FLUOROQUINOLONE ANTIMICROBIALS - SINGLET OXYGEN, SUPEROXIDE AND PHOTOTOXICITY

The fluoroquinolone antibacterial agents possess photosensitizing prop erties that lead to phototoxic responses in both human and animal subj ects, The phototoxicity order reported in humans is: fleroxacin > lome floxacin, pefloxacin >> ciprofloxacin > enoxacin, norfloxacin and oflo xacin, Studies both in vivo and in vitro have related this phototoxici ty to the generation of reactive oxygen species including hydrogen per oxide and the hydroxyl radical. We determined the quantum yields of si nglet oxygen generation (Phi(Delta)) by detection of the singlet oxyge n (O-1(2)) luminescence at 1270 mn for several fluoroquinolones, napht hyridines and other structurally related compounds. All the fluoroquin olones examined have low Phi(Delta) values ranging from 0.06 to 0.09 i n phosphate buffer at pD 7.5, We also determined the O-1(2) quenching constants for these compounds and their values were on the order of 10 (6) M-1 s(-1), except for lomefloxacin whose rate constant was 1.8 x 1 0(7) M-1 s(-1). The Phi(Delta) values were significantly decreased in a solvent of lower polarity such as methanol (0.007 less than or equal to Phi(Delta) less than or equal to 0.02), The production of O-1(2) b y these antibiotics did not correlate with the order reported for thei r phototoxicity, We also measured the photogeneration (lambda > 300 mm ) of superoxide by these antibacterials in dimethylsulfoxide using ele ctron paramagnetic resonance and the spin trap 5,5-dimethyl-1-pyrrolin e N-oxide. Although there is not a one-to-one correspondence between t he relative rates of superoxide generation and the phototoxicity ranki ng of the fluoroquinolones, the more phototoxic compounds tended to pr oduce superoxide at a faster rate. Nevertheless, the magnitudes of the observed differences do not appear sufficient to explain the range of fluoroquinolone phototoxicity potencies in human and animal subjects in general and the high activity of fleroxacin and lomefloxacin in par ticular. For these latter drugs the photoinduced loss of the F-8 atom as fluoride and the concomitant generation of a highly reactive carben e at C-8 provide a more plausible mechanism for their potent phototoxi c and photocarcinogenic properties.