Lindberger M, Tomson T, Wallstedt L, Ståhle L
Department of Neurology, Karolinska Institute, Huddinge University Hospital, S-14186 Huddinge, Sweden.
Epilepsia. 2001 Feb;42(2):256-61. doi: 10.1046/j.1528-1157.2001.26600.x.
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.
我们试图研究单次口服剂量后丙戊酸盐（VPA）在硬膜下脑脊液（CSF）中的分布时间进程，及其与皮下细胞外液（ECF）和血浆的关系，并研究稳态条件下VPA在这三个腔室中的分布情况。采用微透析法估算硬膜下脑脊液和皮下细胞外液中未结合的VPA浓度，并采集血样以估算4例接受硬膜下脑电图监测的耐药性部分性癫痫患者血浆中总VPA浓度和未结合VPA浓度。3例患者单次口服VPA，1例患者接受常规VPA治疗。采用气相色谱-火焰离子化检测法分析VPA。与皮下组织细胞外液相比，VPA向硬膜下脑脊液的分布较快（2例患者Tmax为3.5小时，1例患者为5.5小时），且所有3例患者均有轻微延迟（所有3例患者Tmax为2.5小时），而皮下组织细胞外液与血浆相比无分布延迟迹象。VPA的硬膜下脑脊液水平略低于皮下细胞外液水平（平均比值为0.78）和未结合血浆水平（平均比值为0.91）。VPA以略低于皮下细胞外液和血浆中未结合浓度的形式迅速进入硬膜下脑脊液。这些发现为VPA的急性给药提供了药代动力学依据。皮下细胞外液和硬膜下脑脊液中VPA浓度之间的良好相关性表明，使用微透析采样估算皮下组织中未结合的VPA浓度有可能用于监测目的。
