SELECTIVE INVITRO INHIBITION OF HEPATIC OXIDATIVE-METABOLISM BY QUINOLONES - 7-ETHOXYRESORUFIN AND CAFFEINE AS MODEL SUBSTRATES

The in-vitro inhibition of several metabolic pathways has been studied in 3-methylcholanthrene-treated rats. The specificity of the 7-ethoxyresorufin O-de-ethylase reaction has been determined in the presence and absence of ciprofloxacin, enoxacin, norfloxacin, ofloxacin, nalidixic acid, oxolinic acid and pipemidic acid. For the caffeine N3-demethylation reaction, enoxacin and pipemidic acid were used. Enoxacin (IC50 = 105-mu-M, K(i) = 65-mu-M) and pipemidic acid (IC50 = 115-mu-M, K(i) = 160-mu-M) significantly inhibited 7-ethoxyresorufin O-de-ethylase reaction and caffeine N3-demethylation (IC50 = 60-mu-M for enoxacin and IC50 = 185-mu-M for pipemidic acid) by a competitive mechanism. Other quinolones had lower or no (ofloxacin) inhibitory capacity. The order of inhibitory activity observed is in agreement with results obtained previously from in-vivo studies in man. No activity was detected towards ethylmorphine N-demethylation.