Phenytoin, Free, Serum or Plasma

Phenytoin is 90% bound, but only the free fraction circulates through plasma membranes and is biologically active. Because of rapid equilibration between free and bound portions of drugs, free levels are potentially important only in AEDs that are highly bound (ie, phenytoin but not carbamazepine). Measurement of the free fraction is not cost-effective on a routine outpatient basis, but may be clinically relevant in exceptional circumstances associated with alterations in the binding of phenytoin.¹ Binding kinetics may be altered in uremia, hepatic disease, late pregnancy or postpartum, cases of head injury associated with a hypermetabolic state, and certain instances of polypharmacy, described below.^2-4 Determination of free levels may also be helpful in overdosages, since only the free portion can be cleared by dialysis.

In renal disease, total phenytoin levels may generate falsely high values, leading to inadequate dosage. Dialysis may increase the amount of free phenytoin available.⁵ In hepatic disease, phenytoin competes with endogenous bilirubin for binding sites,⁶ and thus the need for a free level may be greatest if the total bilirubin level is high and albumin low. Available liver function tests are not predictive of free phenytoin levels in patients with liver disease.⁴

Drugs which compete for binding sites on albumin and which may displace phenytoin include valproic acid, acetazolamide, high doses of salicylic acid, phenylbutazone, ceftriaxone, nafcillin, and sulfamethoxazole.⁷ In a clinical setting in which one of these drugs is used with phenytoin and toxicity is suspected despite normal phenytoin levels, a free level may be useful.

The free phenytoin level can be approximated by the total phenytoin level in cerebrospinal fluid or saliva or other body fluids that are albumin-poor.