Transporter-mediated Efflux Influences CNS Side Effects: ABCB1, from Antitarget to Target.
Transporter-mediated Efflux Influences CNS Side Effects: ABCB1, from Antitarget to Target.
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DOI：
10.1002/minf.200900075
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发表时间：
2010-01-12
影响因子：
3.6
通讯作者：
Oprea, Tudor I.
中科院分区：
文献类型：
--
作者：
Broccatelli, Fabio;Carosati, Emanuele;Cruciani, Gabriele;Oprea, Tudor I.
我们研究了镇静和直立性低血压之间的关系，两个中心的副作用和ABCB 1转运介导的外排的一组64推出的药物，记录为组胺H1受体拮抗剂。将该关系置于被动扩散（使用LogP，辛醇/水分配系数估计）、受体亲和力和调整的治疗日剂量的背景下，以解释副作用的变异性。在这一组中，CNS渗透性不依赖于被动扩散，因为LogP及其pH校正等效物LogD 74没有发现显著差异。镇静和体位性低血压可以在ABCB 1介导的外排和调整剂量的框架内解释，而靶向效力的影响较小。ABCB 1是抗癌药物的抗靶标，实际上是非镇静抗组胺药物的药物靶标。基于这两种副作用的发生率、靶向亲和力和剂量的一组经验规则被用于预测许多药物的外排效应。其中，预计氮卓斯汀和咪唑斯汀通过ABCB 1介导的转运外排，而阿立哌唑、氯氮平、赛庚啶、伊潘立酮、奥氮平和齐拉西酮可能为非外排。
We examined the relationship between sedation and orthostatic hypotension, two central side effects and ABCB1 transporter-mediated efflux for a set of 64 launched drugs that are documented as histamine H1 receptor antagonists. This relationship was placed in the context of passive diffusion (estimated using LogP, the octanol/water partition coefficient), receptor affinity, and the adjusted therapeutic daily dose, in order to account for side effect variability. Within this set, CNS permeability was not dependent on passive diffusion, as no significant differences were found for LogP and its pH-corrected equivalent, LogD74. Sedation and orthostatic hypotension can be explained within the framework of ABCB1-mediated efflux and adjusted dose, while target potency has less influence. ABCB1, an antitarget for anti-cancer agents, acts in fact as a drug target for non-sedating antihistamines. An empirical set of rules, based on the incidence of these two side-effects, target affinity and dose was used to predict efflux effects for a number of drugs. Among them, azelastine and mizolastine are predicted to be effluxed via ABCB1-mediated transport, whereas aripiprazole, clozapine, cyproheptadine, iloperidone, olanzapine, and ziprasidone are likely to be non-effluxed.
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影响因子：
6.1
作者：
Mathews, Manu;Muzina, David J.
通讯作者：
Muzina, David J.
影响因子：
14.9
作者：
Harmar AJ;Hills RA;Rosser EM;Jones M;Buneman OP;Dunbar DR;Greenhill SD;Hale VA;Sharman JL;Bonner TI;Catterall WA;Davenport AP;Delagrange P;Dollery CT;Foord SM;Gutman GA;Laudet V;Neubig RR;Ohlstein EH;Olsen RW;Peters J;Pin JP;Ruffolo RR;Searls DB;Wright MW;Spedding M
通讯作者：
Spedding M
影响因子：
10.8
作者：
Benet, LZ;Wu, CY;Wacher, VJ
通讯作者：
Wacher, VJ
影响因子：
4.5
作者：
Chishty, M;Reichel, A;Begley, DJ
通讯作者：
Begley, DJ
影响因子：
3.9
作者：
Feng, Bo;Mills, Jessica B.;de Morais, Sonia M.
通讯作者：
de Morais, Sonia M.