Phenytoin Drug Interactions: Effects of Phenytoin on Other Drugs

May 1, 2006

A focus on the known clinically significant drug-drug interactions of phenytoin.

Phenytoin is well known for causing clinically significant drug-drug interactions. In a previous issue (CONSULTANT, March 2006, page 365), we discussed drug interactions that affect the disposition of phenytoin. Here we focus on the potential effects of phenytoin on concomitant drug therapy.

MECHANISMS OF INTERACTION

Hepatic metabolism. The most common cause of drug interactions with phenytoin is induction of the cytochrome P-450 isoenzymes CYP2C, CYP2D, and CYP3A subfamilies and UDP-glucuronosyltransferase.1 Metabolism of drugs that are substrates for these isoenzymes can be enhanced, thereby decreasing their serum concentrations.

Protein binding. Displacement from protein-binding sites also plays a pivotal role. Phenytoin is 80% to 90% bound to albumin.2 A significant clinical interaction can occur when drugs with narrow therapeutic indexes and high protein binding are displaced from binding sites. Perhaps the most important example of this mechanism for phenytoin-drug interactions is an initial transient increase in the effect of warfarin.3

MANAGEMENT OF INTERACTIONS

Knowledge of the mechanism, time course, and magnitude of effect should guide the management of the interaction. Monitor clinical response and serum concentrations, when appropriate, and adjust the dosage accordingly. The Table lists commonly prescribed drugs that interact with phenytoin.

Table - Examples of drugs affected by phenytoin*

Drug Effect of phenytoin on drug

Theophylline Clearance increased by 45%

Carbamazepine Increased metabolism; decrease in plasma concentration to subtherapeutic range; carbamazepine may also decrease concentration of phenytoin; monitor concentrations of both drugs

Ethosuximide Increased metabolism, higher oral clearance, and slightly decreased volume of distribution

Warfarin Reports of biphasic reaction: an initial increase in activity, with subsequent decrease in hypoprothrombinemic effect

Corticosteroids Reported 45% decrease in serum concentrations of dexamethasone, methylprednisolone, and prednisone

Cyclosporine Dual mechanism: increased metabolism and reduced absorption; potential increased risk of organ rejection

Haloperidol Can result in a 40% to 72% decrease in serum concentrations

Itraconazole Pretreatment with phenytoin reduced the AUC of itraconazole more than 90%; decrease in half-life from 22.3 to 3.8 hours

Vecuronium Duration of action is reduced

Valproic acid Valproic acid levels can decrease after phenytoin is initiated; phenytoin administration may result in an increase in hepatotoxic valproic acid metabolites

Doxycycline Decreased half-life; reduced therapeutic efficacy

Lamotrigine Decreased serum concentrations via induction of UGT

Voriconazole Decreased plasma concentrations by 50% and 70%

Atorvastatin/simvastatin Approximately 50% decrease in plasmaconcentrations; further study needed

Methadone Increased metabolism can induce methadone withdrawal

AUC, area under the concentration-time curve; UGT, UDP-glucuronosyltransferase. *These are examples only. See current texts and reviews for further information.

References:

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