The impact of P-glycoprotein on the disposition of drugs targeted for indications of the central nervous system: Evaluation using the MDR1A/1B knockout mouse model
The impact of P-glycoprotein on the disposition of drugs targeted for indications of the central nervous system: Evaluation using the MDR1A/1B knockout mouse model
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DOI：
10.1124/dmd.104.001230
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发表时间：
2005-01-01
影响因子：
3.9
通讯作者：
Zhang, CH
中科院分区：
文献类型：
--
作者：
Doran, A;Obach, RS;Zhang, CH
皮下注射后，在 P-糖蛋白 (P-gp) 敲除小鼠模型中的脑、血浆和脑脊液中测量了用于治疗中枢神经系统 (CNS) 各种病症的 32 种结构不同的药物，以及两种活性代谢物和 8 种非 CNS 药物，并将数据与野生型小鼠中获得的相应数据进行了比较。 CNS 药物的总脑与血浆 (B/P) 比率范围为 0.060 至 24。在 34 种 CNS 活性药物中，只有 7 种显示 P-gp 敲除小鼠和野生型小鼠之间血浆浓度曲线下的 B/P 面积比与统一没有显着差异。大多数其余药物在 P-gp 敲除小鼠中的 B/P 比值比野生型小鼠高 1.1 至 2.6 倍。第三，利培酮、其活性代谢物 9-羟基利培酮和甲氧氯普胺在基因敲除小鼠和野生型小鼠之间的 B/P 比值显示出显着差异（6.6 至 17 倍）。野生型和基因敲除动物之间的 B/P 比值和脑脊液/血浆比值的差异是相关的。通过使用该模型，大多数 CNS 活性剂似乎至少表现出一些 P-gp 介导的转运，可以影响大脑浓度。然而，对大多数代理商的影响可能很小。利培酮的例子说明，即使是好的 P-gp 底物仍然可以成为临床上有用的 CNS 活性剂。然而，对于此类药物，未结合的血浆浓度可能需要大于使用受体亲和力数据预测的值，以实现足够的受体占据效果。
Thirty-two structurally diverse drugs used for the treatment of various conditions of the central nervous system (CNS), along with two active metabolites, and eight non-CNS drugs were measured in brain, plasma, and cerebrospinal fluid in the P-glycoprotein (P-gp) knockout mouse model after subcutaneous administration, and the data were compared with corresponding data obtained in wild-type mice. Total brain-to-plasma (B/P) ratios for the CNS agents ranged from 0.060 to 24. Of the 34 CNS-active agents, only 7 demonstrated B/P area under the plasma concentration curve ratios between P-gp knockout and wild-type mice that did not differ significantly from unity. Most of the remaining drugs demonstrated 1.1- to 2.6-fold greater B/P ratios in P-gp knockout mice versus wild-type mice. Three, risperidone, its active metabolite 9-hydroxyrisperidone, and metoclopramide, showed marked differences in B/P ratios between knockout and wild-type mice (6.6- to 17-fold). Differences in B/P ratios and cerebrospinal fluid/plasma ratios between wild-type and knockout animals were correlated. Through the use of this model, it appears that most CNS-active agents demonstrate at least some P-gp-mediated transport that can affect brain concentrations. However, the impact for the majority of agents is probably minor. The example of risperidone illustrates that even good P-gp substrates can still be clinically useful CNS-active agents. However, for such agents, unbound plasma concentrations may need to be greater than values projected using receptor affinity data to achieve adequate receptor occupancy for effect.