In a recently reported case, administration of omeprazole, a "proton pump" inhibitor, was temporally associated with the clinical relapse of pemphigus in a 44-year-old woman whose condition had been stabilized with a fixed dose of prednisone, suggesting the possibility of a drug interaction. This placebo-controlled, randomized, double-blind, three-period crossover study was conducted to evaluate and compare the pharmacokinetics of prednisolone after a single dose of prednisone given during multi-dose administration of lansoprazole or omeprazole. Lansoprazole (30 mg), omeprazole (40 mg), or placebo was administered once daily under fasted conditions for 7 days to healthy male volunteers. On the seventh day, a single dose of prednisone (40 mg) was administered concomitantly with the study medication, and plasma prednisolone concentrations were measured by high-performance liquid chromatography for 24 hours thereafter. Two weeks separated the first doses of each study period. Eighteen volunteers entered the study; pharmacokinetic data were evaluable for 15 participants. Safety data were evaluable for 16 participants in the lansoprazole/prednisone group; 17 in the omeprazole/ prednisone group; and 17 in the placebo/prednisone group. The pharmacokinetic parameters for prednisolone, including the maximum observed plasma concentration (Cmax), time to maximum plasma concentration (tmax), terminal-phase half-life (t1/2), and area under the concentration-time curve, were comparable for the three regimens. Adverse events (AEs) rated as possibly or probably drug related were reported by 50%, 24%, and 47% for subjects in the lansoprazole, omeprazole, and placebo treatment groups, respectively. Headache was the most common drug-related AE. No serious AEs were reported, and no subject withdrew from the study because of an AE. Concomitant administration of lansoprazole or omeprazole does not affect the absorption, biotransformation, or disposition of a single dose of prednisone. All three treatment regimens were well tolerated.