Investigation of the effect of active efflux at the blood-brain barrier on the distribution of nonsteroidal aromatase inhibitors in the central nervous system.
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Miyajima M, Kusuhara H, Takahashi K, Takashima T, Hosoya T, Watanabe Y, Sugiyama Y
Investigation of the effect of active efflux at the blood-brain barrier on the distribution of nonsteroidal aromatase inhibitors in the central nervous system.
J Pharm Sci. 2013 Sep;102(9):3309-19. doi: 10.1002/jps.23600. Epub 2013 May 27.
- PubMed ID
- 23712697 [ View in PubMed]
- 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.
DrugBank Data that Cites this Article
- Drugs
- Drug Transporters
Drug Transporter Kind Organism Pharmacological Action Actions Anastrozole P-glycoprotein 1 Protein Humans UnknownSubstrateDetails Letrozole P-glycoprotein 1 Protein Humans UnknownSubstrateDetails