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Low and variable presence of valproic acid in human brain

Epilepsy Center, Department of Neurological Surgery, School of Medicine, University of Washington (Drs. Ojemann and Rapport and P.N. Friel)
Department of Pharmaceutics, School of Pharmacy, University of Washington, and Group Health Cooperative, Seattle, WA (Drs. Shen, Dills, and Levy).

We studied the distribution of valproic acid (VPA) between brain (gray matter) and serum in 13 patients receiving chronic VPA therapy who underwent cortical resections for intractable seizures. Valproate concentration in cerebral cortex was remarkably low compared with either total or unbound valproate concentration in serum. The respective brain-to-serum partition ratios based on total and free drug in serum were 0.111 ± 0.051 and 0.544 ± 0.175. In comparison with other commonly used antiepileptic drugs, valproate has the distinction of exhibiting the lowest brain-to-blood partitioning. Moreover, the brain-to-serum concentration ratio varied over a four-fold range between patients. Some of this variability was related to variation in serum protein binding, as indicated by a modest correlation between the partition ratio and serum free fraction (r = +0.687). However, the brain-to-unbound concentration ratio still showed a three-fold variation. The variability in distribution of VPA between brain and blood is probably one of the underlying factors for the lack of a clearly definable therapeutic range of serum VPA concentration in epileptic patient populations.

Address correspondence and reprint requests to Dr. Danny D. Shen, Department of Pharmaceutics, BG-20, University of Washington, Seattle, WA 98195.

Supported by NIH grants no. NS 17111 and NS 22662.

Received April 30, 1991. Accepted for publication in final form August 9, 1991.

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