Effects of Other Drugs on Phenytoin

Phenytoin is one of the most commonly prescribed antiepileptic drugs in both acute and chronic settings; its use has been extensively described. Nevertheless, interactions between phenytoin and numerous other drugs continue to complicate seizure therapy; these have been documented in case reports, studies, textbooks, and epilepsy reviews.

The narrow therapeutic window of phenytoin (total serum levels, 10 to 20 µg/mL; free levels, 1 to 2 µg/mL) increases the risk of clinically significant drug interactions. Neurotoxicities are the most frequent adverse events associated with supratherapeutic levels. Nystagmus, seizures, and ataxia are the most common of these; rarely, serious events such as psychosis, delirium, and coma have been reported.^1,2 Although some references list specific phenytoin levels for certain adverse events, these cannot be relied on completely because of interpatient variability.

Interpretation of total serum phenytoin levels in the presence of confounding conditions, such as hypoalbuminemia and azotemia, can be misleading. Free serum concentrations are recommended for determining actual phenytoin concentrations.³

Here we focus on the effect that commonly prescribed drugs have on phenytoin disposition and review other variables that influence phenytoin dosing and administration. We also address how to recognize and managepotential drug interactions. In a future issue, we will discuss the effect of phenytoin on the disposition of other drugs.

Metabolism (hepatic induction/inhibition). Phenytoin is metabolized by cytochrome P (CYP)-450 isoenzymes CYP 2C9 and CYP 2C19. CYP 2C9 is the major enzyme involved (responsible for 70% to 90% of phenytoin metabolism).^4,5 Ingestion of drugs that compete for this enzyme system or inhibit it can result in increased phenytoin concentrations that require additional monitoring and a reduction in the phenytoin dose. 

Phenytoin induces CYP isoenzymes CYP 2C, CPY 2D, and CYP 3A subfamilies and UDP-glucuronosyltransferase.⁶ Drugs metabolized by this route will undergo increased metabolic clearance and decreased efficacy.

Metabolic states of altered phenytoin metabolism include pregnancy, fever, and trauma; these states are associated with increased clearance of the drug.^7-10 Polymorphisms have been identified in the isoenzymes involved in metabolism of phenytoin, with variable effects.¹¹

Protein binding. Phenytoin is highly protein-bound to albumin.¹² Drugs that have an affinity for the phenytoin binding site on albumin may displace phenytoin. Hypoalbuminemic patients have fewer phenytoin binding sites, which may result in elevated phenytoin levels. Such conditions as malnutrition and renal disease affect the protein binding of phenytoin and require special equations for correction of total phenytoin levels.^13,14

Known displacers of protein-bound drugs include sulfonamides, valproic acid, and salicylates.^15-17 Although this displacement results in an increased total serum phenytoin concentration, it does not always produce a clinically significant interaction, because free phenytoin levels may remain normal. Drawing free phenytoin levels will determine the significance of the displacement.

Nutrition. Administration of phenytoin with enteral tube feedings decreases absorption.^18-20 This reduction in bioavailability can be minimized by withholding tube feedings 2 hours before and after the phenytoin dose; the phenytoin dose may also need to be increased. Alternatively, changing to the intravenous route of phenytoin administration will circumvent the interaction.

Replacement of folic acid increases phenytoin clearance.²¹ Folate supplementation decreases serum levels of phenytoin by as much as 48%.^22-24 Although other studies have reported variable results in phenytoin levels, supplementation should be individualized and serum concentrations should be carefully monitored.

Monitoring the effect of other drugs on phenytoin disposition primarily involves measurement of serum concentrations, especially during the periods when potentially interacting drugs are added or discontinued. Monitoring for signs of phenytoin toxicity and loss of seizure control is also important. When possible, circumvention of phenytoin drug interactions is preferable.

An understanding of phenytoin metabolism can shed light on potential interactions with concomitantly administered drugs. Awareness of the inhibition and induction potential of concurrent therapy will allow conscious expectations of phenytoin clearance and serve as a valuable tool both for preventing drug interactions and interpreting them correctly when they occur.