Species Comparison of In Vivo P-Glycoprotein-Mediated Brain Efflux Using mdr1a-Deficient Rats and Mice
Species Comparison of In Vivo P-Glycoprotein-Mediated Brain Efflux Using mdr1a-Deficient Rats and Mice
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DOI：
10.1124/dmd.111.043083
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发表时间：
2012-03-01
影响因子：
3.9
通讯作者：
Garmer, Mats
中科院分区：
文献类型：
--
作者：
Bundgaard, Christoffer;Jensen, Christian Jes Nyberg;Garmer, Mats
本文所述的实验比较了一组已知中枢神经系统化合物在大鼠和小鼠之间体内P-糖蛋白（P-gp）介导的脑流出的程度。使用新引入的转基因mdr 1a缺陷大鼠和它们的基因活性对应物，评估脑血浆分布，并与mdr 1a缺陷和野生型小鼠的分布模式进行比较。四种化合物（阿立哌唑、西酞普兰、利培酮和文拉法辛）使用连续皮下渗透微型泵输注模式给药。在mdr 1a缺陷大鼠和小鼠及其野生型对应物中测量化合物（包括选定代谢物（9-羟基利培酮、O-去甲基-文拉法辛和N-去甲基-文拉法辛））的稳态脑和血浆浓度及其游离部分，以确定物种内和物种间基因型之间的总脑和未结合脑血浆分布。结果显示，在大鼠和小鼠的血脑屏障水平上，体内P-gp功能之间存在定性和定量相似性。所有测试的化合物在mdr 1a缺陷的大鼠和小鼠中的脑血浆分布均显著高于野生型。此外，mdr 1a缺陷大鼠和野生型大鼠之间脑渗透程度的相对增强可能与小鼠中获得的增强比率直接相关。从未结合的脑到未结合的血浆分布，P-gp对总体脑渗透能力的影响显示，对于测试的化合物，大鼠和小鼠之间存在微小差异。总之，大鼠和小鼠之间的P-gp的功能性作用，相对于由该转运介导的脑外排的建议。
The experiments described herein compared the extent of in vivo P-glycoprotein (P-gp)-mediated brain efflux between rats and mice for a set of known central nervous system compounds. With use of newly introduced genetically modified mdr1a-deficient rats and their gene-competent counterparts, the brain to plasma distribution was assessed and compared with the distribution pattern in mdr1a-deficient and wild-type mice. Four compounds (aripiprazole, citalopram, risperidone, and venlafaxine) were administered using a continuous subcutaneous osmotic minipump infusion paradigm. Steady-state brain and plasma concentrations of the compounds, including selected metabolites (9-hydroxyrisperidone, O-desmethyl-venlafaxine and N-desmethyl-venlafaxine) were measured in mdr1a-deficient rats and mice and their wild-type counterparts along with their free fractions to determine total and unbound brain to plasma distribution between genotypes within and between species. The results revealed qualitative as well as quantitative similarities between P-gp functionality in vivo at the blood-brain barrier level in rats and mice. All compounds tested were shown to have a significantly higher brain to plasma distribution in both mdr1a-deficient rats and mice compared with that in their wild-type counterparts. Moreover, the relative enhancement in extent of brain penetration between mdr1a-deficient and wild-type rats could be directly correlated to the enhancement ratios obtained in mice. From the unbound brain to unbound plasma distributions, the impact of P-gp on the overall brain penetration capabilities showed minor differences between rats and mice for the compounds tested. In conclusion, a comparable functional role of P-gp between rats and mice with respect to brain efflux mediated by this transporter is suggested.