Human brain phenytoin: correlation with unbound and total serum concentrations

Area of Science:

• Neuroscience
• Clinical Pharmacology
• Analytical Chemistry

Background:

• Phenytoin is a widely used antiepileptic drug.
• Accurate measurement of drug concentration in the brain is essential for effective treatment.
• Phenytoin binding to serum proteins can be variable, potentially affecting therapeutic drug monitoring.

Purpose of the Study:

• To compare the correlation between brain and serum phenytoin concentrations.
• To evaluate the utility of monitoring unbound phenytoin versus total serum phenytoin.
• To investigate phenytoin distribution in epileptic foci versus non-epileptic brain tissue.

Main Methods:

• Simultaneous analysis of brain (gray matter) and serum specimens from 18 patients treated with oral phenytoin.
• High-performance liquid chromatography (HPLC) was used for specimen analysis.
• Correlation coefficients were calculated between brain and serum phenytoin concentrations.

Main Results:

• A significantly better correlation was observed between brain phenytoin concentration and unbound (free) phenytoin (r = 0.98-0.99) compared to total serum phenytoin (r = 0.90-0.93).
• Phenytoin concentrations in tissue from epileptic foci were slightly lower than in non-epileptic brain regions within the same patient (15.0 vs. 15.5 µg/g, P < 0.05).

Conclusions:

• Unbound phenytoin concentration is a more reliable indicator of brain phenytoin levels than total serum concentration.
• Monitoring unbound phenytoin is valuable in clinical settings with variable phenytoin binding.
• These findings support optimizing phenytoin therapy by considering unbound drug levels.