PDF(Pubmed)
Abstract：
BACKGROUND: Oxycodone active uptake across the blood-brain barrier (BBB) is associated with the putative proton-coupled organic cation (H+/OC) antiporter system. Yet, the activity of this system at the blood-cerebrospinal fluid barrier (BCSFB) is not fully understood. Additionally, sex differences in systemic pharmacokinetics and pharmacodynamics of oxycodone has been reported, but whether the previous observations involve sex differences in the function of the H+/OC antiporter system remain unknown. The objective of this study was, therefore, to investigate the extent of oxycodone transport across the BBB and the BCSFB in female and male Sprague-Dawley rats using microdialysis.
METHODS: Microdialysis probes were implanted in the blood and two of the following brain locations: striatum and lateral ventricle or cisterna magna. Oxycodone was administered as an intravenous infusion, and dialysate, blood and brain were collected. Unbound partition coefficients (Kp,uu) were calculated to understand the extent of oxycodone transport across the blood-brain barriers. Non-compartmental analysis was conducted using Phoenix 64 WinNonlin. GraphPad Prism version 9.0.0 was used to perform t-tests, one-way and two-way analysis of variance followed by Tukey\'s or Šídák\'s multiple comparison tests. Differences were considered significant at p < 0.05.
RESULTS: The extent of transport at the BBB measured in striatum was 4.44 ± 1.02 (Kp,uu,STR), in the lateral ventricle 3.41 ± 0.74 (Kp,uu,LV) and in cisterna magna 2.68 ± 1.01 (Kp,uu,CM). These Kp,uu values indicate that the extent of oxycodone transport is significantly lower at the BCSFB compared with that at the BBB, but still confirm the presence of active uptake at both blood-brain interfaces. No significant sex differences were observed in neither the extent of oxycodone delivery to the brain, nor in the systemic pharmacokinetics of oxycodone.
CONCLUSIONS: The findings clearly show that active uptake is present at both the BCSFB and the BBB. Despite some underestimation of the extent of oxycodone delivery to the brain, CSF may be an acceptable surrogate of brain ISF for oxycodone, and potentially also other drugs actively transported into the brain via the H+/OC antiporter system.
METHODS: Microdialysis probes were implanted in the blood and two of the following brain locations: striatum and lateral ventricle or cisterna magna. Oxycodone was administered as an intravenous infusion, and dialysate, blood and brain were collected. Unbound partition coefficients (Kp,uu) were calculated to understand the extent of oxycodone transport across the blood-brain barriers. Non-compartmental analysis was conducted using Phoenix 64 WinNonlin. GraphPad Prism version 9.0.0 was used to perform t-tests, one-way and two-way analysis of variance followed by Tukey\'s or Šídák\'s multiple comparison tests. Differences were considered significant at p < 0.05.
RESULTS: The extent of transport at the BBB measured in striatum was 4.44 ± 1.02 (Kp,uu,STR), in the lateral ventricle 3.41 ± 0.74 (Kp,uu,LV) and in cisterna magna 2.68 ± 1.01 (Kp,uu,CM). These Kp,uu values indicate that the extent of oxycodone transport is significantly lower at the BCSFB compared with that at the BBB, but still confirm the presence of active uptake at both blood-brain interfaces. No significant sex differences were observed in neither the extent of oxycodone delivery to the brain, nor in the systemic pharmacokinetics of oxycodone.
CONCLUSIONS: The findings clearly show that active uptake is present at both the BCSFB and the BBB. Despite some underestimation of the extent of oxycodone delivery to the brain, CSF may be an acceptable surrogate of brain ISF for oxycodone, and potentially also other drugs actively transported into the brain via the H+/OC antiporter system.
摘要：
背景：羟考酮通过血脑屏障（BBB）的主动摄取与推定的质子偶联有机阳离子（H/OC）反转运系统有关。然而，该系统在血-脑脊液屏障（BCSFB）的活性尚未完全了解。此外,已经报道了羟考酮的全身药代动力学和药效学的性别差异，但是先前的观察结果是否涉及H/OC反转运蛋白系统功能的性别差异仍然未知。这项研究的目的是,因此,使用微透析研究雌性和雄性Sprague-Dawley大鼠中羟考酮跨BBB和BCSFB的转运程度。
方法：将微透析探针植入血液和以下两个大脑位置：纹状体和侧脑室或大脑池。羟考酮作为静脉输注给药，和透析液,收集血液和大脑。无界分区系数(Kp，uu）的计算是为了了解羟考酮穿过血脑屏障的转运程度。使用Phoenix64WinNonlin进行非房室分析。GraphPadPrism9.0.0版用于执行t检验，单向和双向方差分析，然后进行Tukey's或Sildák's多重比较检验。在p<0.05时,认为差异显著。
结果：纹状体中测得的BBB的转运程度为4.44±1.02（Kp，uu,STR),在侧脑室3.41±0.74（Kp，uu,LV）和大水箱2.68±1.01（Kp，uu,CM)。这些Kp,uu值表明，与BBB相比，BCSFB的羟考酮转运程度显着降低，但仍然证实在两个血脑界面都存在主动摄取。在羟考酮向大脑的递送程度方面均未观察到显着的性别差异，在羟考酮的全身药代动力学中也没有。
结论：研究结果清楚地表明，BCSFB和BBB均存在主动摄取。尽管低估了羟考酮向大脑的递送程度，CSF可能是可接受的替代脑内ISF的羟考酮，以及潜在的其他药物通过H+/OC反转运系统主动转运到大脑中。
方法：将微透析探针植入血液和以下两个大脑位置：纹状体和侧脑室或大脑池。羟考酮作为静脉输注给药，和透析液,收集血液和大脑。无界分区系数(Kp，uu）的计算是为了了解羟考酮穿过血脑屏障的转运程度。使用Phoenix64WinNonlin进行非房室分析。GraphPadPrism9.0.0版用于执行t检验，单向和双向方差分析，然后进行Tukey's或Sildák's多重比较检验。在p<0.05时,认为差异显著。
结果：纹状体中测得的BBB的转运程度为4.44±1.02（Kp，uu,STR),在侧脑室3.41±0.74（Kp，uu,LV）和大水箱2.68±1.01（Kp，uu,CM)。这些Kp,uu值表明，与BBB相比，BCSFB的羟考酮转运程度显着降低，但仍然证实在两个血脑界面都存在主动摄取。在羟考酮向大脑的递送程度方面均未观察到显着的性别差异，在羟考酮的全身药代动力学中也没有。
结论：研究结果清楚地表明，BCSFB和BBB均存在主动摄取。尽管低估了羟考酮向大脑的递送程度，CSF可能是可接受的替代脑内ISF的羟考酮，以及潜在的其他药物通过H+/OC反转运系统主动转运到大脑中。
