Received for publication July 27, 2005.
Revised December 1, 2005.
Accepted for publication December 1, 2005.

Improving the In Vitro Prediction of In Vivo CNS Penetration: Integrating Permeability, Pgp Efflux and Free Fractions in Blood and Brain

Abstract

This work examines the inter relationship between the unbound drug fractions in blood and brain homogenate, passive membrane permeability, Pgp efflux ratio and cLogP in determining the extent of CNS penetration observed in vivo. The present results demonstrate that compounds often considered to be Pgp substrates in rodents (efflux ratio > 5 in MDR-MDCK cells) with poor passive permeability may still exhibit reasonable CNS penetration in vivo, i.e. where the unbound fractions and non-specific tissue binding act as a compensating force. In these instances, the efflux ratio and in vitro blood-brain partition ratio (Kbb) may be used to predict the in vivo blood-brain ratio. This relationship may be extended to account for the differences in CNS penetration observed in vivo between mdr1a/b wild type and knockout mice. In some instance cross-species differences that might initially appear to be related to differing transporter expression can be rationalised from knowledge of unbound fractions alone. The results presented in this manuscript suggest that the information exists to provide a coherent picture of the nature of CNS penetration in the Drug Discovery setting, allowing the focus to be shifted away from understanding CNS penetration toward the more important aspect of understanding CNS efficacy.

Key words: Pgp, blood-brain barrier, efflux, equilibrium dialysis, free-fraction, non-specific binding

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