کد مقاله | کد نشریه | سال انتشار | مقاله انگلیسی | نسخه تمام متن |
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2484844 | 1114338 | 2013 | 11 صفحه PDF | دانلود رایگان |
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.
Journal: Journal of Pharmaceutical Sciences - Volume 102, Issue 9, September 2013, Pages 3309–3319