EFFECT OF FLUCONAZOLE ON THEOPHYLLINE DISPOSITION IN HUMANS

The effect of fluconazole, an antimycotic that inhibits cytochrome P-4 50-mediated drug metabolism, on theophylline kinetics and the producti on of its metabolites were compared with those of enoxacin in 5 health y subjects. All subjects received a single oral dose of 240 mg theophy lline (aminophylline, 300 mg) after they had been given oral fluconazo le 100 mg every 12 h or enoxacin 200 mg every 8 h for three consecutiv e days. Pretreatment with enoxacin decreased the total clearance (CL(T )) and elimination rate constant (K-el) of theophylline by 50 % and 46 %, respectively, without changing the volume of distribution (V-d), b ut there were no significant change in any pharmacokinetic parameter w hen fluconazole was administered. Enoxacin led to a 50 % reduction in the metabolic clearance (CL(M)) of theophylline and to decreases of 69 %, 59 % and 38 % in the formation clearance of the three theophylline metab elites, 3-methylxanthine (3-MX), 1-methyluric acid (1-MU), and 1,3-dimethyluric acid (1,3-DMU), respectively, accompanied by signific ant changes in the urinary recovery of theophylline and its metabolite s. In contrast, treatment with fluconazole led only to a slight decrea se in the CL, of theophylline (16 %) and in the formation clearance of its metabolites (15 % - 18 %), and there was no change in the renal c learance (CL(R)) of theophylline. The results indicate that fluconazol e is a minor inhibitor of theophylline disposition compared with enoxa cin, and they suggest that the inhibitory action of fluconazole is sel ective for certain cytochrome P-450 isozymes, but not for the cytochro me P-4501A involved in theophylline metabolism.