Phenytoin, Total and 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.
Initial therapy with phenytoin is started at doses of 100 to 300 mg/day for adults or 4 mg/kg/day for children. Because absorption is variable and the drug exhibits zero-order (nonlinear) kinetics, dose must be adjusted within 5 days using blood concentration to guide therapy. Oral bioavailability ranges from 80% to 95% and is diet-dependent.
Phenytoin exhibits zero-order pharmacokinetics; the rate of clearance of the drug is dependent upon the concentration of drug present. Therefore, phenytoin does not have a classical half-life like other drugs, since it varies with blood concentration. At a blood concentration of 15 mcg/mL, approximately half the drug in the patient's body will be eliminated in 20 hours. As the blood concentration drops, the rate at which phenytoin is excreted increases.
Phenytoin has a volume of distribution of 0.65 L/kg, and is highly protein bound (90%), mostly to albumin.
Phenytoin pharmacokinetics are significantly affected by a number of other drugs. Phenytoin and phenobarbital are frequently co-administered. Induction of the cytochrome P450 enzyme system by phenobarbital will increase the rate at which phenytoin is metabolized and cleared. At steady-state, enzyme induction will increase the rate of clearance of phenytoin such that the dose must be increased approximately 30% to maintain therapeutic levels.
Uremia has a similar effect on phenytoin protein binding. In uremia, by-products of normal metabolism accumulate and bind to albumin, displacing phenytoin which causes an increase in the free fraction. Different from the valproic acid circumstance, however, there is not the same opportunity for the free phenytoin fraction to be cleared. 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.
The free phenytoin level is the best indicator of adequate therapy.
Ten percent of the phenytoin circulates in the free, unbound form; thus the reference range for free phenytoin is 1 to 2 mcg/mL.
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, will compete for the same binding sites on albumin as phenytoin. Valproic acid displaces phenytoin from albumin, reducing the bound fraction and increasing the free fraction. 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 free fraction increases; the free concentration of phenytoin, which is the active form, 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 decreases.
Monitoring for appropriate therapeutic concentration
Dose should be adjusted to achieve steady-state blood concentration of free phenytoin between 1 to 2 mcg/mL. In patients with renal failure, total phenytoin is likely to be less than the therapeutic range of 10 to 20 mcg/mL.
Cautions Discusses conditions that may cause diagnostic confusion, including improper specimen collection and handling, inappropriate test selection, and interfering substances
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 occurs when the blood concentration is >30 mcg/mL and is typified by tremor, hyperreflexia, lethargy, and coma.
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: 10.0-20.0 mcg/mL
Toxic concentration: > or =30.0 mcg/mL
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
1. Richens A: Clinical pharmacokinetics of phenytoin. Clin Pharmacokinet 1979;4:153-169
2. Moyer TP: Therapeutic drug monitoring. In Tietz Textbook of Clinical Chemistry. Fourth edition. Edited by CA Burtis, ER Ashwood. Philadelphia, WB Saunders Company, 2005, pp 1237-1285