RT Journal Article
SR Electronic
T1 Improving the in Vitro Prediction of in Vivo Central Nervous System Penetration: Integrating Permeability, P-glycoprotein Efflux, and Free Fractions in Blood and Brain
JF Journal of Pharmacology and Experimental Therapeutics
JO J Pharmacol Exp Ther
FD American Society for Pharmacology and Experimental Therapeutics
SP 1282
OP 1290
DO 10.1124/jpet.105.092916
VO 316
IS 3
A1 Scott G. Summerfield
A1 Alexander J. Stevens
A1 Leanne Cutler
A1 Maria del Carmen Osuna
A1 Beverley Hammond
A1 Sac-Pham Tang
A1 Ann Hersey
A1 David J. Spalding
A1 Phil Jeffrey
YR 2006
UL http://jpet.aspetjournals.org/content/316/3/1282.abstract
AB This work examines the inter-relationship between the unbound drug fractions in blood and brain homogenate, passive membrane permeability, P-glycoprotein (Pgp) efflux ratio, and log octanol/water partition coefficients (cLogP) in determining the extent of central nervous system (CNS) penetration observed in vivo. The present results demonstrate that compounds often considered to be Pgp substrates in rodents (efflux ratio greater than 5 in multidrug resistant Madin-Darby canine kidney cells) with poor passive permeability may still exhibit reasonable CNS penetration in vivo; i.e., where the unbound fractions and nonspecific tissue binding act as a compensating force. In these instances, the efflux ratio and in vitro blood-brain partition ratio 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 instances, cross-species differences that might initially seem to be related to differing transporter expression can be rationalized from knowledge of unbound fractions alone. The results presented in this article 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.