INCREASED GASTRIC PH AND THE BIOAVAILABILITY OF FLUCONAZOLE AND KETOCONAZOLE

In a randomized, four-way crossover study, the effect of increased gastric pH on the relative bioavailability of fluconazole, 200mg, and ketoconazole, 400mg, was assessed in 24 male volunteers. Gastric pH was titrated to 6.0 with intravenous cimetidine and continuously monitored using Heidelberg radiotelemetry capsules. There was a highly significant decrease in the ketoconazole area under the curve, from 34.1 μg · h/mL in the absence of cimetidine to 1.7 μg · h/mL in the presence of cimetidine. The mean maximum ketoconazole concentrations were 7.01 μg/mL in the absence of cimetidine and 0.48 μg/mL in the presence of cimetidine. Time of peak was not affected by pH in the ketoconazole treatment phase. In subjects treated with fluconazole, maximum concentration, time to maximum concentration, and area under the curve were all unaltered by gastric pH. When the gastric pH was maintained (using cimetidine) at a value greater than 6.0, there was a 95% reduction in the relative bioavailability of ketoconazole, whereas fluconazole bioavailability was independent of gastric pH.