Combining PET Biodistribution and Equilibrium Dialysis Assays to Assess the Free Brain Concentration and BBB Transport of CNS Drugs

• Published in: Journal of cerebral blood flow and metabolism Vol. 32; no. 5; pp. 874 - 883
• Main Authors: Gunn, Roger N, Summerfield, Scott G, Salinas, Cristian A, Read, Kevin D, Guo, Qi, Searle, Graham E, Parker, Christine A, Jeffrey, Phil, Laruelle, Marc
• Format: Journal Article
• Language: English
• Published: London, England SAGE Publications 01-05-2012; Nature Publishing Group; Sage Publications Ltd
• Subjects: Active transport; Animals; Antidiarrheals - pharmacokinetics; ATP-Binding Cassette, Sub-Family B, Member 1 - metabolism; Biological and medical sciences; Blood-brain barrier; Blood-Brain Barrier - diagnostic imaging; Blood-Brain Barrier - metabolism; Brain; Central nervous system; Cerebral blood flow; Computer Simulation; Data processing; Diffusion; Drug Design; Drug development; Drugs; Equilibrium dialysis; Humans; Investigative techniques, diagnostic techniques (general aspects); Loperamide - pharmacokinetics; Medical sciences; Models, Biological; Nervous system; Neurology; Original; P-Glycoprotein; Positron emission tomography; Radiography; Swine; Ultrasonic investigative techniques; Vascular diseases and vascular malformations of the nervous system; equilibrium dialysis; passive diffusion; active transport; blood—brain barrier; PET; blood-brain barrier; Nervous system diseases; Blood brain barrier; Cerebral disorder; Encephalon; Central nervous system disease; Diffusion; Transport; Positron emission tomography; Cerebrovascular disease; Emission tomography
• ISSN: 0271-678X; 1559-7016
• DOI: 10.1038/jcbfm.2012.1

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 derisking 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.