The pharmacokinetics and blood-brain barrier permeation of the chelators 1,2-dimethyl-, 1,2-diethyl-, and 1-[ethan-1'ol]-2-methyl-3-hydroxypyridin-4-one in the rat
The pharmacokinetics and blood-brain barrier permeation of the chelators 1,2-dimethyl-, 1,2-diethyl-, and 1-[ethan-1'ol]-2-methyl-3-hydroxypyridin-4-one in the rat
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DOI：
10.1016/0300-483x(95)03301-u
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发表时间：
1996-04-30
期刊：
影响因子：
4.5
通讯作者：
Yokel, RA
中科院分区：
文献类型：
--
作者：
Fredenburg, AM;Sethi, RK;Yokel, RA
3-羟基吡啶-4-酮（HP）是铁和铝螯合剂。它们进入大脑的能力以前没有被直接确定。为了确定它们是否穿过血脑屏障（BBB），检查了具有宽范围亲脂性的三种HP：1-[ethan-1 'ol]-2-methyl-HP（CP 40）、1，2-dimethyl-HP（CP 20，L1，去铁酮）和1，2-diethyl-HP（CP 94，EL 1 NEt）。在大鼠中测定其药代动力学，以确定用于BBB渗透的微透析研究的给药参数。然后用血液、额叶皮质和侧脑室中的微透析探针进行研究，以确定HP BBB渗透性的速率和程度。在HP注射后0-7分钟收集的脑透析液样品中可检测到所有三种HP，表明HP快速进入脑，非约束分布的范围（BBB渗透机制的指标）对于CP 20的额叶皮层和侧脑室为0.9和1.2，对于CP 94为1.1和1.6，CP 40的未结合分布的程度对于额叶皮层和侧脑室两者均为0.2，表明存在将其移出脑细胞外液的转运蛋白。将氰化物引入大脑并不影响大脑与血液的CP 40比率，这表明转运蛋白不是能量依赖性的。CP 94和CP 40均因呼吸衰竭导致死亡，而CP 20则不会。毒性较低的双齿HP螯合剂如CP 20进入脑的能力可使其能够用于治疗涉及中枢神经系统的金属诱导的疾病和铁促进的氧化损伤。
The 3-hydroxypyridin-4-ones (HPs) are iron and aluminium chelators. Their ability to enter the brain had not previously been directly determined. To determine whether they cross the blood-brain barrier (BBB), three HPs possessing a wide range of lipophilicity were examined: 1-[ethan-1'ol]-2-methyl-HP (CP40), 1,2-dimethyl-HP (CP20, L1, deferiprone), and 1,2-diethyl-HP (CP94, EL1NEt). Their pharmacokinetics were determined in rats to establish dosing parameters for microdialysis studies of BBB permeation. Studies were then conducted with microdialysis probes in the blood, frontal cortex, and lateral ventricle to determine the rate and extent of HP BBB permeability, All three HPs were detectable in brain dialysate samples collected 0-7 min after HP injection, demonstrating rapid entry into the brain, The extent of unbound distribution (an indicator of the mechanism of BBB permeation) was 0.9 and 1.2 for the frontal cortex and lateral ventricle for CP20, and was 1.1 and 1.6 for CP94, suggesting diffusion across the BBB, The extent of unbound distribution of CP40 was 0.2 for both the frontal cortex and lateral ventricle, suggesting the presence of a transporter moving it out of brain extracellular fluid. Introduction of cyanide into the brain did not affect the brain to blood CP40 ratio, suggesting that the transporter is not energy-dependent. Both CP94 and CP40 caused death due to respiratory failure, whereas CP20 did not. The ability of less toxic bidentate HP chelators, such as CP20, to enter the brain may enable their use in the treatment of metal-induced diseases and iron-facilitated oxidative injury involving the central nervous system.