Translational Pharmacokinetics/Pharmacodynamics group (tPKPD), Department of Pharmacy, Uppsala University, Box 580, 75123, Uppsala, Sweden.
Pharm Res. 2023 Nov;40(11):2715-2730. doi: 10.1007/s11095-023-03583-0. Epub 2023 Aug 23.
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.
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 (K) 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.
The extent of transport at the BBB measured in striatum was 4.44 ± 1.02 (K), in the lateral ventricle 3.41 ± 0.74 (K) and in cisterna magna 2.68 ± 1.01 (K). These K 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.
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.
阿片类药物穿过血脑屏障（BBB）的主动摄取与假定的质子偶联有机阳离子（H/OC）转运体系统有关。然而，该系统在血脑脊液屏障（BCSFB）中的活性尚未完全了解。此外，已报道阿片类药物在全身药代动力学和药效学方面存在性别差异，但以前的观察结果是否涉及 H/OC 转运体系统的功能存在性别差异尚不清楚。因此，本研究的目的是使用微透析法研究雌性和雄性 Sprague-Dawley 大鼠 BBB 和 BCSFB 中阿片类药物的摄取程度。
将微透析探针植入血液和以下两个脑区之一：纹状体和侧脑室或枕大池。阿片类药物作为静脉输注给药，并收集透析液、血液和脑。计算未结合分配系数（K）以了解阿片类药物穿过血脑屏障的摄取程度。使用 Phoenix 64 WinNonlin 进行非房室分析。GraphPad Prism 版本 9.0.0 用于执行 t 检验、单因素和双因素方差分析，然后进行 Tukey 或 Šídák 的多重比较检验。差异有统计学意义的 p 值<0.05。
纹状体测量的 BBB 转运程度为 4.44±1.02（K），侧脑室为 3.41±0.74（K），枕大池为 2.68±1.01（K）。这些 K 值表明，阿片类药物在 BCSFB 的转运程度明显低于 BBB，但仍证实两种血脑界面均存在主动摄取。在脑内阿片类药物的递送程度或阿片类药物的全身药代动力学方面，均未观察到明显的性别差异。
研究结果清楚地表明，主动摄取存在于 BCSFB 和 BBB 中。尽管对脑内阿片类药物递送程度的估计有些低估，但 CSF 可能是阿片类药物的脑 ISF 的可接受替代物，并且可能也是通过 H/OC 转运体系统主动转运到脑内的其他药物的替代物。
