Effect of Oral Antacid Administration on the Pharmacokinetics of Oral Fluconazole

Abstract

Absorption and elimination of fluconazole after oral administration of a 100-mg capsule were unaffected by concomitant administration of an antacid containing aluminum and magnesium hydroxides.Fluconazole is a new bis-triazole which has shown good antifungal activity in animal models of fungal infection (4) and in clinical studies of vaginal candidiasis (1, 9), oropharyngeal candidiasis in patients with acquired immunodeficiency syndrome and malignancies (3), and dermatophyte infections (10).As well as having good absorption after oral administration (>95% bioavailability), fluconazole has a long half-life (25 to 30 h) in plasma and exhibits low protein binding (12%). Fluconazole is excreted mainly unchanged in the urine (2).Optimal absorption of ketoconazole after oral administration has been shown to require normal gastric acidity. It has been postulated that the low aqueous solubility of ketoconazole in mildly acidic or neutral conditions is the reason for this impaired absorption in patients with hypochlorhydria, and this was later verified with volunteers (12). Fluconazole, a less lipophilic, more weakly basic bis-triazole derivative, is water soluble in both neutral and acidic conditions and may not, therefore, be subject to the same limitations in gastrointestinal absorption. However, a significant proportion of patients who suffer from fungal infections do have impaired gastric acidity, whether it be from gastric secretory failure in patients with acquired immunodeficiency syndrome (6) postadministration. Blood samples (8 ml) were withdrawn immediately before and 1, 2,4,6,8,12, 24, 36, 48, 72, 96, 120, and 144 h after administration of each fluconazole dose. Plasma from each sample was separated, frozen at -20°C, and stored until assay at Biosciences by a gas chromatographic method for which the limit of detection was 0.1 ,ug/ml (13). Standard calibration curves established with samples with concentrations of 0.1 to 5 jig/ml during the study to control the linearity and accuracy of the method had relative standard deviations which varied from 2.4 to 5.4%. Replicate assays (n = 6) on samples with concentrations of 0.25 and 4 ,ug/ml had relative standard deviations of 5.9 and 2.6%, respectively.

Antifungal Agents

“…It demonstrates high bioavailability, approximately 90%, and its absorption is not affected by gastric acidity or food. 6,95,96 Currently, there are 2 oral formulations, a tablet and a powder for suspension, and an intravenous solution. The recommended dosages are not affected by the route of administration (see Table 2).…”

Fluconazole for the treatment of onychomycosis: an update

“…Its bioavailability when taken orally is at least 90%. It is important to note that the absorption of orally administered fluconazole is not reduced in the presence of antacids, 12 , 13 by the concurrent intake of a histamine‐2 receptor (H 2 ‐receptor) antagonist, 14 , 15 or in patients who experience frequent vomiting 16 . Fluconazole has a relatively low lipophilicity and distributes widely to body tissues and fluids 17 .…”

Drug Interactions with Fluconazole

“…More recently, the effect of an antacid on the pharmacokinetics of oral fluconazole was evaluated. 33 On two occasions (2 weeks apart) 14 healthy male volunteers were randomly assigned to receive fluconazole 100 mg alone or immediately following a 20-ml dose of antacid (aluminum hydroxide 1800 mg plus magnesium hydroxide 1200 mg). Maximum concentration, time to maximum concentration, AUCo, , , and the elimination rate constant were determined.…”