Nomogram for the prediction of unbound phenytoin concentrations in patients on a combined treatment of phenytoin and valproic acid

Eur Neurol. 1991;31(1):57-60. doi: 10.1159/000116647.


The interpretation of the total phenytoin (PT) concentration can be problematic if valproic acid (VPA) is given as a comedication, because VPA displaces PT from the protein binding sites and can increase the free fraction of PT. In order to estimate the free or unbound PT concentration (PTf) from the total PT concentration (PTt) and VPA concentration, a nomogram was constructed and evaluated. Data of 84 patients on combined therapy with PT and VPA were used in drawing up the regression equation (PTf = 0.0792.PTt + 0.000636.PTt.VPA) from which the nomogram was constructed. The predictions were checked using another 33 patients whose serum concentrations were determined in the morning and in addition several times during the day. The results show that using this method the PTf concentrations can be accurately estimated from the PTt and VPA concentrations.

Publication types

  • Comparative Study

MeSH terms

  • Adolescent
  • Adult
  • Aged
  • Aged, 80 and over
  • Child
  • Child, Preschool
  • Chromatography, Gas
  • Chromatography, High Pressure Liquid
  • Drug Therapy, Combination
  • Epilepsy / blood
  • Epilepsy / drug therapy
  • Humans
  • Middle Aged
  • Phenytoin / blood
  • Phenytoin / pharmacokinetics*
  • Phenytoin / therapeutic use
  • Protein Binding
  • Regression Analysis
  • Valproic Acid / blood
  • Valproic Acid / pharmacokinetics*
  • Valproic Acid / therapeutic use


  • Valproic Acid
  • Phenytoin