GlaxoSmithKline, Clinical Imaging Centre, Hammersmith Hospital, London, UK.
J Cereb Blood Flow Metab. 2012 May;32(5):874-83. doi: 10.1038/jcbfm.2012.1. Epub 2012 Jan 25.
The passage of drugs in and out of the brain is controlled by the blood-brain barrier (BBB), typically, using either passive diffusion across a concentration gradient or active transport via a protein carrier. In-vitro and preclinical measurements of BBB penetration do not always accurately predict the in-vivo situation in humans. Thus, the ability to assay the concentration of novel drug candidates in the human brain in vivo provides valuable information for de-risking of candidate molecules early in drug development. Here, positron emission tomography (PET) measurements are combined with in-vitro equilibrium dialysis assays to enable assessment of transport and estimation of the free brain concentration in vivo. The PET and equilibrium dialysis data were obtained for 36 compounds in the pig. Predicted P-glycoprotein (P-gp) status of the compounds was consistent with the PET/equilibrium dialysis results. In particular, Loperamide, a well-known P-gp substrate, exhibited a significant concentration gradient consistent with active efflux and after inhibition of the P-gp process the gradient was removed. The ability to measure the free brain concentration and assess transport of novel compounds in the human brain with combined PET and equilibrium dialysis assays can be a useful tool in central nervous system (CNS) drug development.
药物在脑内外的传递受血脑屏障（BBB）的控制，通常通过浓度梯度的被动扩散或通过蛋白载体的主动转运来实现。体外和临床前的 BBB 穿透测量并不总是能准确预测人类体内的情况。因此，能够在体内测定新型候选药物在人脑内的浓度，为药物开发早期候选分子的风险降低提供了有价值的信息。在这里，正电子发射断层扫描（PET）测量与体外平衡透析测定相结合，能够评估转运并估计体内游离脑浓度。在猪身上获得了 36 种化合物的 PET 和平衡透析数据。化合物的预测 P-糖蛋白（P-gp）状态与 PET/平衡透析结果一致。特别是洛哌丁胺，一种众所周知的 P-gp 底物，表现出与主动外排一致的显著浓度梯度，并且在抑制 P-gp 过程后，梯度被消除。用结合 PET 和平衡透析测定来测量新型化合物在人脑内的游离脑浓度和评估转运的能力，可能成为中枢神经系统（CNS）药物开发的有用工具。
