bcrp - publications

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1. Drug Metab Dispos. 2012 Jan 19. [Epub ahead of print]

CSF Can be used as a Surrogate to Assess Brain Exposures of BCRP and PGP
Substrates.

Xiao G, Black C, Hetu G, Sands E, Wang J, Caputo R, Rohde E, Gan LS.

Biogen Idec.

The objectives of the study were to characterize the selectivity of dantrolene to
Bcrp, and to evaluate if CSF can be used as a surrogate to assess brain exposures
of BCRP and Pgp substrates. The impact of Bcrp and Pgp on dantrolene exposures in
brain and CSF was examined in Bcrp and Mdr1a/1b knockout mice, and was further
investigated in wild-type mice in the presence of the Bcrp inhibitor Ko143, the
Pgp inhibitor PSC833, and the dual inhibitor GF120918. The effect of Bcrp and Pgp
on digoxin exposures in brain and CSF was investigated in wild-type mice in the
presence of the inhibitors. In vivo studies showed dantrolene exposures in brain
and CSF, but not the blood, increased in Bcrp (-/-) and Mdr1a/1b(-/-)/Bcrp (-/-)
mice , or in the presence of the Bcrp inhibitors Ko143 or GF1200918. Inhibition
of Pgp by GF120918 and PSC833 significantly increased digoxin exposures in brain,
CSF, and blood to a lesser extent. Results from the present study demonstrated
that inhibition of Bcrp and Pgp not only increased the exposures of dantrolene
and digoxin in brain, but also the exposures in CSF. Furthermore, the change of
exposures in CSF reflected the changes in brain. The present study strongly
suggests that the dantrolene and digoxin exposures in CSF is primarily determined
by the rapid transport from brain to CSF, and inhibition of Bcrp and Pgp exhibits
little impact on using CSF as surrogates to assess brain exposures of Bcrp and
Pgp substrates.

PMID: 22266779 [PubMed - as supplied by publisher]