title: [New findings on the structure-phototoxicity relationship and photostability of fluoroquinolones].
abstract: The present study examined the phototoxicities of a series of 7-(3-aminopyrrolidinyl) quinolones containing various substituents at position 1 by use of a mouse model. For the 7-(3-aminopyrrolidinyl) quinolones with a halogen atom at position 8, well-known substituent groups such as a cyclopropyl, an ethyl, or a difluorophenyl at position 1 were found to be responsible for severe phototoxicity. However, when an aminodifluorophenyl or an isoxazolyl group was placed at position 1, even 8-halogeno quinolones were found to be mildly phototoxic. This is the first report of 8-halogeno quinolones that are not severely phototoxic. Two structurally similar 8-chloro quinolones (the 1-aminodifluorophenyl 8-chloro quinolone and the 1-difluorophenyl 8-chloro quinolone) were investigated further. The former was mildly phototoxic; the latter was severely phototoxic. We demonstrate that these two 8-chloro quinolones have practically the same areas under the concentration-time curves from 0 to 4 h in auricular tissue, suggesting that the mild phototoxicity is not due to pharmacokinetic instability. The rates of UV photodegradation of these compounds were also measured. We found that these two quinolones photodegrade at similar rates, suggesting that the mild phototoxicity is not attained through increased photostability. In conclusion, the phototoxic potentials of fluoroquinolones are influenced not only by the substituent at position 8 but also by that at position 1. We also discovered a mildly phototoxic 8-chloro quinolone which did not have increased photostability.
authors.affiliation: New Lead Pharmacology Laboratory, Institute for Medical Research, Wakunaga Pharmaceutical Co., Ltd., Akitakata City 739-1195, Japan. hayashi_n@wakunaga.co.jp
authors.forename: Norihiro
authors.initials: N
authors.lastname: Hayashi
mesh_terms: D000818:Animals; D017484:Dermatitis, Phototoxic / Q000209:etiology* / Q000517:prevention & control; D015195:Drug Design; D004355:Drug Stability; D024841:Fluoroquinolones / Q000009:adverse effects* / Q000737:chemistry* / Q000528:radiation effects; D051379:Mice; D013329:Structure-Activity Relationship; D014466:Ultraviolet Rays
chemical_list: D024841:Fluoroquinolones