OBJECTIVE To evaluate the potential effect of fluoxetine, a cytochrome P450 isoenzyme inhibitor, on prednisolone disposition and cortisol suppression. METHODS Sequential, two-phase, crossover, open-label pharmacokinetic study. METHODS General clinical research center. METHODS Fourteen healthy volunteers. METHODS A single intravenous dose of prednisolone 40 mg before and after 14 days of treatment with fluoxetine 20 mg/day for 5 days followed by 60 mg/day for 9 days to achieve steady-state concentrations. RESULTS Pharmacokinetic parameters of the prednisolone and resulting pharmacodynamic effects on the time course of plasma cortisol suppression before and after fluoxetine administration were evaluated. No significant differences were observed for the mean +/- SD area under the prednisolone concentration-time curve (3739 +/- 992 vs 3498 +/- 797 microg x hr/L, respectively), clearance (8.58 +/- 2.62 vs 8.92 +/- 2.05 L/hr, respectively), volume of distribution (39.5 +/- 12.4 vs 38.2 +/- 9.9 L, respectively), elimination half-life (3.32 +/- 0.83 vs 3.05 +/- 0.80 hrs, respectively), or duration of plasma cortisol suppression (23.5 +/- 3.1 vs 22.0 +/- 4.2 hrs, respectively). CONCLUSIONS Fluoxetine administration did not significantly affect prednisolone disposition or prolong cortisol suppression. This finding suggests that coadministration of these agents is unlikely to result in clinically important pharmacokinetic or pharmacodynamic drug interactions. Prednisolone may be a useful alternative for patients who require both glucocorticoid and fluoxetine therapy.