RT Journal Article SR Electronic T1 Quantitative Investigation of the Role of Breast Cancer Resistance Protein (Bcrp/Abcg2) in Limiting Brain and Testis Penetration of Xenobiotic Compounds JF Drug Metabolism and Disposition JO Drug Metab Dispos FD American Society for Pharmacology and Experimental Therapeutics SP 995 OP 1002 DO 10.1124/dmd.107.019257 VO 36 IS 6 A1 Junichi Enokizono A1 Hiroyuki Kusuhara A1 Atsushi Ose A1 Alfred H. Schinkel A1 Yuichi Sugiyama YR 2008 UL http://dmd.aspetjournals.org/content/36/6/995.abstract AB The role of breast cancer resistance protein (BCRP/ABCG2) in limiting the brain and testis penetration of xenobiotic compounds in the blood-brain and -testis barriers was investigated using Bcrp–/– mice. Tissue/plasma concentration ratios in the brain (Kp,brain) and testis (Kp,testis) obtained under steady-state conditions were significantly increased in Bcrp–/– mice for PhIP (2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine), N-hydroxyl PhIP, MeIQx (2-amino-3,8-dimethylimidazo[4,5-f]quinoxaline), dantrolene, and prazosin. In addition, the Kp,brain of triamterene and the Kp,testis of 4′-hydroxyl PhIP were also significantly increased in Bcrp–/– mice. The effect of functional impairment of Bcrp on the brain uptake of PhIP, dantrolene, and daidzein in Bcrp–/– mice determined using in situ brain perfusion was weaker than that observed on the Kp values. In vitro transcellular transport experiments using cell lines expressing mouse Bcrp or P-glycoprotein (Mdr1a/Abcb1a) showed that, among the tested Bcrp substrates, PhIP, MeIQx, prazosin, and triamterene are common substrates of Bcrp and P-glycoprotein. The Kp values of common substrates exhibited a smaller increase both in the brain and testis of Bcrp–/– mice than expected from the in vitro Bcrp activities. The Bcrp-specific substrates were weak acids, whereas basic or neutral BCRP substrates were also P-glycoprotein substrates. These results suggest that BCRP limits the tissue penetration of xenobiotic compounds in the blood-brain and -testis barriers, but its in vivo importance is also modulated by P-glycoprotein activity. The American Society for Pharmacology and Experimental Therapeutics