Distribution of unsaturated metabolites of valproate in human and rat brain--pharmacologic relevance?
Distribution of unsaturated metabolites of valproate in human and rat brain--pharmacologic relevance?
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丙戊酸不饱和代谢物在人和大鼠脑中的分布——药理学相关性？
DOI：
10.1111/j.1528-1157.1995.tb01614.x
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发表时间：
1995
期刊：
影响因子：
5.6
通讯作者：
Shen,DD
中科院分区：
文献类型：
--
作者：
Adkison,KD;Ojemann,GA;Rapport,RL;Dills,RL;Shen,DD
在24例接受癫痫手术的患者的血清和皮质脑样本中测定了丙戊酸盐（VPA）及其6种抗癫痫活性不饱和代谢产物（E-δ2-VPA、Z-δ3-VPA、E-δ3-VPA、E，E-δ2，3. -VPA、δ4-VPA和E-δ2，4-VPA）的浓度。总体而言，6种代谢产物的浓度≤ VPA脑浓度的13%。由于六种不饱和代谢物在脑中的浓度如此低，我们得出的结论是，这些代谢物可能对丙戊酸盐的抗惊厥作用没有显着贡献。在大鼠中进行的一项平行药效学研究（VPA每日3次给药，持续8周）的结果支持这一结论。在大鼠脑中仅检测到三种不饱和代谢物（E-δ2-VPA、δ3-VPA、E，E-A2、3-VPA）。未观察到抗惊厥作用的时间进程[通过定时静脉注射戊四氮（PTZ）试验测定]与大鼠脑中VPA或代谢物浓度的时间进程之间存在相关性。尽管VPA及其代谢产物的结构相似，但在血清蛋白结合和血脑分布特性方面观察到显著差异。在人脑中，VPA和δ4‐VPA的脑-游离血清浓度比小于1。相比之下，在2-或3-位具有双键的化合物的脑：游离浓度比远高于1。观察到的VPA及其不饱和代谢产物的结构-分布关系表明，这些支链脂肪酸通过血脑屏障（BBB）的不对称转运不同。
The concentrations of valproate (VPA) and six of its pharmacologically active, unsaturated metabolites (E‐δ2‐VPA, Z‐δ3‐VPA, E‐δ3‐VPA, E, E‐δ2, 3.‐VPA, δ4‐VPA, and E‐δ2, 4‐VPA) were measured in serum and cortical brain samples from 24 patients undergoing epilepsy surgery. Collectively, the six metabolites were present at concentrations ≤13% of VPA brain concentrations. Because the six unsaturated metabolites were present at such low brain concentrations, we concluded that these metabolites probably did not contribute significantly to the anticonvulsant effect of VPA. Results from a parallel pharmacodynamic study in rats in which VPA was administered three times daily for 8 weeks supported this conclusion. Only three unsaturated metabolites (E‐δ2‐VPA, δ3‐VPA, E, E‐A2, 3‐VPA)were detected in rat brain. No correlation was observed between the time course of anticonvulsant effect [as measured by the timed intravenous pentylenetetrazol (PTZ) test] and the time course of VPA or metabolite concentrations in rat brain. Despite the structural similarity of VPA and its metabolites, striking differences were observed in their serum protein binding and blood‐brain distribution properties. In the human brain, VPA and δ4‐VPA exhibited brain‐to‐free serum concentration ratios that were less than unity. In contrast, compounds with the double bond at the 2‐or 3‐position had brain: free concentration ratios that were much higher than unity. The structure‐distribution relationship observed with VPA and its unsaturated metabolites suggested that these branched‐chain fatty acids differ in their asymmetric transport across the blood‐brain barrier (BBB).