Translational Pharmacokinetics/Pharmacodynamics Group (tPKPD), Department of Pharmacy, Uppsala University, Husargatan 3, 752 37, Uppsala, Sweden.
School of Applied Sciences, Abertay University, Bell Street, Dundee, DD1 1HG, Scotland, UK.
Fluids Barriers CNS. 2024 Oct 23;21(1):86. doi: 10.1186/s12987-024-00583-z.
The primary objective of this study was to advance our understanding of active drug uptake at brain barriers in higher species than rodents, by examining oxycodone brain concentrations in pigs.
This was investigated by a microdialysis study in healthy and endotoxemic conditions to increase the understanding of inter-species translation of putative proton-coupled organic cation (H/OC) antiporter-mediated central nervous system (CNS) drug delivery in health and pathology, and facilitate the extrapolation to humans for improved CNS drug treatment in patients. Additionally, we sought to evaluate the efficacy of lumbar cerebrospinal fluid (CSF) exposure readout as a proxy for brain unbound interstitial fluid (ISF) concentrations. By simultaneously monitoring unbound concentrations in blood, the frontal cortical area, the lateral ventricle (LV), and the lumbar intrathecal space in healthy and lipopolysaccharide (LPS)-induced inflammation states within the same animal, we achieved exceptional spatiotemporal resolution in mapping oxycodone transport across CNS barriers.
Our findings provide novel evidence of higher unbound oxycodone concentrations in brain ISF compared to blood, yielding an unbound brain-to-plasma concentration ratio (K) of 2.5. This supports the hypothesis of the presence of the H/OC antiporter system at the blood-brain barrier (BBB) in pigs. Despite significant physiological changes, reflected in pig Sequential Organ Failure Assessment, pSOFA scores, oxycodone blood concentrations and its active net uptake across the BBB remained nearly unchanged during three hours of i.v. infusion of 4 µg/kg/h LPS from Escherichia coli (O111:B4). Mean K values indicated active uptake also at the blood-CSF barrier in healthy and endotoxemic pigs. Lumbar CSF concentrations showed minimal inter-individual variability during the experiment, with a mean K of 1.5. LPS challenge caused a slight decrease in K, while K remained unaffected.
This study enhances our understanding of oxycodone pharmacokinetics and CNS drug delivery in both healthy and inflamed conditions, providing crucial insights for translating these findings to clinical settings.
本研究的主要目的是通过研究猪体内的羟考酮脑浓度，深入了解高于啮齿动物的高等物种中脑屏障的主动药物摄取。
这是通过一项微透析研究来实现的，研究对象包括健康和内毒素血症两种情况，旨在增加对健康和病理状态下假定质子偶联有机阳离子（H/OC）转运体介导的中枢神经系统（CNS）药物传递的种间转化的理解，并促进向人类的外推，以改善患者的中枢神经系统药物治疗。此外，我们还试图评估腰椎脑脊液（CSF）暴露读数作为脑无结合间隙液（ISF）浓度的替代指标的效果。通过同时监测血液、额皮质区、侧脑室（LV）和健康及脂多糖（LPS）诱导的炎症状态下的腰椎鞘内空间中未结合的浓度，我们在映射羟考酮穿过中枢神经系统屏障的过程中实现了卓越的时空分辨率。
我们的发现为脑 ISF 中未结合的羟考酮浓度高于血液提供了新的证据，得出了脑-血浆未结合浓度比（K）为 2.5。这支持了 H/OC 转运体系统在猪血脑屏障（BBB）存在的假说。尽管存在显著的生理变化，反映在猪序贯器官衰竭评估（Sequential Organ Failure Assessment，SOFA）评分上，但在大肠杆菌（O111:B4）4μg/kg/h LPS 静脉输注 3 小时期间，羟考酮的血药浓度及其主动净透过 BBB 仍几乎保持不变。健康和内毒素血症猪的平均 K 值表明在血脑屏障和血脑脊液屏障中也存在主动摄取。在实验过程中，腰椎 CSF 浓度的个体间差异最小，平均 K 值为 1.5。LPS 挑战导致 K 值略有下降，而 K 值不受影响。
本研究增强了我们对健康和炎症状态下羟考酮药代动力学和中枢神经系统药物传递的理解，为将这些发现转化为临床环境提供了关键的见解。
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