title: Investigation of the effect of active efflux at the blood-brain barrier on the distribution of nonsteroidal aromatase inhibitors in the central nervous system.
abstract: 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.
authors.affiliation: Graduate School of Pharmaceutical Sciences, the University of Tokyo, Tokyo, Japan.
authors.forename: Mari
authors.initials: M
authors.lastname: Miyajima
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Kusuhara
authors.forename: Kayo
authors.initials: K
authors.lastname: Takahashi
authors.forename: Tadayuki
authors.initials: T
authors.lastname: Takashima
authors.forename: Takamitsu
authors.initials: T
authors.lastname: Hosoya
authors.forename: Yasuyoshi
authors.initials: Y
authors.lastname: Watanabe
authors.forename: Yuichi
authors.initials: Y
authors.lastname: Sugiyama
mesh_terms: D018435:ATP Binding Cassette Transporter, Subfamily B / Q000378:metabolism; D000077384:Anastrozole; D000818:Animals; D001141:Aromatase / Q000378:metabolism; D047072:Aromatase Inhibitors / Q000097:blood / Q000378:metabolism / Q000493:pharmacokinetics* / Q000494:pharmacology; D001812:Blood-Brain Barrier / Q000378:metabolism*; D001921:Brain / Q000378:metabolism; D002460:Cell Line; D006801:Humans; D000077289:Letrozole; D008297:Male; D051379:Mice; D009570:Nitriles / Q000097:blood / Q000378:metabolism* / Q000493:pharmacokinetics* / Q000494:pharmacology; D014230:Triazoles / Q000097:blood / Q000378:metabolism* / Q000493:pharmacokinetics* / Q000494:pharmacology
chemical_list: D018435:ATP Binding Cassette Transporter, Subfamily B; D047072:Aromatase Inhibitors; D009570:Nitriles; D014230:Triazoles; C060523:vorozole; D000077384:Anastrozole; D000077289:Letrozole; D001141:Aromatase
keywords: CNS; P-glycoprotein; blood-brain barrier; disposition; efflux pumps; endothelial; transporters