Abstract

This study investigated the impact of the active efflux mediated by P-glycoprotein (P-gp) and breast cancer resistance protein (Bcrp) at the blood-brain barrier (BBB) on the predictability of the unbound brain concentration (C_u,brain) by the concentration in the cerebrospinal fluid (CSF) (C_u,CSF) in rats. C_u,brain is obtained as the product of the total brain concentration and unbound fraction in the brain (f_u,brain) determined in vitro in brain slices. Twenty-five compounds, including P-gp and/or Bcrp substrates, were given a constant intravenous infusion, and their plasma, brain, and CSF concentrations were determined. P-gp and/or Bcrp substrates, such as verapamil, loperamide, flavopiridol, genistein, quinidine, dantrolene, daidzein, cimetidine, and pefloxacin, showed a higher CSF-to-brain unbound concentration ratio (K_{p,uu,CSF/brain}) compared with non-P-gp and non-Bcrp substrates. K_{p,uu,CSF/brain} values of P-gp-specific (quinidine and verapamil) and Bcrp-specific (daidzein and genistein) substrates were significantly decreased in Mdr1a/1b(−/−) and Bcrp(−/−) mice, respectively. Furthermore, consistent with the contribution of P-gp and Bcrp to the net efflux at the BBB, K_{p,uu,CSF/brain} values of the common substrates (flavopiridol and erlotinib) were markedly decreased in Mdr1a/1b(−/−)/Bcrp(−/−) mice, but only moderately or weakly in Mdr1a/1b(−/−) mice and negligibly in Bcrp(−/−) mice. In conclusion, predictability of C_u,brain by C_u,CSF decreases along with the net transport activities by P-gp and Bcrp at the BBB. C_u,CSF of non-P-gp and non-Bcrp substrates can be a reliable surrogate of C_u,brain for lipophilic compounds.