Mechanistic studies of the phototoxic potential of PD 117596, a quinolone antibacterial compound.
PD 117596 is a novel quinolone compound that is being investigated for use as an antibacterial agent. Early investigations demonstrated a significant phototoxic liability associated with this compound. These studies were undertaken to investigate the mechanism of phototoxicity using an in vitro model. In the UVA region, PD 117596 was found to be a more efficient producer of singlet oxygen than rose bengal, ciprofloxacin, nalidixic acid, or PD 118879, another quinolone under investigation. The quantum yield of photoreaction for PD 117596 was relatively low (phi = 0.021); however, it was approximately 10-fold higher than other tested quinolones. In vitro studies using a mouse erythrocyte model were used to further investigate the mechanism of phototoxicity. PD 117596-induced photohemolysis was found to be oxygen dependent with a relatively rapid onset that progressed even after removal of light. Preirradiation of the compound prevented subsequent hemolytic or photohemolytic action. BHA, BHT, alpha-tocopherol, and the iron chelator DTPA were all found to be effective at ameliorating the photohemolytic response. The photohemolytic response was markedly enhanced when D2O was substituted for H2O in the incubation medium, indicating a singlet oxygen-mediated mechanism of action. A rise in thiobarbituric acid products was noted within 1 hr of irradiation and was maximal at the time of onset of overt photohemolysis. These data suggest that singlet oxygen production by irradiated PD 117596 is responsible for secondary changes in mouse red blood cells including lipid peroxidation and ultimately results in cellular lysis.
Robertson
D G
DG
Department of Pathology and Experimental Toxicology, Parke-Davis Pharmaceutical Research Division, Ann Arbor, Michigan 48106-1047.
Epling
G A
GA
Kiely
J S
JS
Bailey
D L
DL
Song
B
B
D042462:4-Quinolones; D000818:Animals; D000890:Anti-Infective Agents / Q000009:adverse effects* / Q000378:metabolism; D000975:Antioxidants / Q000494:pharmacology; D002939:Ciprofloxacin / Q000009:adverse effects / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D024841:Fluoroquinolones; D016166:Free Radical Scavengers; D006461:Hemolysis / Q000187:drug effects; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D009268:Nalidixic Acid / Q000009:adverse effects / Q000378:metabolism; D009603:Nitroso Compounds / Q000494:pharmacology; D010100:Oxygen / Q000378:metabolism; D010777:Photochemistry; D010782:Photolysis; D015363:Quinolones / Q000009:adverse effects* / Q000378:metabolism; D013858:Thiobarbiturates / Q000378:metabolism
D042462:4-Quinolones; D000890:Anti-Infective Agents; D000975:Antioxidants; D024841:Fluoroquinolones; D016166:Free Radical Scavengers; D009603:Nitroso Compounds; D015363:Quinolones; D013858:Thiobarbiturates; C008651:4-nitrosodimethylaniline; D009268:Nalidixic Acid; D002939:Ciprofloxacin; C071833:PD 118879; C057711:PD-117596; C029684:thiobarbituric acid; D010100:Oxygen