Wu D, Pardridge W M
Department of Medicine, UCLA School of Medicine, Los Angeles, California 90095, USA.
Pharm Res. 1999 Mar;16(3):415-9. doi: 10.1023/a:1018829920158.
The brain is relatively resistant to folic acid deficiency, indicating specialized transport systems may exist for this vitamin localized within the brain capillary endothelial wall, which makes up the blood-brain barrier (BBB) in vivo. The present studies quantify the BBB transport of [3H]-methyltetrahydrofolic acid (MTFA) in vivo and in isolated human brain capillaries in vitro.
BBB transport of [3H]-MTFA was compared to that of 14C]-sucrose, a plasma volume marker, following either intravenous injection or intracarotid perfusion in anesthetized rats. Competition by 10 microM MTFA or 10 microM folic acid was examined to determine whether folic acid is also transported by the MTFA uptake system.
The BBB permeability-surface area (PS) product of [3H]-MTFA, 1.1 +/- 0.3 microL/min/g, was 6-fold greater than that of [14C]-sucrose following intravenous injection. The BBB PS product determined by intracarotid arterial perfusion was not significantly different from the BBB PS product calculated following intravenous injection. A time- and temperature- dependent uptake of [3H]-MTFA in human brain capillaries was observed. The uptake of [3H]-MTFA by either rat brain in vivo or by human brain capillaries in vitro was equally inhibited by 10 microM concentrations of either unlabeled MTFA or unlabeled folic acid.
(1) A saturable transport system exists at the BBB for folic acid derivatives and since this transport is equally inhibited by either folic acid or MTFA, it is inferred that this transport system is the folic acid receptor, and not the reduced folic acid carrier. (2) The presence of a folate transport system at the BBB may offer an endogenous transport system for brain drug delivery of conjugates of folates and drugs that do not normally cross the BBB in vivo.
大脑对叶酸缺乏具有相对抗性，这表明可能存在专门的转运系统，用于体内构成血脑屏障（BBB）的脑毛细血管内皮壁中的这种维生素。本研究定量了体内和体外分离的人脑毛细血管中[3H]-甲基四氢叶酸（MTFA）的血脑屏障转运。
在麻醉大鼠中静脉注射或颈内动脉灌注后，将[3H]-MTFA的血脑屏障转运与血浆容积标志物[14C]-蔗糖的转运进行比较。检测10 microM MTFA或10 microM叶酸的竞争性，以确定叶酸是否也通过MTFA摄取系统转运。
静脉注射后，[3H]-MTFA的血脑屏障通透表面积（PS）乘积为1.1±0.3微升/分钟/克，比[14C]-蔗糖的乘积大6倍。颈内动脉灌注测定的血脑屏障PS乘积与静脉注射后计算的血脑屏障PS乘积无显著差异。观察到[3H]-MTFA在人脑毛细血管中的摄取具有时间和温度依赖性。体内大鼠脑或体外人脑毛细血管对[3H]-MTFA的摄取同样受到10 microM浓度的未标记MTFA或未标记叶酸的抑制。
（1）血脑屏障存在叶酸衍生物的可饱和转运系统，由于叶酸或MTFA对该转运的抑制作用相同，推测该转运系统是叶酸受体，而非还原型叶酸载体。（2）血脑屏障存在叶酸转运系统，可能为叶酸与药物的缀合物提供内源性转运系统，这些缀合物在体内通常不能穿过血脑屏障。
