Beck et al. compared free phenytoin concentrations predicted by three different equations with measured values. The authors used the Gugler method, Sheiner-Tozer equation, and the Sheiner-Tozer nomogram for predicting free phenytoin concentrations from measured total phenytoin concentration and albumin concentration. Authors concluded that all three methods for predicting free phenytoin concentrations suffered from bias and should not be used for predicting free phenytoin concentrations. The authors recommended direct measurement of free phenytoin concentration (115). Dager et al. (116) concluded that although the Sheiner-Tozer equation underestimates the measured free phenytoin concentration by an average of 12.4%, the equation still has some reliability in normalizing total phenytoin reliably in patients with hypoal-buminemia. Tadon et al. also reported that in patients with serum albumin level in the hyper and hypoalbuminemic range, corrected phenytoin levels for albumin using Sheiner-Tozer equation were better indicator for clinical outcome than simply total phenytoin level. The authors further commented that in developing countries such as India where direct measurement of free drug level is expensive such indirect measurement may have clinical value (117). However, in our experience, direct measure of free level of phenytoin is always clinically more valuable than such indirect measures to correct phenytoin levels.

May et al. reported that although free phenytoin measured by HPLC correlated well with free phenytoin measured by FPIA using the TDx analyzer, the free phenytoin concentrations obtained by using FPIA showed positive bias compared with HPLC values. Moreover, free phenytoin determined by HPLC fits better with calculated phenytoin value in patients also taking valproic acid (118). However, again our recommendation is to measure free phenytoin concentration directly instead of using any equation.

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