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,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,brain values of 7 compounds out of 12 P-gp substrates (K_p,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,uu,brain). The cerebral spinal fluid (CSF) drug concentrations (C_CSF), a surrogate for unbound brain concentration (C_u,brain), were also compared between dog and monkey, and the CSF-to-plasma unbound concentration ratios (K_p,uu,CSF) of BCRP substrates in dog were notably higher than those in monkey, although non-bcrp substrates showed good correlation. Also, the K_p,uu,CSF values of BCRP substrates in dog were clearly higher than the K_p,uu,brain values, indicating that the dog C_CSF of BCRP substrates was not suitable as a surrogate of C_u,brain. These observations should be useful when selecting the appropriate animal models for CNS drug discovery.