INCREASED BLOOD-BRAIN-BARRIER TRANSPORT OF PROTEIN-BOUND ANTI-CONVULSANT DRUGS IN THE NEWBORN
INCREASED BLOOD-BRAIN-BARRIER TRANSPORT OF PROTEIN-BOUND ANTI-CONVULSANT DRUGS IN THE NEWBORN
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DOI：
10.1038/jcbfm.1983.42
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发表时间：
1983-01-01
影响因子：
6.3
通讯作者：
OLDENDORF, WH
中科院分区：
文献类型：
--
作者：
CORNFORD, EM;PARDRIDGE, WM;OLDENDORF, WH
测定了新生儿、哺乳期和成人脑中海洛因、咖啡因、苯基海妥英和苯巴比妥的提取量。抗惊厥药物如二苯基苯妥英和苯巴比妥与血浆蛋白结合，一般认为只有体外游离（可透析）的部分药物可在体内通过血脑屏障运输。在成年和新生大鼠或家兔，脂质介导的游离苯妥英转运发生。进入毛细血管与血浆蛋白结合的一部分药物也可以进入大脑。大量的蛋白结合药物渗透到新生儿大脑，这是由于新生儿的毛细血管转运时间较长。关于苯巴比妥，总（即游离和蛋白结合）血浆药物进入新生儿大脑。没有蛋白质结合的苯巴比妥渗透到成人的大脑中，只有游离药物部分进入大脑。由于两种抗惊厥药的血脑屏障通透性-表面积产物在新生和老年动物中没有变化，因此与年龄相关的脑摄取蛋白结合药物的差异可归因于脑血流量和毛细血管转运时间的发育变化。新生儿中蛋白结合药物运输的增加可能导致这些抗惊厥药物在新生儿脑中浓度（即脑/血浆比率）的增加。[对人类癫痫治疗的影响进行了讨论。]
The extraction of heroin, caffeine, diphenylhydantoin and phenobarbital was measured in the newborn, suckling and adult brain. Anticonvulsant drugs such as diphenylhydantoin and phenobarbital are bound by plasma protein, and it is generally believed that only the fraction of drug that is free (dialyzable) in vitro is available for transport through the blood-brain barrier in vivo. In both the adult and neonatal rat or rabbit, lipid-mediated transport of free phenytoin occurs. A fraction of the drug that enters the capillary bound to plasma protein also gains access to the brain. A greater amount of protein-bound drug permeates the newborn brain, and this is ascribed to a longer capillary transit time in the neonate. With regard to phenobarbital, the total (i.e., both free and protein-bound) plasma drug enters the newborn brain. No protein-bound phenobarbital permeates the adult brain, and it is only the free drug fraction that gains access to the brain. Since the blood-brain barrier permeability-surface area product for the 2 anticonvulsants is unchanged in newborn and older animals, the age-related differences in brain uptake of protein-bound drugs can be attributed to developmental changes in cerebral blood flow and capillary transit time. The increased transport of protein-bound drugs in the newborn may cause increased concentrations (i.e., brain/plasma ratios) of these anticonvulsants in the neonatal brain. [Implications for treatment of epilepsy in humans are discussed.].