title: Metabolism of theophylline and its inhibition by fluoroquinolones in rat hepatic microsomes.
abstract: 1. The effects of beta-naphthoflavone, dexamethasone, phenobarbitone and isosafrole on the metabolism of theophylline by rat liver microsomes have been studied. Only beta-naphthoflavone, a known P4501A inducer, increased the rate of 1-methylxanthine formation (3-fold), whereas all the inducers studied increased the rate of 1,3-dimethyluric acid production (2.5-3-fold). 2. To study the effects of a range of fluoroquinolones on theophylline metabolism, beta-naphthoflavone-induced microsomes were used, as the ratio for metabolite production rates was similar to that of untreated microsomes (4:1,3-dimethyluric acid: 1-methylxanthine at 2 mM theophylline). High concentrations of fluoroquinolones (0.5-1.5 mM) were required to affect microsomal theophylline metabolism. 1-Methylxanthine was more sensitive to fluoroquinolone inhibition by enoxacin, ciprofloxacin, norfloxacin and pipemidic acid than 1,3-dimethyluric acid; CP67015, had a significant effect on 1,3-dimethyluric acid production only; binfloxacin had no effect on either pathway. 3. Ethoxycoumarin, a rapidly metabolized substrate, was also investigated as a surrogate for theophylline in in vitro experiments. Fluoroquinolone inhibition of ethoxycoumarin O-de-ethylation in beta-naphthoflavone-induced microsomes was quantitatively greater but qualitatively similar to theophylline metabolism (IC50s 440-870 microM at 2 microM 7-ethoxycoumarin). 4. These data are comparable with previous rat experiments in vivo, indicating that enoxacin, ciprofloxacin and norfloxacin have similar intrinsic activity in the inhibition of theophylline metabolism.
mesh_terms: D000818:Animals; D000890:Anti-Infective Agents / Q000737:chemistry / Q000494:pharmacology*; D001571:Benzoflavones / Q000494:pharmacology; D003374:Coumarins / Q000378:metabolism; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D015365:Enoxacin / Q000494:pharmacology; D066298:In Vitro Techniques; D008297:Male; D008862:Microsomes, Liver / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013806:Theophylline / Q000378:metabolism*; D014527:Uric Acid / Q000031:analogs & derivatives / Q000378:metabolism; D014970:Xanthines / Q000378:metabolism; D019324:beta-Naphthoflavone
chemical_list: D000890:Anti-Infective Agents; D001571:Benzoflavones; D003374:Coumarins; D014970:Xanthines; D014527:Uric Acid; C017299:7-ethoxycoumarin; D015365:Enoxacin; D019324:beta-Naphthoflavone; C053085:1-methylxanthine; D003577:Cytochrome P-450 Enzyme System; D013806:Theophylline; C031274:1,3-dimethyluric acid