QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text Full Text (PDF) All Versions of this Article: jpet.105.092916v1 316/3/1282    most recent Submit a response Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Summerfield, S. G. Articles by Jeffrey, P. Search for Related Content PubMed PubMed Citation Articles by Summerfield, S. G. Articles by Jeffrey, P.

ABSORPTION, DISTRIBUTION, METABOLISM, AND EXCRETION

Improving the in Vitro Prediction of in Vivo Central Nervous System Penetration: Integrating Permeability, P-glycoprotein Efflux, and Free Fractions in Blood and Brain

Drug Metabolism and Pharmacokinetics Department, Neurology and Gastrointestinal Centre of Excellence for Drug Discovery, GlaxoSmithKline R&D, Harlow, Essex, United Kingdom (S.G.S., A.J.S., L.C., M.d.C.O., B.H., S.-P.T., D.J.S., P.J.); and Computational Chemistry, GlaxoSmithKline Medicines Research Centre, Stevenage, Hertfordshire, United Kingdom (A.H.)

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.

Address correspondence to: Scott Summerfield, Drug Metabolism and Pharmacokinetics Department, Neurology, and Gastrointestinal Centre of Excellence for Drug Discovery, GlaxoSmithKline R&D, New Frontiers Science Park, Third Avenue, Harlow, Essex CM19 5AW, UK. E-mail: scott.g.summerfield{at}gsk.com

This article has been cited by other articles:

				S. G. Summerfield, K. Read, D. J. Begley, T. Obradovic, I. J. Hidalgo, S. Coggon, A. V. Lewis, R. A. Porter, and P. Jeffrey Central Nervous System Drug Disposition: The Relationship between in Situ Brain Permeability and Brain Free Fraction J. Pharmacol. Exp. Ther., July 1, 2007; 322(1): 205 - 213. [Abstract] [Full Text] [PDF]

				J. C. Kalvass, T. S. Maurer, and G. M. Pollack Use of Plasma and Brain Unbound Fractions to Assess the Extent of Brain Distribution of 34 Drugs: Comparison of Unbound Concentration Ratios to in Vivo P-Glycoprotein Efflux Ratios Drug Metab. Dispos., April 1, 2007; 35(4): 660 - 666. [Abstract] [Full Text] [PDF]