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Steady-state interaction between amiodarone and phenytoin in normal subjects
P E Nolan1, B L Erstad, G L Hoyer
1Department of Pharmacy Practice, College of Pharmacy, University of Arizona, Tucson 85721.
The American Journal of Cardiology
|May 15, 1990
Summary
Amiodarone significantly increases phenytoin levels by reducing its metabolism, leading to higher drug concentrations. This pharmacokinetic interaction necessitates at least a 25% dose reduction of phenytoin when used with amiodarone.
Area of Science:
- Pharmacology
- Drug Interactions
- Clinical Pharmacokinetics
Background:
- Amiodarone is known to elevate phenytoin serum levels.
- The pharmacokinetic mechanisms underlying this drug interaction require elucidation, especially at steady-state conditions.
Purpose of the Study:
- To investigate the pharmacokinetic basis of the amiodarone-phenytoin interaction at steady-state.
- To quantify changes in phenytoin pharmacokinetics during concurrent amiodarone administration.
Main Methods:
- Seven healthy male subjects received oral phenytoin (2-4 mg/kg/day) for 14 days.
- Pharmacokinetic parameters of phenytoin were assessed before and after a 6-week course of oral amiodarone (200 mg/day).
- Phenytoin metabolism was indirectly assessed by measuring urinary excretion of its primary metabolite.
Main Results:
- Amiodarone significantly increased phenytoin's area under the concentration-time curve (208 to 292 mg.hr/liter) and peak concentrations (10.75 to 14.26 µg/ml).
- Oral clearance of phenytoin decreased from 1.29 to 0.93 L/hr due to reduced metabolism, evidenced by lower metabolite excretion.
- The unbound fraction of phenytoin remained unchanged, indicating the interaction primarily affects metabolism, not protein binding.
Conclusions:
- Amiodarone significantly alters phenytoin pharmacokinetics at steady-state, primarily by inhibiting its metabolism.
- Concurrent administration of amiodarone necessitates a reduction in phenytoin dosage by at least 25%.
- Clinical monitoring and therapeutic drug level monitoring are crucial when adjusting phenytoin doses during amiodarone therapy.