Steady-state interaction between amiodarone and phenytoin in normal subjects

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Abstract

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 dairy 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 μg/ml to 14.26 ± 3.97 (p = 0.016) and 10.27 ± 4.67 μg/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.

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    This work was supported in part by grants from the American Heart Association, Arizona Affiliate, Phoenix, Arizona; the Flinn Foundation, Phoenix; the Gustavus and Louise Pfeiffer Research Foundation, Santa Monica, California; the Stanley Trust, Phoenix; and Sanofi Pharmaceuticals, Inc., New York, New York.

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