TY - JOUR T1 - Quantitative Evaluation of the Impact of Active Efflux by P-Glycoprotein and Breast Cancer Resistance Protein at the Blood-Brain Barrier on the Predictability of the Unbound Concentrations of Drugs in the Brain Using Cerebrospinal Fluid Concentration as a Surrogate JF - Journal of Pharmacology and Experimental Therapeutics JO - J Pharmacol Exp Ther SP - 935 LP - 944 DO - 10.1124/jpet.111.180398 VL - 339 IS - 3 AU - Hiroshi Kodaira AU - Hiroyuki Kusuhara AU - Takuya Fujita AU - Junko Ushiki AU - Eiichi Fuse AU - Yuichi Sugiyama Y1 - 2011/12/01 UR - http://jpet.aspetjournals.org/content/339/3/935.abstract N2 - 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 (Cu,brain) by the concentration in the cerebrospinal fluid (CSF) (Cu,CSF) in rats. Cu,brain is obtained as the product of the total brain concentration and unbound fraction in the brain (fu,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 (Kp,uu,CSF/brain) compared with non-P-gp and non-Bcrp substrates. Kp,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, Kp,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 Cu,brain by Cu,CSF decreases along with the net transport activities by P-gp and Bcrp at the BBB. Cu,CSF of non-P-gp and non-Bcrp substrates can be a reliable surrogate of Cu,brain for lipophilic compounds. ER -