Metabolism of theophylline and its inhibition by fluoroquinolones in rat hepatic microsomes

Abstract

1. The effects of β-naphthoflavone, dexamethasone, phenobarbitone and isosafrole on the metabolism of theophylline by rat liver microsomes have been studied. Only β-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. β-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 2mM 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 β-naphthoflavone-induced microsomes was quantitatively greater but qualitatively similar to theophylline metabolism (IC_50S 440–870μM at 2μM 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.