Distribution of Valproate to Subdural Cerebrospinal Fluid, Subcutaneous Extracellular Fluid, and Plasma in Humans: A Microdialysis Study

Abstract

Summary We sought to study the time course of the distribution of valproate (VPA) to subdural cerebrospinal fluid (CSF) in relation to subcutaneous extracellular fluid (ECF) and plasma after a single oral dose and to study the distribution to these three compartments under steady‐state conditions. Microdialysis was used to estimate unbound VPA concentrations in subdural CSF and subcutaneous ECF, and blood samples were drawn for estimation of total and unbound VPA plasma concentrations in four patients with drug‐resistant partial epilepsy undergoing presurgical evaluation with subdural EEG monitoring. Three patients were given a single oral dose of VPA, and one patient was receiving regular VPA treatment. VPA was analyzed by gas chromatography with flame ionization detection. The distribution of VPA to subdural CSF was rapid (Tmax, 3.5 h in two patients and 5.5 h in one patient) and subject to a minor delay in all three patients compared with that in the subcutaneous tissue ECF (Tmax, 2.5 h in all three patients), which in turn exhibited no evidence of a distribution delay compared with plasma. Subdural CSF levels of VPA were slightly lower than subcutaneous ECF levels (mean ratio, 0.78) and unbound plasma levels (mean ratio, 0.91). VPA rapidly enters the subdural CSF in unbound concentrations marginally lower than those obtained in subcutaneous ECF and plasma. These findings provide a pharmacokinetic rationale for acute administration of VPA. The good correlation between VPA concentrations in subcutaneous ECF and subdural CSF indicates that estimation of unbound VPA concentrations in subcutaneous tissue using microdialysis sampling has the potential to be useful for monitoring purposes.

Microdialysis Sampling of Carbamazepine, Phenytoin and Phenobarbital in Subcutaneous Extracellular Fluid and Subdural Cerebrospinal Fluid in Humans: An in vitro and in vivo Study of Adsorption to the Sampling Device

“…For the estimation of carbamazepine and phenobarbital in subdural cerebrospinal fluid, subcutaneous extracellular fluid and plasma, two patients with drug resistent partial epilepsy, undergoing presurgical evaluation with subdural EEG monitoring, were investigated. Both were part of a previously published study of distribution of valproate to subdural cerebrospinal fluid, subcutaneous extracellular fluid and plasma (Lindberger et al 2001). The patient demographics and drug treatments are shown in table 1.…”

“…Thus, it can be used to sample subcutaneous extracellular valproate, giving reliable estimates of the protein unbound concentrations in plasma (Lindberger et al 1998). We also used microdialysis to sample cerebrospinal fluid and found that protein unbound subdural cerebrospinal fluid levels of valproate were only slightly lower than unbound levels in subcutaneous extracellular fluid and plasma (Lindberger et al 2001).…”

Valproate: Past, Present, and Future

“…A microdialysis study in humans demonstrated the pharmacokinetic rationale for acute treatment with VPA. It is based on the rapid distribution of VPA to the brain (75). Recently, Marson et al (83) performed a meta-analysis that compares VPA with carbamazepine in the monotherapy of epilepsy.…”

Microdialysis of large molecules

“…It has an advantage over other sampling techniques in that it can be used to follow temporal variations in the generation and release of a substance at a discreet location within the tissue space. Since its initial use in the brain of experimental animals for the recovery of neurotransmitters and other small hydrophilic solutes, 1 microdialysis has been adapted for use in many other tissues, including skin, 2-9 adipose tissue, 10 muscle, 11 , 12 and gastrointestinal tract. 13 However, the ability to recover molecules of higher molecular mass has, until recently, been limited by the availability of dialysis probes with high molecular weight cutoffs (MWCOs).…”