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01.12.2012 | Research article | Ausgabe 1/2012 Open Access

BMC Medical Informatics and Decision Making 1/2012

Clinical decision support of therapeutic drug monitoring of phenytoin: measured versus adjusted phenytoin plasma concentrations

BMC Medical Informatics and Decision Making > Ausgabe 1/2012
Matthew D Krasowski, Louis E Penrod
Wichtige Hinweise

Electronic supplementary material

The online version of this article (doi:10.​1186/​1472-6947-12-7) contains supplementary material, which is available to authorized users.

Competing interests

The authors declare that they have no competing interests.

Authors' contributions

MDK and LEP were both involved in the study concept and design, analysis and interpretation of the data. MDK drafted the manuscript. Both authors have read and approved the final manuscript.



Therapeutic drug monitoring of phenytoin by measurement of plasma concentrations is often employed to optimize clinical efficacy while avoiding adverse effects. This is most commonly accomplished by measurement of total phenytoin plasma concentrations. However, total phenytoin levels can be misleading in patients with factors such as low plasma albumin that alter the free (unbound) concentrations of phenytoin. Direct measurement of free phenytoin concentrations in plasma is more costly and time-consuming than determination of total phenytoin concentrations. An alternative to direct measurement of free phenytoin concentrations is use of the Sheiner-Tozer equation to calculate an adjusted phenytoin that corrects for the plasma albumin concentration. Innovative medical informatics tools to identify patients who would benefit from adjusted phenytoin calculations or from laboratory measurement of free phenytoin are needed to improve safety and efficacy of phenytoin pharmacotherapy. The electronic medical record for an academic medical center was searched for the time period from August 1, 1996 to November 30, 2010 for patients who had total phenytoin and free phenytoin determined on the same blood draw, and also a plasma albumin measurement within 7 days of the phenytoin measurements. The measured free phenytoin plasma concentration was used as the gold standard.


In this study, the standard Sheiner-Tozer formula for calculating an estimated (adjusted) phenytoin level more frequently underestimates than overestimates the measured free phenytoin relative to the respective therapeutic ranges. Adjusted phenytoin concentrations provided superior classification of patients than total phenytoin measurements, particularly at low albumin concentrations. Albumin plasma concentrations up to 7 days prior to total phenytoin measurements can be used for adjusted phenytoin concentrations.


The results suggest that a measured free phenytoin should be obtained where possible to guide phenytoin dosing. If this is not feasible, then an adjusted phenytoin can supplement a total phenytoin concentration, particularly for patients with low plasma albumin.
Additional file 1:Figure S1 (correlation of PHTfree versus PHTtotal/10 and PHTfree versus PHTadj_free), Figure S2 (Bland-Altman plots), Figure S3 (three-by-three contingency tables of PHTtotal and PHTfree), Figure S4 (three-bv-three contingency tables of PHTadj_free and PHTfree comparing those with recent seizures or no recent seizures), Figure S5 (three-bv-three contingency tables of PHTadj_free and PHTfree comparing those on phenytoin monotherapy versus polytherapy with other anti-epileptic drugs), Figure S6 (effect of albumin concentration on free phenytoin estimation), and Figure S7 (effect of patient age on free phenytoin estimation). (PDF 276 KB)
Authors’ original file for figure 1
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