Protein Binding And Free Phenytoin Fractions

Phenytoin is extensively (90 percent) bound to plasma proteins, especially albumin. The free, unbound, form is the biologically active moiety responsible for the drug's clinical effect and toxicity. The free phenytoin fraction normally constitutes 10 percent of the plasma level. The unbound fraction of the drug is greater in the following groups of patients: neonates; the elderly; pregnant women; individuals with uremia, hypoalbuminemia (cirrhosis, nephrosis, malnutrition, burns, trauma, or cystic fibrosis), and hyperbilirubinemia; and individuals taking drugs that displace phenytoin from binding sites (salicylate, valproate, phenylbutazone, tolbutamide, and sulfisoxazole).

Although patients with decreased protein binding may have higher levels of free phenytoin and a greater biologic effect, they may have lower levels of total phenytoin, since more of the drug is available for metabolism. Theoretically, such patients may become toxic with total phenytoin levels in the therapeutic range. Patients who exhibit toxic signs in the therapeutic range and those with decreased protein binding should have free phenytoin levels measured.

Phenytoin concentrations are most commonly measured by an enzyme-mediated immunoassay (EMIT) technique, which is specific and sensitive to less than 1 pg/mL. If available, free phenytoin concentrations are more useful to predict toxicity. Corrected serum phenytoin levels can be calculated in hypoproteinemic patients with a known serum albumin level. To calculate the phenytoin concentration (C norma) that would be present if a patient's serum albumin were normal, the following equation is used:

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