Steady-state interaction between amiodarone and phenytoin in normal subjects

Paul E. Nolan, Brian L Erstad, Gifford L. Hoyer, Marla Bliss, Kathleen Gear, Frank I. Marcus

Research output: Contribution to journalArticle

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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.

Original languageEnglish (US)
Pages (from-to)1252-1257
Number of pages6
JournalThe American journal of cardiology
Volume65
Issue number18
DOIs
StatePublished - May 15 1990

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Amiodarone
Phenytoin
Pharmacokinetics
Drug Monitoring
Healthy Volunteers

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine

Cite this

Steady-state interaction between amiodarone and phenytoin in normal subjects. / Nolan, Paul E.; Erstad, Brian L; Hoyer, Gifford L.; Bliss, Marla; Gear, Kathleen; Marcus, Frank I.

In: The American journal of cardiology, Vol. 65, No. 18, 15.05.1990, p. 1252-1257.

Research output: Contribution to journalArticle

Nolan, Paul E. ; Erstad, Brian L ; Hoyer, Gifford L. ; Bliss, Marla ; Gear, Kathleen ; Marcus, Frank I. / Steady-state interaction between amiodarone and phenytoin in normal subjects. In: The American journal of cardiology. 1990 ; Vol. 65, No. 18. pp. 1252-1257.
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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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