Effect of Phenytoin on the Clinical Pharmacokinetics of Amiodarone

Five healthy male volunteers were given oral amiodarone hydrochloride, 200 mg per day for 6½ weeks, to determine its effects on the pharmacokinetics of both intravenous and oral phenytoin. Predose amiodarone and N‐desethylamiodarone serum concentrations were obtained weekly during weeks 2–6. Amiodarone serum concentrations (ASC) increased during weeks 2–4 and then decreased sharply during weeks 5–6 when oral phenytoin, 2–4 mg/kg/day, was co‐administered. In addition, N‐desethylamiodarone serum concentrations (DEASC) exceeded corresponding ASC during weeks 5–6 whereas during weeks 2–4, DEASC were less than ASC. Because of the long elimination half‐life for amiodarone previously reported in healthy volunteers after single doses of amiodarone and the frequent administration of amiodarone associated with this half‐life, a modified equation for a continuous infusion was used to describe each subject's ASC versus time data. Pre‐phenytoin ASC were fitted to an appropriate function to predict ASC during weeks 5–6 assuming no interaction. Observed versus predicted ASC were compared for weeks 5 and 6. Observed ASC during weeks 5 and 6 were (mean ± SD) 0.25 ± 0.09 μg/mL and 0.19 ± 0.07 μg/mL, respectively. Corresponding predicted ASC were 0.36 ± 0.12 μg/mL (P = .011) and 0.38 ± 0.13 μg/mL (P = .004). These represented percent differences of 32.2 ± 12.5% and 49.3 ± 5.6% for weeks 5 and 6, respectively. Assuming there were no changes in the bioavailability of amiodarone during continuous administration, these findings strongly suggest induction of amiodarone metabolism by phenytoin. The clinical significance of this interaction remains to be determined.