Shannon Richard J, Timofeev Ivan, Nortje Jürgens, Hutchinson Peter J, Carpenter Keri L H
Division of Neurosurgery, Department of Clinical Neurosciences, University of Cambridge, Cambridge, UK.
Br J Clin Pharmacol. 2014 Nov;78(5):981-95. doi: 10.1111/bcp.12414.
The aims were to determine blood-brain barrier penetration and brain extracellular pharmacokinetics for the anticonvulsant vigabatrin (VGB; γ-vinyl-γ-aminobutyric acid) in brain extracellular fluid and plasma from severe traumatic brain injury (TBI) patients, and to measure the response of γ-aminobutyric acid (GABA) concentration in brain extracellular fluid.
Severe TBI patients (n = 10) received VGB (0.5 g enterally, every 12 h). Each patient had a cerebral microdialysis catheter; two patients had a second catheter in a different region of the brain. Plasma samples were collected 0.5 h before and 2, 4 and 11.5 h after the first VGB dose. Cerebral microdialysis commenced before the first VGB dose and continued through at least three doses of VGB. Controls were seven severe TBI patients with microdialysis, without VGB.
After the first VGB dose, the maximum concentration of VGB (Cmax ) was 31.7 (26.9-42.6) μmol l(-1) (median and interquartile range for eight patients) in plasma and 2.41 (2.03-5.94) μmol l(-1) in brain microdialysates (nine patients, 11 catheters), without significant plasma-brain correlation. After three doses, median Cmax in microdialysates increased to 5.22 (4.24-7.14) μmol l(-1) (eight patients, 10 catheters). Microdialysate VGB concentrations were higher close to focal lesions than in distant sites. Microdialysate GABA concentrations increased modestly in some of the patients after VGB administration.
Vigabatrin, given enterally to severe TBI patients, crosses the blood-brain barrier into the brain extracellular fluid, where it accumulates with multiple dosing. Pharmacokinetics suggest delayed uptake from the blood.
本研究旨在确定抗惊厥药物vigabatrin（VGB；γ-乙烯基-γ-氨基丁酸）在重度创伤性脑损伤（TBI）患者的脑细胞外液和血浆中的血脑屏障穿透率及脑细胞外药代动力学，并测量脑细胞外液中γ-氨基丁酸（GABA）浓度的变化。
10例重度TBI患者接受VGB治疗（0.5g，口服，每12小时一次）。每位患者均置入一根脑微透析导管；2例患者在大脑不同区域置入第二根导管。在首次给予VGB剂量前0.5小时以及给药后2、4和11.5小时采集血浆样本。脑微透析在首次给予VGB剂量前开始，并持续至少三次VGB给药。对照组为7例接受微透析但未使用VGB的重度TBI患者。
首次给予VGB剂量后，血浆中VGB的最大浓度（Cmax）为31.7（26.9 - 42.6）μmol l⁻¹（8例患者的中位数和四分位数间距），脑微透析液中为2.41（2.03 - 5.94）μmol l⁻¹（9例患者，11根导管），血浆与脑内浓度无显著相关性。三次给药后，微透析液中的Cmax中位数增至5.22（4.24 - 7.14）μmol l⁻¹（8例患者，10根导管）。微透析液中VGB浓度在局灶性病变附近高于远处。部分患者在给予VGB后，微透析液中GABA浓度略有升高。
重度TBI患者口服vigabatrin后可穿过血脑屏障进入脑细胞外液，并在多次给药后蓄积。药代动力学表明其从血液中的摄取延迟。
