RT Journal Article
SR Electronic
T1 New Photosafety Assessment Strategy Based on the Photochemical and Pharmacokinetic Properties of Both Parent Chemicals and Metabolites
JF Drug Metabolism and Disposition
JO Drug Metab Dispos
FD American Society for Pharmacology and Experimental Therapeutics
SP 1815
OP 1822
DO 10.1124/dmd.115.065060
VO 43
IS 11
A1 Masashi Kato
A1 Gen Suzuki
A1 Hiroto Ohtake
A1 Yoshiki Seto
A1 Satomi Onoue
YR 2015
UL http://dmd.aspetjournals.org/content/43/11/1815.abstract
AB Photoreactivity and dermal/ocular deposition of compounds have been recognized as key considerations for evaluating the phototoxic risk of compounds. Because some drugs are known to cause phototoxic reactions via generation of potent phototoxic metabolites, photosafety assessments on parent drugs alone may lead to false predictions about their photosafety. This study aimed to establish a new photosafety assessment strategy for evaluating the in vivo phototoxic potential of both a parent substance and its metabolites. The in vivo phototoxic risk of fenofibrate (FF) and its metabolites, fenofibric acid (FA) and reduced fenofibric acid, were evaluated based on photochemical and pharmacokinetic analyses. FF and FA exhibited intensive UV absorption, with molar extinction coefficient values of 17,000 (290 nm) and 14,000 M−1cm−1 (295 nm), respectively. Superoxide generation from FA was significantly higher than from FF, and a marked increase in superoxide generation from FF was observed after incubation with rat hepatic S9 fractions, suggesting enhanced photoreactivity of FF after metabolism. FA showed high dermal/ocular deposition after oral administration (5 mg/kg, p.o.) although the concentration of FF was negligible, suggesting high exposure risk from FA. On the basis of these findings, FA was deduced to be a major contributor to phototoxicity induced by FF taken orally, and this prediction was in accordance with the results from in vitro/in vivo phototoxicity tests. Results from this study suggest that this new screening strategy for parent substances and their metabolites provides reliable photosafety information on drug candidates and would be useful for drug development with wide safety margins.