Analytical studies on the prediction of photosensitive/phototoxic potential of pharmaceutical substances.
OBJECTIVE
Phototoxic responses after administration of photosensitive pharmaceutics have been recognized as undesirable side effects, and predicting potential hazardous side effects is gaining importance as new drugs are introduced to the market. In this work, we characterize the photochemical/photobiological properties of model compounds to develop an effective screening method for the prediction of phototoxic/photosensitive potential.


METHODS
Twenty-one known photosensitive/phototoxic compounds and five weak/nonphototoxic compounds were subjected to ultraviolet (UV) spectral analyses and photochemical evaluation including the determination of produced reactive oxygen species (ROS) and photostability study. The photooxidation of linoleic acid was also monitored in the presence of tested compounds, guided on the formation of thiobarbituric acid reactive substances.


RESULTS
Most photosensitive/phototoxic drugs tested, even weak UV absorbers, at a concentration of 200 microM showed significant production of ROS under 18 h light exposure (30,000 lx). On the other hand, ROS generated from weak/nonphototoxic compounds, including strong UV absorber benzocaine, were low or negligible. Although exposure of quinine to light resulted in significant degradation (half-life, t1/2=6.4 h), it was dramatically attenuated by the addition of ROS scavengers, especially sodium azide (t1/2=122.6 h). Furthermore, concomitant exposure of photosensitive/phototoxic compounds (200 microM) and linoleic acid (1 mM) for 18 h led to the marked formation of lipoperoxide.


CONCLUSIONS
Results indicated that known photosensitive/phototoxic compounds tested have the ability to generate ROS under light exposure, and this photochemical reaction could be associated with their photoinstability and/or phototoxic responses. Based on these findings, determination of ROS, generated from photoirradiated compounds, may be an effective predictive model in recognizing their photosensitive/phototoxic potential.
Onoue
Satomi
S
Analytical Research and Development, Pfizer Global Research and Development, Nagoya Laboratories, Pfizer Japan Inc., 5-2 Taketoyo, Aichi, 470-2393, Japan. satomi.onoue@pfizer.com
Tsuda
Yoshiko
Y
D000465:Algorithms; D002851:Chromatography, High Pressure Liquid; D003124:Colorimetry; D017484:Dermatitis, Phototoxic / Q000503:physiopathology*; D004353:Drug Evaluation, Preclinical / Q000379:methods*; D064420:Drug-Related Side Effects and Adverse Reactions; D019787:Linoleic Acid / Q000737:chemistry / Q000528:radiation effects; D015227:Lipid Peroxidation / Q000528:radiation effects; D010787:Photosensitivity Disorders / Q000139:chemically induced*; D011803:Quinine / Q000737:chemistry / Q000528:radiation effects; D017382:Reactive Oxygen Species / Q000737:chemistry / Q000528:radiation effects; D013056:Spectrophotometry, Ultraviolet; D013481:Superoxides / Q000737:chemistry / Q000528:radiation effects; D017392:Thiobarbituric Acid Reactive Substances / Q000737:chemistry; D014466:Ultraviolet Rays
D017382:Reactive Oxygen Species; D017392:Thiobarbituric Acid Reactive Substances; D013481:Superoxides; D019787:Linoleic Acid; D011803:Quinine