Development of a Rat Plasma and Brain Extracellular Fluid Pharmacokinetic Model for Bupropion and Hydroxybupropion Based on Microdialysis Sampling, and Application to Predict Human Brain Concentrations
Development of a Rat Plasma and Brain Extracellular Fluid Pharmacokinetic Model for Bupropion and Hydroxybupropion Based on Microdialysis Sampling, and Application to Predict Human Brain Concentrations
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DOI：
10.1124/dmd.115.068932
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发表时间：
2016-05-01
影响因子：
3.9
通讯作者：
Stratford, Robert E., Jr.
中科院分区：
文献类型：
--
作者：
Cremers, Thomas I. F. H.;Flik, Gunnar;Stratford, Robert E., Jr.
给大鼠施用安非他酮[(+/-)-2-(叔丁基氨基)-1-(3-氯苯基)丙-1-酮]及其预先形成的活性代谢物羟基安非他酮[(6)-1-(3-氯苯基)-2-[(1-羟基-2-甲基-2-丙基)氨基]1-丙酮]，通过血浆和脑细胞外液的定量微透析采样测量未结合浓度，开发隔室药代动力学模型来描述两种物质的血脑屏障转运。群体模型揭示了两个实体穿过血脑屏障的快速平衡，由此得出的安非他酮和羟基安非他酮的稳态脑细胞外液/血浆未结合浓度比估计值分别为 1.9 和 1.7，因此表明净摄取不对称。使用安非他酮观察到早期时间点脑细胞外液/血浆未结合浓度比的超调；这被建模为药物穿过血脑屏障的时间依赖性吸收清除。该模型的翻译用于预测每日两次施用 150 mg 安非他酮后人脑细胞外液中安非他酮和羟基安非他酮的暴露量。预测浓度表明，在该治疗剂量下，预计代谢物会优先抑制多巴胺和去甲肾上腺素转运蛋白，而安非他酮几乎没有作用。因此，这些结果扩展了对多巴胺转运蛋白占用的核成像研究，并表明抑制两种转运蛋白对安非他酮的治疗功效有显着贡献。
Administration of bupropion [(+/-)-2-(tert-butylamino)-1-(3-chlorophenyl) propan-1-one] and its preformed active metabolite, hydroxybupropion [(6)-1-(3-chlorophenyl)-2-[(1-hydroxy-2-methyl-2-propanyl) amino]1-propanone], to rats with measurement of unbound concentrations by quantitative microdialysis sampling of plasma and brain extracellular fluid was used to develop a compartmental pharmacokinetics model to describe the blood-brain barrier transport of both substances. The population model revealed rapid equilibration of both entities across the blood-brain barrier, with resultant steady-state brain extracellular fluid/plasma unbound concentration ratio estimates of 1.9 and 1.7 for bupropion and hydroxybupropion, respectively, which is thus indicative of a net uptake asymmetry. An overshoot of the brain extracellular fluid/plasma unbound concentration ratio at early time points was observed with bupropion; this was modeled as a time-dependent uptake clearance of the drug across the blood-brain barrier. Translation of the model was used to predict bupropion and hydroxybupropion exposure in human brain extracellular fluid after twice-daily administration of 150 mg bupropion. Predicted concentrations indicate that preferential inhibition of the dopamine and norepinephrine transporters by the metabolite, with little to no contribution by bupropion, would be expected at this therapeutic dose. Therefore, these results extend nuclear imaging studies on dopamine transporter occupancy and suggest that inhibition of both transporters contributes significantly to bupropion's therapeutic efficacy.