Effects of enoxacin on renal and metabolic clearance of theophylline in rats.

The effects of enoxacin and its metabolite 4-oxoenoxacin on the disposition of theophylline were investigated in rats. Systemic clearance of theophylline was significantly decreased by approximately 40, 46, and 50% after oral coadministration of 25, 100, and 200 mg of enoxacin per kg, respectively. No significant changes in the volume of distribution of theophylline were observed. 4-Oxoenoxacin had no direct effect on theophylline disposition. Significant changes in urinary excretion of theophylline and its metabolites were observed. (i) Urinary excretion of unchanged theophylline was significantly increased in proportion to increases in enoxacin dosage. (ii) Decreases in renal clearance of theophylline and metabolic clearance of 1-methyluric acid and 1,3-dimethyluric acid were observed. (iii) The percent decreases in the metabolic clearance of 1-methyluric acid were dependent on enoxacin dosage. It is likely that enoxacin inhibits the elimination process, which depends on cytochrome P-450-mediated isozymes for N demethylation and oxidation, and that the capacity of the inhibitory effect of enoxacin is greater in the N-demethylation pathway than it is in oxidation.