Species difference in brain penetration of P-gp and BCRP substrates among monkey, dog and mouse

The brain penetration of 19 drugs, including P-glycoprotein (P-gp) and/or breast cancer resistance protein (BCRP) substrates, was compared among mice, cynomolgus monkeys and beagle dogs. The brain-to-plasma concentration ratios (K-p,K-brain) of the tested compounds in monkey and dog showed good correlation, whereas species differences were observed between non-rodents (monkey/dog) and rodents (mouse). In particular, the K-p,K-brain values of 7 compounds out of 12 P-gp substrates (K-p,K-brain ratio in P-gp knockout mice versus wild-type mice >= 3) in monkey and dog were more than three-fold higher than those in mice and a similar trend was observed in the brain-to-plasma unbound concentration ratios (K-p,K-uu,K-brain). The cerebral spinal fluid (CSF) drug concentrations (C-CSF), a surrogate for unbound brain concentration (C-u,C-brain), were also compared between dog and monkey, and the CSF-to-plasma unbound concentration ratios (K-p,K-uu,K-CSF) of BCRP substrates in dog were notably higher than those in monkey, although non- bcrp substrates showed good correlation. Also, the K-p,K-uu,K-CSF values of BCRP substrates in dog were clearly higher than the K-p,K-uu,K-brain values, indicating that the dog C-CSF of BCRP substrates was not suitable as a surrogate of C-u,C-brain. These observations should be useful when selecting the appropriate animal models for CNS drug discovery. (C) 2021 The Japanese Society for the Study of Xenobiotics. Published by Elsevier Ltd. All rights reserved.