Effect of fluconazole on theophylline disposition in humans.
The effect of fluconazole, an antimycotic that inhibits cytochrome P-450-mediated drug metabolism, on theophylline kinetics and the production of its metabolites were compared with those of enoxacin in 5 healthy subjects. All subjects received a single oral dose of 240 mg theophylline (aminophylline, 300 mg) after they had been given oral fluconazole 100 mg every 12 h or enoxacin 200 mg every 8 h for three consecutive days. Pretreatment with enoxacin decreased the total clearance (CLT) and elimination rate constant (Kel) of theophylline by 50% and 46%, respectively, without changing the volume of distribution (Vd), but there were no significant change in any pharmacokinetic parameter when fluconazole was administered. Enoxacin led to a 50% reduction in the metabolic clearance (CLM) of theophylline and to decreases of 69%, 59% and 38% in the formation clearance of the three theophylline metabolites, 3-methylxanthine (3-MX), 1-methyluric acid (1-MU), and 1,3-dimethyluric acid (1,3-DMU), respectively, accompanied by significant changes in the urinary recovery of theophylline and its metabolites. In contrast, treatment with fluconazole led only to a slight decrease in the CLM of theophylline (16%) and in the formation clearance of its metabolites (15%-18%), and there was no change in the renal clearance (CLR) of theophylline. The results indicate that fluconazole is a minor inhibitor of theophylline disposition compared with enoxacin, and they suggest that the inhibitory action of fluconazole is selective for certain cytochrome P-450 isozymes, but not for the cytochrome P-4501A involved in theophylline metabolism.
Department of Hospital Pharmacy, Shiga University of Medical Science, Ohtsu, Japan.
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H
Konishi
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Morita
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Yamaji
D000328:Adult; D018592:Cross-Over Studies; D015365:Enoxacin / Q000008:administration & dosage / Q000494:pharmacology*; D005260:Female; D015725:Fluconazole / Q000008:administration & dosage / Q000494:pharmacology*; D006801:Humans; D008297:Male; D008657:Metabolic Clearance Rate; D013806:Theophylline / Q000097:blood / Q000493:pharmacokinetics* / Q000652:urine; D014527:Uric Acid / Q000031:analogs & derivatives / Q000378:metabolism; D014970:Xanthines / Q000378:metabolism
D014970:Xanthines; D014527:Uric Acid; C030530:1-methyluric acid; D015365:Enoxacin; D015725:Fluconazole; D013806:Theophylline; C031274:1,3-dimethyluric acid; C029703:3-methylxanthine