Absorption of ketoconazole is impaired in subjects with an increased gastric pH due to administration of antacids, H2-receptor antagonists, proton pump inhibitors, or the presence of hypochlorhydria. Sucralfate could provide an attractive alternative in patients receiving ketoconazole who require therapy for acid-peptic disorders. Twelve healthy human volunteers were administered a single 400-mg oral dose of ketoconazole in each of three randomized treatment phases. In phase A, ketoconazole was administered orally with 240 ml of water. In phase B, ketoconazole and sucralfate (1.0 g) were administered simultaneously with 240 ml of water. In phase C, ketoconazole was administered with 240 ml of water 2 h after administration of sucralfate (1.0 g) orally with 240 ml of water. A 680-mg oral dose of glutamic acid hydrochloride was administered 10 min prior to and with each dose of ketoconazole, sucralfate, or ketoconazole plus sucralfate. Simultaneous administration of ketoconazole and sucralfate led to a significant reduction in the area under the concentration-time curve and maximal concentration of ketoconazole in serum (78.12 ± 12.20 versus 59.32 ± 13.61 ,ug * h/ml and 12.34 ± 3.07 versus 8.92 ± 2.57 ,ug/ml, respectively; P < 0.05). When ketoconazole was administered 2 h after sucralfate, the observed ketoconazole area under the concentration-time curve was not significantly decreased compared with that of ketoconazole alone. The time to maximal concentrations in serum and the ketoconazole elimination rate constant were not significantly different in any of the three treatment phases. In patients receiving concurrent administration of ketoconazole and sucralfate, doses should be separated by at least 2 h.Ketoconazole is a dibasic oral antifungal agent with a pKal of 6.51 and a PKa2 of 2.94. Thus, ketoconazole is virtually insoluble in neutral or slightly acidic solutions (4, 30). Predictably, absorption of ketoconazole is impaired in subjects with an increased gastric pH due to the administration of antacids, H2-receptor antagonists, or the presence of achlorhydria (2,16,17,25,28).Frequently, patients receiving ketoconazole also require therapy for the treatment or prevention of acid-peptic disorders. Because sucralfate does not increase gastric pH as efficiently as antacids or antisecretory agents, it provides an attractive alternative in this setting (10, 22). However, simultaneous administration with sucralfate results in a significant decrease in the oral bioavailability of phenytoin or fluoroquinolone antibiotics (11,13,27,29). The interaction between sucralfate and ciprofloxacin can be minimized by administration of ciprofloxacin 2 h prior to or 6 h after administration of sucralfate (29).We studied the in vitro interaction between ketoconazole and sucralfate in acidified solutions with various pHs. A marked decrease in the concentration of ketoconazole was observed following the addition of sucralfate (14). On the basis of these in vitro studies, we undertook a pharmacokinetic study with 12 healthy human v...