Graduate School of Pharmaceutical Sciences, the University of Tokyo, Tokyo, Japan.
J Pharm Sci. 2013 Sep;102(9):3309-19. doi: 10.1002/jps.23600. Epub 2013 May 27.
The brain distribution of nonsteroidal aromatase inhibitors was investigated in mice to understand their interactions with brain aromatase. The brain-to-plasma ratio (Kp,brain , mL/g brain) of anastrozole was 0.0299 ± 0.0068, which was lower than that of letrozole (0.383 ± 0.048) and vorozole (0.185 ± 0.031) despite their similar physicochemical properties. The brain-to-plasma unbound concentration ratio of anastrozole, measured using microdialysis, was 0.118 ± 0.037 mL/g brain. In situ mouse brain perfusion also demonstrated that the uptake clearance [mL/(min·g brain)] of anastrozole by the brain (0.108 ± 0.018) was lower than that for letrozole and vorozole (0.422 ± 0.068 and 0.910 ± 0.152, respectively). Anastrozole and vorozole were transported by P-glycoprotein (P-gp) in vitro, whereas none of the compounds were transported by breast cancer resistance protein (BCRP). The Kp,brain of anastrozole and vorozole were increased by 12- and 3.3-fold, respectively, in Mdr1a/b/Bcrp(-/-) mice. IC50 (nM) of anastrozole and letrozole against human aromatase was 12.9 ± 0.7 and 3.59 ± 0.75, respectively. Taken together, these results suggest that active efflux mediated by P-gp at the blood-brain barrier limits the effect of anastrozole in the central nervous system, whereas vorozole and letrozole easily traverse the barrier.
研究了非甾体芳香酶抑制剂在小鼠中的脑分布，以了解它们与脑芳香酶的相互作用。阿那曲唑的脑-血浆比（Kp,brain, mL/g 脑）为 0.0299 ± 0.0068，低于来曲唑（0.383 ± 0.048）和伏罗唑（0.185 ± 0.031），尽管它们具有相似的物理化学性质。使用微透析测量的阿那曲唑脑-血浆未结合浓度比为 0.118 ± 0.037 mL/g 脑。原位小鼠脑灌注也表明，阿那曲唑的脑摄取清除率[mL/(min·g 脑)]（0.108 ± 0.018）低于来曲唑和伏罗唑（0.422 ± 0.068 和 0.910 ± 0.152）。阿那曲唑和伏罗唑在体外由 P-糖蛋白（P-gp）转运，而这些化合物均不由乳腺癌耐药蛋白（BCRP）转运。阿那曲唑和伏罗唑的 Kp,brain 分别增加了 12 倍和 3.3 倍。在 Mdr1a/b/Bcrp(-/-) 小鼠中。阿那曲唑和来曲唑对人芳香酶的 IC50（nM）分别为 12.9 ± 0.7 和 3.59 ± 0.75。综上所述，这些结果表明，血脑屏障中 P-gp 介导的主动外排限制了阿那曲唑在中枢神经系统中的作用，而伏罗唑和来曲唑容易穿过屏障。
