The reciprocal effects on pharmacokinetic parameters after a single oral dose of the nonsteroidal antiinflammatory drugs (NSAIDs) indomethacin and sulindac and repeated oral doses of the H2-receptor antagonists cimetidine and ranitidine were determined in two groups of nine healthy subjects each (indomethacin and sulindac groups). Administration of NSAIDs increased the AUC and decreased the oral clearance and apparent volume of distribution of the H2-receptor antagonists without modifying their t1/2. Urinary data and observed modifications in ranitidine and cimetidine metabolites seem to justify a greater increase of H2-receptor antagonist bioavailability with indomethacin (p less than 0.05) than with sulindac (NS). The administration of ranitidine significantly reduced the sulindac volume of distribution without modifying its clearance, which caused an increase in the maximum concentration and a decrease in the t1/2 (p less than 0.05). The effects of cimetidine on the two NSAIDs were more intense than the effect of ranitidine: the decrease in sulindac volume of distribution (p less than 0.02) was accompanied by a significant reduction in sulindac clearance (p less than 0.05). AUC and urinary amounts of sulindac's sulfone metabolite were decreased. These results show that NSAIDs increased the bioavailability of H2-receptor antagonists, and that the latter drugs decrease the volume of distribution of NSAIDs. Furthermore, cimetidine modifies the oxidation metabolism of sulindac.