THE POSSIBLE MECHANISM OF INTERACTION BETWEEN XANTHINES AND QUINOLONE

Abstract— To clarify the mechanism of interaction between theophylline and enoxacin, the effects of enoxacin and its metabolite, 4‐oxo‐enoxacin, on the disposition of new xanthine derivatives, 1‐methyl‐3‐propylxanthine (MPX) and 3‐propylxanthine (enprofylline), as models of theophylline have been investigated in rats. Pretreatment with enoxacin significantly delayed the elimination of MPX from plasma. No significant change in the volume of distribution of MPX was observed in the presence of enoxacin, but the total body clearance of MPX was significantly decreased by approximately 60 and 80% after pretreatment with 25 and 100 mg kg−1 of enoxacin, respectively. The amount of the decrease in total body clearance depended on the dose of enoxacin. 4‐Oxo‐enoxacin had little or no effect on MPX disposition. A newly developed quinolone, NY‐198, which does not affect the disposition of theophylline, also did not affect the disposition of MPX. Enoxacin also had no effect on the disposition of enprofylline. These results indicate that the mechanism for decrease in theophylline clearance induced by enoxacin may not be due to its metabolite, 4‐oxo‐enoxacin, but to enoxacin itself, and that enoxacin does not inhibit solely the elimination process depending on cytochrome P450 isoenzyme for N‐demethylation. It is likely that enoxacin has no influence on the renal excretion of xanthines. 1990 Royal Pharmaceutical Society of Great Britain