Inhibition of Drug Metabolism by Quinolone Antibiotics

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Abstract
A number of quinolone antibiotics have been found to reduce the hepatic clearance of coadministered drugs such as theophylline. Enoxacin appears to be the most potent inhibitor, consistently decreasing theophylline clearance by more than 50%, while a single study suggests a similar degree of inhibition with pipemidic acid. Ciprofloxacin and pefloxacin reduce theophylline clearance to a smaller extent (approximately 20 to 30%). However, with ciprofloxacin, larger changes and theophylline toxicity have been reported in some subjects. Norfloxacin, ofloxacin and nalidixic acid appear to have minimal effects on theophylline clearance. Enoxacin and ciprofloxacin have also been found to reduce the clearance of caffeine, while ofloxacin has no effect. Few other substrates have been studied. Enoxacin decreases the clearance of R-warfarin with no effect on S-warfarin. In addition, enoxacin has been reported to reduce the clearance of antipyrine, with no effect on chlorpropamide, glibenclamide (glyburide) or phenytoin. The mechanism of these interactions is largely unexplored. It has been suggested that inhibition may be related to the production of 4-oxoquinolone metabolites; however, this hypothesis has not been confirmed. No unique structural feature has been identified to date which explains differences between these compounds in their propensity to affect drug metabolism. Further studies are needed to evaluate the effects of these drugs on other substrates not yet examined and to assess whether or not inhibition is dose related. Clinically, caution is advised when using a quinolone, particularly enoxacin, pipemidic acid, ciprofloxacin or pefloxacin, in combination with theophylline. Close monitoring of theophylline concentrations is recommended in any patient receiving these drugs. The clinical significance of inhibited metabolism of other substrates remains unclear at present. Until further data are available, clinicians should be aware of the possibility of reduced drug clearance resulting in adverse effects whenever the fluoroquinolones are coadministered with drugs that depend on hepatic metabolism for their elimination.