ASSESSMENT OF VALPROIC ACID SERUM CEREBROSPINAL-FLUID TRANSPORT BY MICRODIALYSIS
ASSESSMENT OF VALPROIC ACID SERUM CEREBROSPINAL-FLUID TRANSPORT BY MICRODIALYSIS
复制标题
DOI：
10.1023/a:1018982300285
复制
发表时间：
1993-12-01
影响因子：
3.7
通讯作者：
POLLACK, GM
中科院分区：
文献类型：
--
作者：
GOLDEN, PL;BROUWER, KR;POLLACK, GM
在大鼠中检查丙戊酸（VPA）推注、持续输注或与丙磺舒联合给药后的全身处置和血清-脑脊液（CSF）易位。通过体内微透析连续监测CSF中的VPA。延长VPA输注和丙磺舒预处理均增加了饱和VPA消除的K（m），降低了固有肝脏清除率，这可能是由于丙磺舒或蓄积的VPA代谢产物竞争葡萄糖醛酸化或肝脏UDP-葡萄糖醛酸消耗所致。在所有三个组中，CSF/血清VPA比值最初迅速升高，然后在整个实验剩余时间内随时间降低。这种时间和/或浓度依赖性行为表明，CSF渗透速率随着血清VPA的增加而不成比例地增加，并且可以通过结合VPA流入CSF的浓度依赖性一级速率常数的动力学模型进行描述。在所有实验条件下，CSF中的VPA外排似乎是饱和的;丙磺舒预处理后和VPA输注期间观察到外排的米氏常数增加，表明丙磺舒和VPA衍生代谢产物分别竞争性抑制转运。负责血清和CSF之间VPA不对称转运的机制，特别是控制CSF渗透的速率常数的明显浓度依赖性变化，仍有待阐明。
The systemic disposition and serum-cerebrospinal fluid (CSF) translocation of valproic acid (VPA) were examined in rats after administration of VPA as a bolus, as a continuous infusion, or with probenecid. VPA in CSF was monitored continuously by in vivo microdialysis. Both prolonged VPA infusion and probenecid pretreatment increased the K(m) for saturable VPA elimination and decreased intrinsic hepatic clearance, perhaps due to competition of probenecid or accumulated VPA metabolites for glucuronidation or depletion of hepatic UDP-glucuronic acid. The CSF/serum VPA ratio increased rapidly initially, then decreased with time throughout the remainder of the experiment in all three groups. This time- and/or concentration-dependent behavior suggested that the rate of CSF penetration increased disproportionately with increasing serum VPA and could be described by a kinetic model incorporating a concentration-dependent first-order rate constant for VPA influx into CSF. Under all experimental conditions, the VPA efflux from CSF appeared to be saturable; an increase in the Michaelis constant for efflux was observed following probenecid pretreatment and during VPA infusion, suggesting competitive inhibition of transport by probenecid and derived metabolites of VPA, respectively. The mechanisms responsible for asymmetric VPA transport between serum and CSF, in particular the apparent concentration-dependent change in the rate constant governing CSF penetration, remain to be elucidated.