Clinical Response in Epilepsy in Relation to Total and Free Serum Levels of Phenytoin

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Abstract
The relationships between total and free serum concentrations of phenytoin and the clinical control of seizures were investigated retrospectively in 114 patients. Total phenytoin levels were measured by enzyme-modified immunoassay (EMIT), and the free fraction by ultrafiltration at 37°C using 14C-labelled phenytoin as a tracer. The median free fraction in 188 serum samples was 13.7% (range 8.9–27.0%). The free fraction was >18% in 34 (18.1%) of the serum samples. In all but 5 samples, a likely reason for the elevated free fraction could be determined. The identifiable reasons were commonly hypoalbuminaemia and the presence of liver or renal disease. There was a significant negative correlation between serum albumin level and free fraction of phenytoin (n = 90, r = −0.68, p < 0.001). The free phenytoin concentration was strongly correlated with the total phenytoin concentration in serum (n = 188, r = 0.94, p < 0.001). The total phenytoin concentration provided as good an indication of clinical response as the free concentration in 91 patients (85.8% of the patients for whom response could be reliably determined). In the other 15 (14.2%) patients, free phenytoin concentrations were better related to clinical effect. These patients generally had significant reductions in the serum protein binding of phenytoin. The relationship between phenytoin toxicity and free serum concentrations was particularly strong—in 14 patients with toxicity, the total serum concentration of phenytoin was >80 μmol/L in only 42.9% of cases, while the free phenytoin concentration was >8 μmol/L in 85.7% of the cases (p < 0.05 by chi-square test). The availability in therapeutic drug monitoring laboratories of an assay service for free serum concentrations of phenytoin is warranted by the fact that significant proportions of epileptic patients have altered serum protein binding of phenytoin and display better correlations between clinical response and free, rather than total, serum levels of the drug.

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