The effects of quinolones on xanthine pharmacokinetics

Caffeine, theobromine, and theophylline are among the most widely consumed compounds in beverages and in pharmaceutical preparations. These methylxanthine alkaloids are metabolized by similar pathways involving demethylation and hydroxylation that are predominantly cytochrome P-450 mediated. In vivo and in vitro evidence suggests that the cytochrome P-450 isozymes involved in the demethylation pathways are distinct from the cytochrome P-450 isozymes involved in the hydroxylation pathways. Although distinctions can be made between demethylation and hydroxylation pathways, the evidence suggests that these different cytochrome P-450 isozymes are under common regulatory control. Any drug inhibiting the family of cytochrome P-450 isozymes involved in the metabolism of the methylxanthines would, therefore, be expected to have a similar effect on theophylline, theobromine, and caffeine. A number of quinolones, including enoxacin, pipemidic acid, ciprofloxacin, norfloxacin, and pefloxacin, have been shown to reduce the clearance of theophylline, while lomefloxacin has no effect on theophylline or caffeine clearance. It has been hypothesized that only fluoroquinolones that form a 4-oxo-metabolite inhibit theophylline clearance. Lomefloxacin, which does not form a 4-oxo-metabolite, would therefore not be expected to inhibit the clearance of theophylline or caffeine. In contrast, ciprofloxacin, which does form a 4-oxo-metabolite, has been shown to reduce theophylline and caffeine clearances by about one third. Another hypothesis for the differences among quinolones suggests that quinolones that have a greater impact on theophylline clearances are more stereochemically similar to theophylline. Substitutions at position 8 on the quinolone nucleus (as in lomefloxacin) would result in stearic hindrance and decrease the structural similarity to theophylline.