Affinity for the P-glycoprotein efflux pump at the blood-brain barrier may explain the lack of CNS side-effects of modern antihistamines
Affinity for the P-glycoprotein efflux pump at the blood-brain barrier may explain the lack of CNS side-effects of modern antihistamines
复制标题
DOI：
10.3109/10611860108997930
复制
发表时间：
2001-01-01
影响因子：
4.5
通讯作者：
Begley, DJ
中科院分区：
文献类型：
--
作者：
Chishty, M;Reichel, A;Begley, DJ
第一代H1受体拮抗剂通常与不利的CNS作用如镇静作用相关，而现代的第二代抗组胺药通常不具有镇静作用。治疗特征的差异主要是由于现代衍生物的CNS渗透性差。目前的经典和现代抗组胺药的差异能力的解释，通过血脑屏障（BBB），亲脂性或蛋白结合的基础上的差异，是不够的。我们已经验证了这样的假设，即非镇静性抗组胺药不能进入CNS是由于在体内形成BBB的脑内皮细胞的管腔表面上表达的P-糖蛋白（Pgp）药物外排泵的识别。使用永生化的大鼠脑内皮细胞系RBE 4，建立的表达Pq的BBB的体外模型。测试的所有第二代抗组胺药均显著增加[H-3]-秋水仙碱的净蓄积至与Pgp抑制剂维拉帕米引起的水平相似的水平。相比之下，第一代抗组胺药对Pgp没有亲和力。结果表明，经典和现代抗组胺药在BBB与Pgp相互作用的能力的差异可能决定了它们的CNS渗透性，从而决定了是否存在中枢副作用。
First generation Hl receptor antagonists are often associated with adverse CNS effects such as sedation, whereas modem, second generation antihistamines are generally non-sedating. The difference in therapeutic profile is mainly due to the poor CNS penetration of the modem derivatives. Current explanations for the differential ability of classical and modem antihistamines to cross the blood-brain barrier (BBB), based on differences in lipophilicity or protein binding, are inadequate. We have tested the hypothesis that non-sedating antihistamines fail to enter the CNS due to recognition by the P-glycoprotein (Pgp) drug efflux pump expressed on the luminal surface of cerebral endothelial cells forming the BBB in vivo.The ability of several sedating and non-sedating antihistamines to affect the uptake of the Pgp model substrate [H-3]-colchicine was examined using the immortalised rat brain endothelial cell line, RBE4, an established in vitro model of the BBB expressing Pq. All second generation antihistamines tested, significantly increased net accumulation of [H-3]-colchicine to a level similar to that caused by the Pgp inhibitor verapamil. By contrast, the first generation antihistamines showed no affinity for Pgp. The results indicate that differences in the ability of classical and modem antihistamines to interact with Pgp at the BBB may determine their CNS penetration and as a consequence the presence or absence of central side-effects.