Chishty M, Reichel A, Siva J, Abbott N J, Begley D J
Blood-Brain Barrier Research Group, Centre for Neuroscience Research, GKT School of Biomedical Sciences, King's College London, Hodgkin Building, Guy's Campus, London SE1 1UL, U.K.
J Drug Target. 2001 Jun;9(3):223-8. doi: 10.3109/10611860108997930.
First generation H1 receptor antagonists are often associated with adverse CNS effects such as sedation, whereas modern, second generation antihistamines are generally non-sedating. The difference in therapeutic profile is mainly due to the poor CNS penetration of the modern derivatives. Current explanations for the differential ability of classical and modern 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 [3H]-colchicine was examined using the immortalised rat brain endothelial cell line, RBE4, an established in vitro model of the BBB expressing Pgp. All second generation antihistamines tested, significantly increased net accumulation of [3H]-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 modern 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.
第一代H1受体拮抗剂常与诸如镇静等不良中枢神经系统效应相关，而现代的第二代抗组胺药通常不具有镇静作用。治疗特性的差异主要是由于现代衍生物对中枢神经系统的穿透性较差。基于亲脂性或蛋白质结合的差异，目前对经典和现代抗组胺药穿越血脑屏障（BBB）能力不同的解释并不充分。我们检验了这样一个假设：无镇静作用的抗组胺药由于被体内形成血脑屏障的脑内皮细胞腔表面表达的P-糖蛋白（Pgp）药物外排泵识别而无法进入中枢神经系统。使用永生化大鼠脑内皮细胞系RBE4（一种已建立的表达Pgp的血脑屏障体外模型）检测了几种有镇静作用和无镇静作用的抗组胺药影响Pgp模型底物[3H] -秋水仙碱摄取的能力。所有测试的第二代抗组胺药均显著增加了[3H] -秋水仙碱的净积累，使其达到与Pgp抑制剂维拉帕米所引起的水平相似。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血脑屏障处与Pgp相互作用能力的差异可能决定它们的中枢神经系统穿透性，进而决定是否存在中枢副作用。
