Interpretive Handbook

Test 6794 :
Phenytoin, Free, Serum

Clinical Information Discusses physiology, pathophysiology, and general clinical aspects, as they relate to a laboratory test

Phenytoin is the drug of choice to treat and prevent tonic-clonic and psychomotor seizures. If phenytoin alone will not prevent seizure activity, coadministration with phenobarbital is usually effective.


Phenytoin is highly protein-bound (90%), mostly to albumin. Ten percent of the phenytoin circulates in the free, unbound form. Free phenytoin is the active form of the drug, available to cross biologic membranes and bind to receptors. Increased free phenytoin produces an enhanced pharmacologic effect. At the same time, the free fraction is more available to the liver to be metabolized, so it is cleared more quickly.


Valproic acid, an antiepileptic frequently coadministered with phenytoin, competes for the same binding sites on albumin as phenytoin. Valproic acid displaces phenytoin from albumin, reducing the bound fraction and increasing the free fraction of phenytoin. The overall effect of coadministration of a therapeutic dose of valproic acid is that the total concentration of phenytoin decreases due to increased clearance, but the concentration of free phenytoin remains virtually the same. Thus, no dosage adjustment is needed when valproic acid is added to maintain the same pharmacologic effect, but the total concentration of phenytoin should decrease.


In renal failure, the opportunity for the free phenytoin fraction to be cleared is significantly reduced. The end result is that both the total and free concentration of phenytoin increase, with the free concentration increasing faster than the total. Dosage must be reduced to avoid toxicity. Accordingly, the free phenytoin level is the best indicator of adequate therapy in renal failure.


Toxicity is a constant possibility because of the manner in which phenytoin is metabolized. Small increases in dose can lead to very large increases in blood concentration, resulting in early signs of toxicity such as nystagmus, ataxia, and dysarthria. Severe toxicity is typified by tremor, hyperreflexia, lethargy, and coma.

Useful For Suggests clinical disorders or settings where the test may be helpful

Monitoring for appropriate therapeutic concentration: free phenytoin level is the best indicator of adequate therapy in renal failure


Assessing compliance and toxicity

Interpretation Provides information to assist in interpretation of the test results

Dose should be adjusted to achieve steady-state blood concentration of free phenytoin between 1 and 2 mcg/mL.


Severe toxicity occurs when the total blood concentration exceeds 30 mcg/mL.

Cautions Discusses conditions that may cause diagnostic confusion, including improper specimen collection and handling, inappropriate test selection, and interfering substances

No significant cautionary statements.

Reference Values Describes reference intervals and additional information for interpretation of test results. May include intervals based on age and sex when appropriate. Intervals are Mayo-derived, unless otherwise designated. If an interpretive report is provided, the reference value field will state this.

Therapeutic concentration: 1.0-2.0 mcg/mL

Toxic concentration: > or =2.5 mcg/mL

Clinical References Provides recommendations for further in-depth reading of a clinical nature

Richens A: Clinical pharmacokinetics of phenytoin. Clin Pharmacokinet 1979;4:153-169