In vivo blood-brain barrier transport of oxycodone in the rat:: Indications for active influx and implications for pharmacokinetics/pharmacodynamics
In vivo blood-brain barrier transport of oxycodone in the rat:: Indications for active influx and implications for pharmacokinetics/pharmacodynamics
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DOI：
10.1124/dmd.106.009746
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发表时间：
2006-09-01
影响因子：
3.9
通讯作者：
Hammarlund-Udenaes, Margareta
中科院分区：
文献类型：
--
作者：
Bostrom, Emma;Simonsson, Ulrika S. H.;Hammarlund-Udenaes, Margareta
本文研究了羟考酮在大鼠体内的血脑屏障转运。将微透析探头插入纹状体和颈静脉。10只动物被给予团注剂量，然后恒速输注120分钟，以研究羟考酮BBB平衡的稳态概念。另外10只动物被给予60分钟的恒速输液，以研究血脑屏障的平衡速度。羟考酮-D3作为微透析实验的校准剂。样品用液相色谱-串联质谱仪分析，群体药代动力学模型用NONMEM同时拟合出所有数据。两室模型允许静脉和动脉室之间的延迟是最好的血浆，而一室模型足以描述脑内的药代动力学。羟考酮的血脑屏障转运被参数化为Clin和K-p，K-Uu。Clin描述羟考酮通过血脑屏障进入大脑的清除，而Kp，Uu描述跨血脑屏障药物平衡的程度。跨血脑屏障密度估计为1910亩L/分钟(.)G大脑。Kp、Uu估计为3.0，说明羟考酮在脑内的游离浓度是血中的3倍，这是羟考酮主动进入血脑屏障的标志。这是阿片类药物在大脑中具有高于1的非结合稳态浓度的第一个证据，这可以解释羟考酮和其他阿片类药物之间的效力差异。
The blood-brain barrier (BBB) transport of oxycodone was studied in rats. Microdialysis probes were inserted into the striatum and vena jugularis. Ten animals were given a bolus dose followed by a 120-min constant rate infusion to study the steady-state concepts of oxycodone BBB equilibration. Another 10 animals were given a 60-min constant rate infusion to study the rate of equilibration across the BBB. Oxycodone-D3 was used as a calibrator for the microdialysis experiments. The samples were analyzed with a liquid chromatography-tandem mass spectrometry method and a population pharmacokinetic model was used to simultaneously fit all the data using NONMEM. A two-compartment model which allowed for a delay between the venous and arterial compartments best plasma, whereas a one-compartment model was sufficient to describe the pharmacokinetics in the brain. The BBB transport of oxycodone was parameterized as CLin and K-p,K-uu. CLin describes the clearance of oxycodone across the BBB into the brain, whereas Kp, uu describes the extent of drug equilibration across the BBB. CLin across the BBB was estimated to 1910 mu l/min (.) g brain. Kp, uu was estimated to 3.0, meaning that the unbound concentration of oxycodone in brain was 3 times higher than in blood, which is an indication of active influx of oxycodone at the BBB. This is the first evidence of an opioid having an unbound steady-state concentration in brain that is higher than unity, which can explain potency discrepancies between oxycodone and other opioids.