Saleh Mohammed A A, de Lange Elizabeth C M
Division of Systems Biomedicine and Pharmacology, Leiden Academic Center for Drug Research, Leiden University, 2333 CC Leiden, The Netherlands.
Pharmaceutics. 2021 Jan 13;13(1):95. doi: 10.3390/pharmaceutics13010095.
The blood-brain barrier (BBB) is equipped with unique physical and functional processes that control central nervous system (CNS) drug transport and the resulting concentration-time profiles (PK). In CNS diseases, the altered BBB and CNS pathophysiology may affect the CNS PK at the drug target sites in the brain extracellular fluid (brain) and intracellular fluid (brain) that may result in changes in CNS drug effects. Here, we used our human CNS physiologically-based PK model (LeiCNS-PK3.0) to investigate the impact of altered cerebral blood flow (CBF), tight junction paracellular pore radius (para), brain volume, and pH of brain (pH) and of brain (pH) on brain and brain PK for 46 small drugs with distinct physicochemical properties. LeiCNS-PK3.0 simulations showed a drug-dependent effect of the pathophysiological changes on the rate and extent of BBB transport and on brain and brain PK. Altered para, pH, and pH affected both the rate and extent of BBB drug transport, whereas changes in CBF and brain volume modestly affected the rate of BBB drug transport. While the focus is often on BBB paracellular and active transport processes, this study indicates that also changes in pH should be considered for their important implications on brain and brain target site PK.
血脑屏障（BBB）具有独特的物理和功能过程，可控制中枢神经系统（CNS）药物转运以及由此产生的浓度-时间曲线（PK）。在中枢神经系统疾病中，血脑屏障和中枢神经系统病理生理学的改变可能会影响脑细胞外液（脑）和细胞内液（脑）中药物靶点部位的中枢神经系统PK，这可能导致中枢神经系统药物效应的变化。在此，我们使用我们的基于人体中枢神经系统生理学的PK模型（LeiCNS-PK3.0），研究脑血流量（CBF）、紧密连接旁细胞孔半径（para）、脑体积以及脑（pH）和脑（pH）的改变对46种具有不同理化性质的小分子药物的脑和脑PK的影响。LeiCNS-PK3.0模拟显示，病理生理变化对血脑屏障转运速率和程度以及脑和脑PK具有药物依赖性效应。Para、pH和pH的改变影响血脑屏障药物转运的速率和程度，而CBF和脑体积的变化对血脑屏障药物转运速率有适度影响。虽然研究重点通常是血脑屏障的旁细胞和主动转运过程，但本研究表明，pH的变化因其对脑和脑靶点部位PK的重要影响也应予以考虑。
