Selective in-vitro 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 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.
Department of Pharmacology and Toxicology, Institut Municipal d'Investigació Mèdica, Barcelona, Spain.
F
F
Valero
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R
de la Torre
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J
Segura
D042462:4-Quinolones; D000818:Animals; D000890:Anti-Infective Agents / Q000494:pharmacology*; D002110:Caffeine / Q000378:metabolism*; D019363:Cytochrome P-450 CYP1A1; D065607:Cytochrome P-450 Enzyme Inhibitors; D007700:Kinetics; D008297:Male; D008748:Methylcholanthrene / Q000494:pharmacology; D008862:Microsomes, Liver / Q000187:drug effects* / Q000201:enzymology; D010078:Oxazines / Q000378:metabolism*; D010084:Oxidation-Reduction; D010088:Oxidoreductases / Q000037:antagonists & inhibitors; D051381:Rats; D011919:Rats, Inbred Strains
D042462:4-Quinolones; D000890:Anti-Infective Agents; D065607:Cytochrome P-450 Enzyme Inhibitors; D010078:Oxazines; D002110:Caffeine; D008748:Methylcholanthrene; C007649:ethoxyresorufin; D010088:Oxidoreductases; D019363:Cytochrome P-450 CYP1A1