Displacement of phenytoin from plasma binding sites by salicylate

Six healthy male subjects received phenytoin sodium as 9 100-mg capsules alone or with aspirin in a randomized, crossover fashion. Aspirin, 975 mg every 6 hr, was started 22 hr before a phenytoin dose and continued for an additional 48 hr during blood sampling. Mean 4-hr plasma salicylate levels ranged from 104 to 157 micrograms/ml during the sampling period. Individual mean values for the free fraction of salicylate varied from 0.107 to 0.167. The fraction of free phenytoin in plasma rose from 0.128 +/- 0.004 to 0.163 +/- 0.009 when aspirin was given (p less than 0.001). Subjects had lower total phenytoin 48-hr area under the curve (AUC) values when on aspirin (323 +/- 36 without and 261 +/- 49 micrograms . hr . ml-1 with aspirin; p less than 0.001) but free phenytoin AUC values were unchanged (41.4 +/- 4.5 and 42.4 +/- 9.0 micrograms . hr . ml-1; p less than 0.5). Thus, more rapid clearance of total phenytoin probably compensated for salicylate displacement of phenytoin from plasma protein binding sites. Total phenytoin levels for therapeutic monitoring must be interpreted cautiously when patients also receive salicylate.