Selective in-vitro inhibition of hepatic oxidative metabolism by quinolones: 7-ethoxyresorufin and caffeine as model substrates

J Pharm Pharmacol. 1991 Jan;43(1):17-21. doi: 10.1111/j.2042-7158.1991.tb05440.x.

Abstract

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 microM, Ki = 65 microM) and pipemidic acid (IC50 = 115 microM, Ki = 160 microM) significantly inhibited 7-ethoxyresorufin O-de-ethylase reaction and caffeine N3-demethylation (IC50 = 60 microM for enoxacin and IC50 = 185 microM 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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 4-Quinolones
  • Animals
  • Anti-Infective Agents / pharmacology*
  • Caffeine / metabolism*
  • Cytochrome P-450 CYP1A1
  • Cytochrome P-450 Enzyme Inhibitors
  • Kinetics
  • Male
  • Methylcholanthrene / pharmacology
  • Microsomes, Liver / drug effects*
  • Microsomes, Liver / enzymology
  • Oxazines / metabolism*
  • Oxidation-Reduction
  • Oxidoreductases / antagonists & inhibitors
  • Rats
  • Rats, Inbred Strains

Substances

  • 4-Quinolones
  • Anti-Infective Agents
  • Cytochrome P-450 Enzyme Inhibitors
  • Oxazines
  • Caffeine
  • Methylcholanthrene
  • ethoxyresorufin
  • Oxidoreductases
  • Cytochrome P-450 CYP1A1