Synergistic effect of valproate coadministration and hypoalbuminemia on the serum-free phenytoin concentration in patients with severe motor and intellectual disabilities.

We investigated whether a combination of risk factors affects the free phenytoin (PHT) fraction by multiple regression analyses in 30 patients with severe motor and intellectual disabilities (SMID) with epilepsy. The risk factors analyzed were gender, age, total PHT concentration, albumin concentration, aspartate aminotransferase, alanin aminotransferase, serum creatinine, blood urea nitrogen, and antiepileptic drug concentrations. Serum levels of total and free PHT were measured by fluorescence polarization immunoassay. Free PHT fractions were between 7.2% and 17.3% (average 10.9%). Two factors, hypoalbuminemia and valproate (VPA) coadministratation with PHT, increased free PHT fraction, and a combination of these two markedly increased free PHT fraction. Patients with these double risk factors have a high risk of exceeding the therapeutic range of serum-free PHT concentration even if their total PHT concentration does not. Therefore, we should monitor free PHT concentration, especially in SMID patients with epilepsy, because they may have hypoalbuminemia and are treated with antiepileptic drug polytherapy and, moreover, cannot report adverse effects of the drugs.