Löscher W, Nau H, Siemes H
Department of Pharmacology, Toxicology, and Pharmacy, School of Veterinary Medicine, Hannover, F.R.G.
Epilepsia. 1988 May-Jun;29(3):311-6. doi: 10.1111/j.1528-1157.1988.tb03725.x.
Levels of the antiepileptic drug valproate (VPA) and five of its active metabolites (2-en-VPA, 3-keto-VPA, and 3-,4-, and 5-hydroxy-VPA) were determined by gas chromatography-mass spectrometry in cerebrospinal fluid (CSF) of 15 epileptic children undergoing chronic treatment with VPA. In eight of these children, total and free drug and metabolite concentrations in plasma were also measured. All VPA metabolites present in plasma could also be detected in CSF, although concentrations were substantially lower than those of the parent compound. CSF concentrations of VPA and most of its metabolites were positively correlated with total and free concentrations in plasma. However, concentrations in CSF were always significantly lower than free plasma concentrations, which may be explained by asymmetric transport at the blood-CSF barrier. The data on low CSF levels of VPA metabolites do not exclude the possibility that accumulation of active metabolite(s) may occur in certain brain areas during chronic treatment of epileptic patients with VPA.
采用气相色谱-质谱联用技术测定了15例接受丙戊酸（VPA）长期治疗的癫痫患儿脑脊液（CSF）中抗癫痫药物丙戊酸及其5种活性代谢物（2-烯丙戊酸、3-酮丙戊酸、3-、4-和5-羟基丙戊酸）的水平。其中8例患儿还检测了血浆中药物和代谢物的总浓度及游离浓度。血浆中存在的所有丙戊酸代谢物在脑脊液中也能检测到，尽管其浓度明显低于母体化合物。脑脊液中丙戊酸及其大多数代谢物的浓度与血浆中的总浓度和游离浓度呈正相关。然而，脑脊液中的浓度总是显著低于血浆游离浓度，这可能是由于血脑屏障处的不对称转运所致。关于脑脊液中丙戊酸代谢物水平较低的数据并不排除在癫痫患者接受丙戊酸长期治疗期间，某些脑区可能会出现活性代谢物蓄积的可能性。
