Boström Emma, Simonsson Ulrika S H, Hammarlund-Udenaes Margareta
Division of Pharmacokinetics and Drug Therapy, Department of Pharmaceutical Biosciences, Uppsala University, Box 591, SE-751 24 Uppsala, Sweden.
Drug Metab Dispos. 2006 Sep;34(9):1624-31. doi: 10.1124/dmd.106.009746. Epub 2006 Jun 8.
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 described the pharmacokinetics for oxycodone in blood and plasma, whereas a one-compartment model was sufficient to describe the pharmacokinetics in the brain. The BBB transport of oxycodone was parameterized as CL(in) and K(p,uu). CL(in) describes the clearance of oxycodone across the BBB into the brain, whereas K(p,uu) describes the extent of drug equilibration across the BBB. CL(in) across the BBB was estimated to 1910 microl/min x g brain. K(p,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.
在大鼠中研究了氧可酮的血脑屏障（BBB）转运。将微透析探针插入纹状体和颈静脉。10只动物给予单次推注剂量，随后进行120分钟的恒速输注，以研究氧可酮血脑屏障平衡的稳态概念。另外10只动物给予60分钟的恒速输注，以研究跨血脑屏障的平衡速率。氧可酮-D3用作微透析实验的校准剂。样品采用液相色谱-串联质谱法进行分析，并使用群体药代动力学模型，通过NONMEM同时拟合所有数据。一个允许静脉和动脉隔室之间存在延迟的二室模型最能描述血液和血浆中氧可酮的药代动力学，而一室模型足以描述脑中的药代动力学。氧可酮的血脑屏障转运参数化为CL（in）和K（p，uu）。CL（in）描述了氧可酮跨血脑屏障进入脑内的清除率，而K（p，uu）描述了药物跨血脑屏障的平衡程度。跨血脑屏障的CL（in）估计为1910微升/分钟×克脑。K（p，uu）估计为3.0，这意味着脑内氧可酮的未结合浓度比血液中高3倍，这表明氧可酮在血脑屏障处有主动内流。这是阿片类药物在脑内具有高于1的未结合稳态浓度的首个证据，这可以解释氧可酮与其他阿片类药物之间的效价差异。
