Drug interactions at the blood-brain barrier: fact or fantasy?
Drug interactions at the blood-brain barrier: fact or fantasy?
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DOI：
10.1016/j.pharmthera.2009.03.017
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发表时间：
2009-07
影响因子：
13.5
通讯作者：
Unadkat, Jashvant D.
中科院分区：
文献类型：
--
作者：
Eyal, Sara;Hsiao, Peng;Unadkat, Jashvant D.
关键词：
在血脑屏障（BBB）和血脑脊液屏障（BCSFB）的药物相互作用的治疗和不良后果有相当大的兴趣。这些包括用于治疗中枢神经系统疾病（如艾滋病痴呆和恶性肿瘤）的药物的疗效改变，以及通常难以渗透到大脑中的药物的神经毒性增强。BBB和BCSFB介导的相互作用是可能的，因为这些界面不仅是被动的解剖屏障，而且是动态的，因为它们表达各种流入和流出转运蛋白和药物代谢酶。基于在啮齿动物中的研究，已经广泛假设外排转运蛋白在药物递送方面在人血脑屏障中起重要作用。此外，假设啮齿动物中转运蛋白的化学抑制或其遗传消融可预测预期在人BBB处的相互作用的程度。然而，在人体中的研究挑战了这种成熟的范式，并声称这种药物相互作用的程度较小，但可能具有临床意义。本文综述了目前已知的药物在血脑屏障和血脑脊液屏障的相互作用机制，以及这种相互作用对人类的潜在影响。我们还探讨了这种药物相互作用是否可以从临床前研究中预测。明确BBB中药物间相互作用的机制和影响，对于改善CNS疾病治疗药物的疗效，同时最大限度地降低其毒性以及非CNS药物的神经毒性非常重要。
There is considerable interest in the therapeutic and adverse outcomes of drug interactions at the blood-brain barrier (BBB) and the blood-cerebrospinal fluid barrier (BCSFB). These include altered efficacy of drugs used in the treatment of CNS disorders, such as AIDS dementia and malignant tumors, and enhanced neurotoxicity of drugs that normally penetrate poorly into the brain. BBB- and BCSFB-mediated interactions are possible because these interfaces are not only passive anatomical barriers, but are also dynamic in that they express a variety of influx and efflux transporters and drug metabolizing enzymes. Based on studies in rodents, it has been widely postulated that efflux transporters play an important role at the human BBB in terms of drug delivery. Furthermore, it is assumed that chemical inhibition of transporters or their genetic ablation in rodents is predictive of the magnitude of interaction to be expected at the human BBB. However, studies in humans challenge this well-established paradigm and claim that such drug interactions will be lesser in magnitude but yet may be clinically significant. This review focuses on current known mechanisms of drug interactions at the blood-brain and blood-CSF barriers and the potential impact of such interactions in humans. We also explore whether such drug interactions can be predicted from preclinical studies. Defining the mechanisms and the impact of drug-drug interactions at the BBB is important for improving efficacy of drugs used in the treatment of CNS disorders while minimizing their toxicity as well as minimizing neurotoxicity of non-CNS drugs.
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DOI：
10.1124/jpet.106.104364
发表时间：
2006-08-01
影响因子：
3.5
作者：
Badagnani, Ilaria;Castro, Richard A.;Giacomini, Kathleen M.
通讯作者：
Giacomini, Kathleen M.
RLIP76，一种非ABC转运蛋白和癫痫中的耐药性。
影响因子：
2.4
作者：
Awasthi, S;Hallene, KL;Fazio, V;Singhal, SS;Cucullo, L;Awasthi, YC;Dini, G;Janigro, D
通讯作者：
Janigro, D
影响因子：
3.7
作者：
Adachi, Y;Suzuki, H;Sugiyama, Y
通讯作者：
Sugiyama, Y
影响因子：
5.7
作者：
Bart, J;Willemsen, ATM;Hendrikse, NH
通讯作者：
Hendrikse, NH
影响因子：
7.3
作者：
Baehr, Carsten;Reichel, Valeska;Fricker, Gert
通讯作者：
Fricker, Gert