EFFECT OF ENOXACIN ON HEPATIC DRUG-METABOLIZING-ENZYMES - COMPARISON BETWEEN RAT AND MAN

In the present study, the effect of enoxacin (EX) on hepatic microsomal drug metabolizing enzymes was investigated in rat and man. Antipyrine (AP) and trimethadione (TMO) were used as model probes. No significant changes were observed in rat microsomal enzyme activities and contents of cytochrome P-450 by the single administration of EX (100 mg kg-1 200 mg kg-1). Treatment with EX (100 mg kg-1, tid) for 3 days resulted in the slight (15-24%) but significant increase in P-450 content (p < 0.01) and the activities of aniline hydroxylase (p < 0.05) and 7-ethoxycoumarin O-deethylase (p < 0.05). Single dose of EX decreased CL(AP) in a dose-related manner. About 30% decrease was observed for CL(AP) by the multiple administration of EX in rat. The changes in formation CL of AP metabolites by the multiple dose of EX in rat were as follows: about 53% decrease was seen for CL(HMA) (p < 0.01), while 155% increase was observed for CL(NORA) (P < 0.05), and no significant change in CL(OHA). EX had no effect on TMO metabolism in rat. In man there were significant changes in the AP pharmacokinetic parameters after EX treatment (200 mg, p.o., tid) for 3 days: the elimination constant (k) was significantly decreased (p < 0.01), t1/2 was prolonged by about two-fold (p < 0.001), AUC was increased by 93.8% (p < 0.001) and CL(AP) was decreased by 44.6% (p < 0.01). CL(HMA), CL(NORA) and CL(OHA) were all significantly decreased by 60.7% (p < 0.01), 38.3% (p < 0.01) and 60.2% (p < 0.01), respectively, after the EX treatment in man. On the metabolism of TMO, however, EX increased dimethadione (DMO)/TMO ratio from 0.57 +/- 0.05 to 1.06 +/- 0.04 (P < 0.001) in man. These results suggest that EX affects several P-450 enzymes in different manner such as inhibition and induction of P-450 isozymes and that characteristics of P-450 enzymes involved in AP and TMO metabolism are possibly different between rat and man.