Steady-state interaction between amiodarone and phenytoin in normal subjects

Amiodarone has been reported to increase phenytoin levels. This study was designed to evaluate the pharmacokinetic basis of this interaction at steady-state. Pharmacokinetic parameters for phenytoin were determined after 14 days of oral phenytoin, 2 to 4 mg/kg/day, before and after oral amiodarone, 200 mg daily for 6 weeks in 7 healthy male subjects. During amiodarone therapy, area under the serum concentration time curve for phenytoin was increased from 208 +/- 82.8 (mean +/- standard deviation) to 292 +/- 108 mg.hr/liter (p = 0.015). Both the maximum and 24-hour phenytoin concentrations were increased from 10.75 +/- 3.75 and 6.67 +/- 3.51 micrograms/ml to 14.26 +/- 3.97 (p = 0.016) and 10.27 +/- 4.67 micrograms/ml (p = 0.012), respectively, during concomitant amiodarone treatment. Amiodarone caused a decrease in the oral clearance of phenytoin from 1.29 +/- 0.30 to 0.93 +/- 0.25 liters/hr (p = 0.002). These results were due to a reduction in phenytoin metabolism by amiodarone as evidenced by a decrease in the urinary excretion of the principal metabolite of phenytoin, 5-(p-hydroxyphenyl)-5-phenylhydantoin, 149 +/- 39.7 to 99.3 +/- 40.0 mg (p = 0.041) and no change in the unbound fraction of the total phenytoin concentration expressed as a percentage, 10.3 +/- 2.7 versus 10.7 +/- 2.1% (p = 0.28) during coadministration of amiodarone. The alterations in phenytoin pharmacokinetics suggest that steady-state doses of phenytoin of 2 to 4 mg/kg/day should be reduced at least 25% when amiodarone is concurrently administered. All dosage reductions should be guided by clinical and therapeutic drug monitoring.