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Test Catalog

Test ID: PNTFT    
Phenytoin, Total and Free, Serum

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

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

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 coadministered. 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 (active) fraction.

 

Concurrent use of phenytoin and valproic acid (another frequently used antiepileptic) may result in altered valproic acid levels and/or altered phenytoin levels. Due to the complex situation involving displacement of protein-bound phenytoin and inhibition of phenytoin metabolism, as well as the potential for decreased valproic acid concentrations, patients should be monitored for both phenytoin toxicity and therapeutic efficacy. Free phenytoin levels should be measured to provide the most accurate assessmet of phenytoin acivity early in therapy. At steady-state, free phenytoin and free valproic acid concentrations should be normalized.

 

The free phenytoin level is the best indicator of adequate therapy.

 

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. The outcome of phenytoin toxicity is not as serious as phenobarbital because phenytoin is not a central nervous system sedative.

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.

Phenytoin, Total

Therapeutic: 10.0-20.0 mcg/mL

Critical value: > or =30.0 mcg/mL

 

Phenytoin, Free

Therapeutic: 1.0-2.0 mcg/mL

Critical value: > or =2.5 mcg/mL

Interpretation Provides information to assist in interpretation of the test results

Dose should be adjusted to achieve steady-state concentrations of total phenytoin between 10.0 and 20.0 mcg/mL, and free phenytoin between 1.0 and 2.0 mcg/mL. The range for percent free phenytoin is 8% to 14%. However, response and side effects will be individual.

 

In patients with renal failure, total phenytoin is likely to be less than the therapeutic range of 10.0 to 20.0 mcg/mL. Severe toxicity occurs when the total blood concentration exceeds 30.0 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.

Clinical Reference Recommendations for 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