PT  - JOURNAL ARTICLE
AU  - Becker, Stacey
AU  - Liu, Xingrong
TI  - EVALUATION OF THE UTILITY OF BRAIN SLICE METHODS TO STUDY BRAIN PENETRATION
AID  - 10.1124/dmd.105.007914
DP  - 2006 May 01
TA  - Drug Metabolism and Disposition
PG  - 855--861
VI  - 34
IP  - 5
4099  - http://dmd.aspetjournals.org/content/34/5/855.short
4100  - http://dmd.aspetjournals.org/content/34/5/855.full
SO  - Drug Metab Dispos2006 May 01; 34
AB  - The objective of this study was to evaluate the utility of brain tissue slices to determine the effect of plasma and brain tissue nonspecific binding on the brain-to-plasma ratio (Kp). Mouse or rat brain slices (400 μm) were prepared using a McIlwain tissue chopper (Surrey, UK) and incubated with 1 μg/ml of compound at 37°C either in a physiological buffer to determine the buffer-to-slice concentration ratio, i.e., unbound fraction in brain tissue (fu,slice), or in plasma to determine the slice-to-plasma concentration ratio (Cslice/Cplasma). The unbound fraction in plasma, fu,plasma, was determined using equilibrium dialysis. In vitro-in vivo correlation of the brain-to-plasma ratio was examined for 13 and eight model compounds in mice and rats, respectively. Cslice/Cplasma and fu,plasma/fu,slice predicted the Kp in rats, and Cslice/Cplasma predicted the Kp in FVB mice for non-P-glycoprotein substrates within 3-fold but overpredicted Kp for P-glycoprotein substrates by more than 3-fold. However, Cslice/Cplasma predicted the Kp in mdr1a/1b knockout mice for both non-P-glycoprotein and P-glycoprotein substrates. Our present study demonstrates that a brain slice method can be used to differentiate whether a compound having a low Kp is due to the effect of low nonspecific binding to brain tissue relative to plasma proteins or because of efflux transport at the blood-brain barrier. The American Society for Pharmacology and Experimental Therapeutics