Breast cancer resistance protein (BCRP) expressed in the blood-brain barrier plays a major role in limiting drug distribution into the central nervous system (CNS). However, functional involvement of BCRP in drug distribution into the brain and cerebrospinal fluid (CSF) remains unclear. The aim of present study was to reveal the role and quantitative impact of BCRP on CNS distribution. The brain-to-plasma unbound concentration ratio (K_p,uu,brain) and CSF-to-plasma unbound concentration ratio (K_p,uu,CSF) values of BCRP-specific substrates were determined in rats. The K_p,uu,brain values decreased, as the in vitro BCRP corrected flux ratio (CFR) increased. The K_p,uu,CSF values of BCRP-specific substrates were greater than the K_p,uu,brain values. Increase in the K_p,uu,brain values induced by co-administration of BCRP inhibitor correlated with the in vitro BCRP CFR and were greater than the increase in K_p,uu,CSF values induced by BCRP inhibitor except nebicapone. The contribution of BCRP to the brain and CSF distribution of the dual P-glycoprotein/BCRP substrates, imatinib and prazosin, was similar to that of BCRP-specific substrates. Thus, we revealed that the impact of in vivo BCRP on CNS distribution is correlated with in vitro BCRP CFR, and that BCRP limits drug distribution into the brain more strongly than into the CSF.

在血脑屏障中表达的乳腺癌耐药蛋白 (BCRP) 在限制药物分布到中枢神经系统 (CNS) 中起主要作用。然而，BCRP 在药物分布到大脑和脑脊液 (CSF) 中的功能仍不清楚。本研究的目的是揭示 BCRP 对 CNS 分布的作用和定量影响。在大鼠中测定了 BCRP 特异性底物的脑与血浆未结合浓度比 (K _p,uu,brain ) 和 CSF 与血浆未结合浓度比 (K _{p,uu,CSF ) 值。}随着体外 BCRP 校正通量比 (CFR) 的增加， K _{p,uu,brain值降低。}BCRP 特异性底物的 K _p,uu,CSF值大于 K_p,uu,脑值。共同给药 BCRP 抑制剂诱导的 K _p,uu,brain值增加与体外 BCRP CFR 相关并且大于除奈比卡朋以外的 BCRP 抑制剂诱导的K _{p,uu,CSF值增加。}BCRP 对双 P-糖蛋白/BCRP 底物伊马替尼和哌唑嗪的脑和脑脊液分布的贡献与 BCRP 特异性底物相似。因此，我们揭示了体内 BCRP 对 CNS 分布的影响与体外 BCRP CFR 相关，并且 BCRP 比进入 CSF 更强烈地限制药物分布到大脑中。