RT Journal Article
SR Electronic
T1 EVALUATION OF THE UTILITY OF BRAIN SLICE METHODS TO STUDY BRAIN PENETRATION
JF Drug Metabolism and Disposition
JO Drug Metab Dispos
FD American Society for Pharmacology and Experimental Therapeutics
SP 855
OP 861
DO 10.1124/dmd.105.007914
VO 34
IS 5
A1 Stacey Becker
A1 Xingrong Liu
YR 2006
UL http://dmd.aspetjournals.org/content/34/5/855.abstract
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