Neuropharmacokinetics of two investigational compounds in rats: Divergent temporal profiles in the brain and cerebrospinal fluid

Two investigational compounds (FRM-1, (R)-7-fluoro-N-(quinuclidin-3-yl)benzo[b]thiophene-2-carboxamide and FRM-2, (R)-7-cyano-N-(quinuclidin-3-yl)benzo[b]thiophene-2-carboxamide) resided in rat brain longer than in systemic circulation. In Caco-2 directional transport studies, they both showed good...

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Bibliographic Details
Published in:Biochemical pharmacology 2014-10, Vol.91 (4), p.543-551
Main Authors: Tang, Cuyue, Chen, Ting, Kapadnis, Sudarshan, Hodgdon, Hilliary, Tao, Yi, Chen, Xing, Wen, Melody, Costa, Don, Murphy, Deirdre, Nolan, Scott, Flood, Dorothy G., Welty, Devin F., Koenig, Gerhard
Format: Article
Language:English
Subjects:
Animals
Blood-Brain Barrier
Blood–cerebrospinal fluid barrier
Brain - metabolism
Brain tissue binding, Semi-PBPK modeling
Brain–blood barrier
Caco-2 Cells
Humans
Male
Models, Theoretical
P-glycoprotein
Rats
Rats, Wistar
Thiophenes - cerebrospinal fluid
Thiophenes - pharmacokinetics
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Summary:Two investigational compounds (FRM-1, (R)-7-fluoro-N-(quinuclidin-3-yl)benzo[b]thiophene-2-carboxamide and FRM-2, (R)-7-cyano-N-(quinuclidin-3-yl)benzo[b]thiophene-2-carboxamide) resided in rat brain longer than in systemic circulation. In Caco-2 directional transport studies, they both showed good intrinsic passive permeability but differed significantly in efflux susceptibility (efflux ratio of
ISSN:0006-2952
1873-2968
DOI:10.1016/j.bcp.2014.07.023