Study on the mechanism of photosensitive dermatitis caused by ketoprofen in the guinea pig.
To investigate the mechanism on photosensitive dermatitis caused by ketoprofen (KP) in humans, the following experiments were performed by topical application on guinea pigs. The phototoxicity study involving treatment with 10% solution of KP, its enantiomers (R-KP and S-KP), loxoprofen, and flurbiprofen revealed no phototoxic reactions. In the photoallergenicity study, KP and its enantiomers (0.5-2% solution) induced skin reaction at all dosages; however, loxoprofen and flurbiprofen (1-5% solution) did not induce such a photoallergenic reaction. These results suggest that the chemical structure of the benzophenone chromophore in KP would be one of the important factors for induction of the photoallergy since both loxoprofen and flurbiprofen do not possess this structure and hence lack photoallergenic potential. Furthermore, to assess time profiles of KP concentration in the skin and plasma, guinea pigs received a repeated topical application of R-KP and S-KP at a dosage of 40 mg/kg over a period of 3 days. Plasma KP concentrations were extremely low as compared to skin KP concentrations and were not detected at 72 h after the final dosing. At 24 h after the final dosing, KP concentrations in the skin with R-KP and S-KP treatment were 187.4 and 254.7 microg/g, respectively, and their half-lives were 80.5 and 84.4 h, respectively. KP concentrations at 336 h after final dosing were 11.3 microg/g for R-KP and 15.7 microg/g for S-KP treatment. The acylglycerol-combined KP concentrations at 336 h were 2% or less as compared to KP concentrations with R-KP and S-KP treatment. There were no differences in KP concentrations in the skin between R-KP and S-KP and in combined KP concentrations between the enantiomers. The present study indicates that photosensitive dermatitis after topical application of KP in humans, caused by photoallergenicity and not phototoxicity, can be reproduced in the animal testing, and suggests that the skin reaction may be caused by the long period of retention of KP in the skin.
Nakazawa
Takashi
T
Research Laboratories 2, Fuji Yakuhin Co. Ltd, 331-0068, Saitama, Japan. L2-20640@fujiyakuhin.co.jp
Shimo
Takeo
T
Chikamatsu
Noriko
N
Igarashi
Takako
T
Nagata
Osamu
O
Yamamoto
Masaharu
M
D000287:Administration, Topical; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000493:pharmacokinetics / Q000633:toxicity*; D017484:Dermatitis, Phototoxic / Q000209:etiology* / Q000473:pathology; D004305:Dose-Response Relationship, Drug; D005260:Female; D005480:Flurbiprofen / Q000633:toxicity; D006168:Guinea Pigs; D007660:Ketoprofen / Q000493:pharmacokinetics / Q000633:toxicity*; D010666:Phenylpropionates / Q000633:toxicity; D012867:Skin / Q000187:drug effects / Q000473:pathology / Q000528:radiation effects; D013237:Stereoisomerism; D014466:Ultraviolet Rays
D000894:Anti-Inflammatory Agents, Non-Steroidal; D010666:Phenylpropionates; C040656:loxoprofen; D005480:Flurbiprofen; D007660:Ketoprofen