Unbound Drug Concentration in Brain Homogenate and Cerebral Spinal Fluid at Steady State as a Surrogate for Unbound Concentration in Brain Interstitial Fluid
Unbound Drug Concentration in Brain Homogenate and Cerebral Spinal Fluid at Steady State as a Surrogate for Unbound Concentration in Brain Interstitial Fluid
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DOI：
10.1124/dmd.108.024125
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发表时间：
2009-04-01
影响因子：
3.9
通讯作者：
Monshouwer, Mario
中科院分区：
文献类型：
--
作者：
Liu, Xingrong;Van Natta, Kristine;Monshouwer, Mario
本研究的目的是检验用脑匀浆法测定的非结合脑浓度（C(ub)）、脑脊液浓度（C(CSF)）和非结合血浆浓度（C(up)）代替脑微透析测定的脑间质液浓度（C(m)）的准确性。选择卡马西平、西酞普兰、更昔洛韦、甲氧氯普胺、n -去甲基氯氮平、奎尼丁、利培酮、9-羟基利培酮和硫喷妥9种化合物，分别在大鼠体内静脉注射（最高5mg /kg），然后持续静脉输注（1- 9mg /kg/h） 6小时。9个化合物中有8个化合物的C(b)s与C(m)的比值在3倍以内；硫喷妥钠的C(m)是C(b)的4倍。9个化合物中有8个化合物的C(CSF)s在其对应C(m)的3倍以内；9-羟基利培酮的C（CSF）是其C(m)的5倍。9个化合物中有5个化合物的C(up)s值在其C(m)值的3倍以内；四种化合物（更昔洛韦、甲氧氯普胺、奎尼丁和9-羟基利培酮）的C（up）是其C(m)的6- 14倍。综上所述，大多数化合物的C（ub）和C（CSF）在C(m)的3倍以内。对于亲脂性非p糖蛋白（-P-gp）底物，C(up)s小于C(m)的3倍，对于亲水性或P-gp底物，C(up)s大于C(m)的3倍。目前的研究表明，脑匀浆和脑脊液方法可以作为替代方法，在药物发现和开发环境中预测脑间质液浓度的误差在3倍以内。
The objective of the present study was to examine the accuracy of using unbound brain concentration determined by a brain homogenate method (C(ub)), cerebral spinal fluid concentration (C(CSF)), and unbound plasma concentration (C(up)) as a surrogate for brain interstitial fluid concentration determined by brain microdialysis (C(m)). Nine compounds-carbamazepine, citalopram, ganciclovir, metoclopramide, N-desmethylclozapine, quinidine, risperidone, 9-hydroxyrisperidone, and thiopental-were selected, and each was administered as an intravenous bolus (up to 5 mg/kg) followed by a constant intravenous infusion (1-9 mg/kg/h) for 6 h in rats. For eight of the nine compounds, the C(ub)s were within 3-fold of their C(m); thiopental had a C(m) 4-fold of its C(ub). The C(CSF)s of eight of the nine compounds were within 3-fold of their corresponding C(m); 9-hydroxyrisperidone showed a C(CSF) 5-fold of its C(m). The C(up)s of five of the nine compounds were within 3-fold of their C(m); four compounds (ganciclovir, metoclopramide, quinidine, and 9-hydroxyrisperidone) had C(up)s 6- to 14-fold of their C(m). In conclusion, the C(ub) and C(CSF) were within 3-fold of the C(m) for the majority of the compounds tested. The C(up)s were within 3-fold of C(m) for lipophilic non-P-glycoprotein (-P-gp) substrates and greater than 3-fold of C(m) for hydrophilic or P-gp substrates. The present study indicates that the brain homogenate and cerebral spinal fluid methods may be used as surrogate methods to predict brain interstitial fluid concentrations within 3-fold of error in drug discovery and development settings.