang
Yongxia
Y
Kennedy-Gabb
Sonya A
SA
Lynch
Anthony M
AM
Geddes
Chris D
CD
D016475:3T3 Cells; D000465:Algorithms; D000818:Animals; D017484:Dermatitis, Phototoxic / Q000209:etiology*; D064420:Drug-Related Side Effects and Adverse Reactions; D016018:Least-Squares Analysis; D051379:Mice; D009499:Neutral Red / Q000378:metabolism; D004364:Pharmaceutical Preparations / Q000737:chemistry; D055668:Photochemical Processes; D010777:Photochemistry / Q000379:methods; D025341:Principal Component Analysis; D026082:Singlet Oxygen / Q000737:chemistry; D013481:Superoxides / Q000737:chemistry; D018675:Toxicity Tests / Q000379:methods; D014466:Ultraviolet Rays
D004364:Pharmaceutical Preparations; D013481:Superoxides; D026082:Singlet Oxygen; D009499:Neutral Red