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EVALUATION OF THE UTILITY OF BRAIN SLICE METHODS TO STUDY BRAIN PENETRATION

Pharmacokinetics, Dynamics and Metabolism, Pfizer Global Research and Development, Groton, Connecticut

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 (K_p). 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 (f_u,slice), or in plasma to determine the slice-to-plasma concentration ratio (C_slice/C_plasma). The unbound fraction in plasma, f_u,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. C_slice/C_plasma and f_u,plasma/f_u,slice predicted the K_p in rats, and C_slice/C_plasma predicted the K_p in FVB mice for non-P-glycoprotein substrates within 3-fold but overpredicted K_p for P-glycoprotein substrates by more than 3-fold. However, C_slice/C_plasma predicted the K_p 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 K_p 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.

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