To investigate whether sulindac once daily in the evening might be equivalent to the currently recommended twice-daily dose schedule in sustaining plasma concentrations of bioactive sulfide metabolite, 12 healthy subjects received, in a randomized crossover study, sulindac, 200 mg b.i.d. (at 9:00 A.M. and 9:00 P.M.) and 400 mg once daily (at 9:00 P.M.), each for 7 days. At steady state the area under the plasma concentration-time curve (AUC) over 24 hr for sulfide metabolite was greater after once-daily dosing (112 and 84 micrograms . hr . ml-1, P less than 0.05), while mean trough concentrations did not differ. The greater AUC seemed to be related to diurnal variation in metabolite cumulation. A circadian rhythm was apparent at steady state during twice-daily dosing; the mean AUC and peak plasma concentration (C(max)) were greater between 9 A.M. and 9 P.M. than between 9 P.M. and 9 A.M. (50 and 34 micrograms . hr . ml-1; 6.85 and 4.23 micrograms/ml). Although C(max) values of sulfide were higher after morning doses of sulindac, it was apparent that much of the plasma sulfide after morning doses was actually derived from the previous evening dose. This may be a consequence of circadian rhythm in gallbladder emptying. While renal clearance of sulindac was related to urinary pH, diurnal changes in urinary acidity did not cause the fluctuations in the plasma sulfide. Since once-daily sulindac in the evening is as, if not more, effective than twice-daily drug in sustaining plasma sulfide levels, further studies on the therapeutic efficacy of once-daily dosing are warranted.