Abstract
Species independence of brain tissue binding was assessed with a large number of structurally diverse compounds using equilibrium dialysis with brain homogenates of seven species and strains (Wistar Han rat, Sprague-Dawley rat, CD-1 mouse, Hartley guinea pig, beagle dog, cynomolgus monkey, and human). The results showed that the fractions unbound of the seven species and strains were strongly correlated with correlation coefficients ranging from 0.93 to 0.99. The cross-species/strain correlations were not significantly different from the interassay correlation with the same species. The linear correlation between Wistar Han and other species had a slope close to 1 and an intercept near 0. Based on orthogonal statistical analysis, no correction is needed for extrapolation of fraction unbound from Wistar Han rat to the other species or strains. Hence, brain tissue binding of Wistar Han rat can be used to obtain binding of other species and strains in drug discovery.
Footnotes
Article, publication date, and citation information can be found at http://dmd.aspetjournals.org.
doi:10.1124/dmd.111.038778.
-
ABBREVIATIONS:
- CNS
- central nervous system
- PK
- pharmacokinetic
- PD
- pharmacodynamic
- CSF
- cerebrospinal fluid
- IS
- internal standard
- LC
- liquid chromatography
- MS
- mass spectrometry
- DPBS
- Dulbecco's phosphate buffer solution
- ACN
- acetonitrile
- TPSA
- topological polar surface area
- CP-628374
- (2E)-3-(4-{[(2S,3S,4S,5R)-5-{(1E)-N-[(3-chloro-2,6-difluorobenzyl)oxy]ethanimidoyl}-3,4-dihydroxytetrahydrofuran-2-yl]oxy}-3-hydroxyphenyl)-2-methyl-N-[(3aS,4R,5R,6S,7R,7aR)-4,6,7-trihydroxyhexahydro-1,3-benzodioxol-5-yl]prop-2-enamide
- UK-240455
- N-(6,7-dichloro-2,3-dioxo-1,2,3,4-tetrahydroquinoxalin-5-yl)-N-(2-hydroxyethyl)methanesulfonamide.
- Received February 15, 2011.
- Accepted April 7, 2011.
- Copyright © 2011 by The American Society for Pharmacology and Experimental Therapeutics
DMD articles become freely available 12 months after publication, and remain freely available for 5 years.Non-open access articles that fall outside this five year window are available only to institutional subscribers and current ASPET members, or through the article purchase feature at the bottom of the page.
|