Structure-related inhibitory effect of antimicrobial enoxacin and derivatives on theophylline metabolism by rat liver microsomes.
Enoxacin, an antimicrobial fluoroquinolone with a 7-piperazinyl-1, 8-naphthyridine skeleton, is a potent inhibitor of cytochrome P-450-mediated theophylline metabolism. The present study was designed to clarify, using seven enoxacin derivatives, the molecular characteristics of the fluoroquinolone responsible for the inhibition. Three derivatives with methyl-substituted 7-piperazine rings inhibited rat liver microsomal theophylline metabolism to 1,3-dimethyluric acid to an extent similar to that of enoxacin (50% inhibitory concentrations [IC50s] = 0.39 to 0.48 mM). 7-Piperazinyl-quinoline derivatives, 8-hydroenoxacin (8-Hy) and 1-cyclopropyl-8-fluoroenoxacin (8-F1), which have a hydrogen and a fluorine at position 8, respectively, more weakly inhibited metabolite formation (IC50s = 0.88 and 1.29 mM, respectively). Little inhibition (IC50 > 2 mM) was observed in those with 3'-carbonyl and 4'-N-acetyl groups on the piperazine rings. The substrate-induced difference spectra demonstrated that the affinities of enoxacin, 8-Hy, and 8-F1 to cytochrome P-450 were parallel with their inhibitory activities. The substituent at position 8 was found to determine the molecular conformations of the fluoroquinolones, and the planarity in molecular shape decreased in the same order as the inhibitory activity (enoxacin > 8-Hy > 8-F1). Moreover, the 3'-carbonyl and 4'-N-acetyl groups decreased the basicity of their vicinal 4'-nitrogen atoms when judged from their electrostatic potentials, which showed a remarkably broadened negative charge around the nitrogens. As a result, the planarity of the whole molecule and the basicity of the 4'-nitrogen atom of enoxacin are likely to be dominant factors in the inhibition of theophylline metabolism by cytochrome P-450.
Mizuki
Y
Y
Department of Pharmacokinetics, Dainippon Pharmaceutical Co., Ltd., Osaka, Japan.
Fujiwara
I
I
Yamaguchi
T
T
Sekine
Y
Y
D000818:Animals; D000890:Anti-Infective Agents / Q000494:pharmacology*; D018360:Crystallography, X-Ray; D004563:Electrochemistry; D015365:Enoxacin / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology*; D008297:Male; D008748:Methylcholanthrene / Q000494:pharmacology; D008862:Microsomes, Liver / Q000187:drug effects / Q000378:metabolism*; D008968:Molecular Conformation; D015394:Molecular Structure; D051381:Rats; D017208:Rats, Wistar; D013056:Spectrophotometry, Ultraviolet; D013329:Structure-Activity Relationship; D013806:Theophylline / Q000378:metabolism*; D014527:Uric Acid / Q000031:analogs & derivatives / Q000378:metabolism
D000890:Anti-Infective Agents; D014527:Uric Acid; D015365:Enoxacin; D008748:Methylcholanthrene; D013806:Theophylline; C031274:1,3-dimethyluric acid