TY - JOUR
T1 - Combining PET biodistribution and equilibrium dialysis assays to assess the free brain concentration and BBB transport of CNS drugs
AU - Gunn, Roger N.
AU - Summerfield, Scott G.
AU - Salinas, Cristian A.
AU - Read, Kevin D.
AU - Guo, Qi
AU - Searle, Graham E.
AU - Parker, Christine A.
AU - Jeffrey, Phil
AU - Laruelle, Marc
PY - 2012/5
Y1 - 2012/5
N2 - 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. Journal of Cerebral Blood Flow & Metabolism (2012) 32, 874-883; doi:10.1038/jcbfm.2012.1; published online 25 January 2012
AB - 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. Journal of Cerebral Blood Flow & Metabolism (2012) 32, 874-883; doi:10.1038/jcbfm.2012.1; published online 25 January 2012
U2 - 10.1038/jcbfm.2012.1
DO - 10.1038/jcbfm.2012.1
M3 - Article
C2 - 22274741
SN - 0271-678X
VL - 32
SP - 874
EP - 883
JO - Journal of Cerebral Blood Flow and Metabolism
JF - Journal of Cerebral Blood Flow and Metabolism
IS - 5
ER -