TABLE 5

Impact of four parameters on species differences in the K_p,brain and K_p,uu,brain values between cynomolgus monkeys and mice

The contributions of individual parameters (P-gp protein expression levels at the BBB, the intrinsic transport activity per P-gp molecule, and the unbound fractions in the plasma and brain) to the species differences in the K_p,brain and K_p,uu,brain values between cynomolgus monkeys and mice are presented. PL_p-gp,vivo represents the protein expression levels of P-gp in isolated brain microvessels. TA_int,p-gp represents the intrinsic transport activity per P-gp molecule and is calculated as [(In vitro P-gp efflux ratio) – 1]/[P-gp protein expression levels in P-gp–transfected LLC-PK1 cells]. The values of PL_p-gp,vivo, TA_int,p-gp, f_u,plasma, and f_u,brain in cynomolgus monkeys were divided by the corresponding values in mice to obtain the Monkey/Mouse values for each compound. The cynomolgus monkey data were taken from Tables 2 and 3, and the mouse data were cited from Uchida et al. (2011a). The values of the Impact on K_p,monkey/K_p,mouse and the Impact on K_p,uu,monkey/K_p,uu,mouse describe the contributions of individual parameters to the species differences in the brain-to-plasma concentration ratio (K_p,brain) and K_p,uu,brain values between cynomolgus monkeys and mice and were calculated using eqs. 10 and 11, respectively.