title: Microsomal metabolism of ciprofloxacin generates free radicals.
abstract: Ciprofloxacin (CPFX) is a widely used fluoroquinolone antibiotic with a broad spectrum of activity. However, clinical experience has shown a possible incidence of undesirable adverse effects including gastrointestinal, skin, hepatic, and central nervous system (CNS) functions, and phototoxicity. Several examples in the literature data indicate that free radical formation might play a role in the mechanism of some of these adverse effects, including phototoxicity and cartilage defects. The purpose of this study is to investigate free radical formation during the metabolism of CPFX in hepatic microsomes using electron spin resonance (ESR) spectroscopy and spin trapping technique. We then investigate the effects of a cytochrome P450 inhibitor, SKF 525A, Trolox, and ZnCl2 on CPFX-induced free radical production. Our results show that CPFX induces free radical production in a dose- and time-dependent manner. The generation of 4-POBN/radical adduct is dependent on the presence of NADPH, CPFX, and active microsomes. Furthermore, free radical production is completely inhibited by SKF 525A, Trolox, or ZnCl2.
authors.affiliation: Hacettepe University, Faculty of Pharmacy, Department of Pharmaceutical Toxicology, Ankara, Turkey.
authors.forename: A
authors.initials: A
authors.lastname: Gürbay
authors.forename: B
authors.initials: B
authors.lastname: Gonthier
authors.forename: D
authors.initials: D
authors.lastname: Daveloose
authors.forename: A
authors.initials: A
authors.lastname: Favier
authors.forename: F
authors.initials: F
authors.lastname: Hincal
mesh_terms: D000818:Animals; D000975:Antioxidants / Q000494:pharmacology; D002712:Chlorides / Q000494:pharmacology; D002839:Chromans / Q000494:pharmacology; D002939:Ciprofloxacin / Q000378:metabolism*; D065607:Cytochrome P-450 Enzyme Inhibitors; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D004578:Electron Spin Resonance Spectroscopy; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005609:Free Radicals / Q000378:metabolism*; D008297:Male; D008862:Microsomes, Liver / Q000187:drug effects / Q000378:metabolism*; D010084:Oxidation-Reduction / Q000187:drug effects*; D011335:Proadifen / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D017967:Zinc Compounds / Q000494:pharmacology
chemical_list: D000975:Antioxidants; D002712:Chlorides; D002839:Chromans; D065607:Cytochrome P-450 Enzyme Inhibitors; D004791:Enzyme Inhibitors; D005609:Free Radicals; D017967:Zinc Compounds; D002939:Ciprofloxacin; C016837:zinc chloride; D003577:Cytochrome P-450 Enzyme System; D011335:Proadifen; C010643:6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxylic acid