To determine the mechanism of the amiodarone-phenytoin interaction, seven healthy male subjects were given intravenous phenytoin, 5 mg/kg, before (phase I) and after (phase II) 3 weeks of oral amiodarone, 200 mg/day. Serum AUC increased from 245 +/- 37.6 to 342 +/- 87.3 mg.hr/L (p = 0.007); area under the first moment curve increased from 5666 +/- 1003 to 11,632 +/- 4198 mg.hr2/L (p = 0.008); the time-averaged total body clearance decreased from 1.57 +/- 0.3 to 1.17 +/- 0.33 L/hr (p = 0.0004); and the apparent elimination half-life increased from 16.1 +/- 1.32 to 22.6 +/- 3.8 hours (p = 0.001) for phenytoin during phase II. The volume of distribution at steady state and the unbound fraction for phenytoin remained unchanged. However, the formation of p-hydroxyphenytoin as a function of serum phenytoin concentration decreased during phase II. These findings suggest that amiodarone inhibits phenytoin metabolism. These observations also suggest that phenytoin doses will need to be reduced when coadministered with amiodarone. The magnitude of this reduction is difficult to predict because of the saturable pharmacokinetics of phenytoin, and therapeutic monitoring is recommended if amiodarone is added to the phenytoin regimen.