title: Improving the in vitro prediction of in vivo central nervous system penetration: integrating permeability, P-glycoprotein 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, 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.
authors.affiliation: 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. scott.g.summerfield@gsk.com
authors.forename: Scott G
authors.initials: SG
authors.lastname: Summerfield
authors.forename: Alexander J
authors.initials: AJ
authors.lastname: Stevens
authors.forename: Leanne
authors.initials: L
authors.lastname: Cutler
authors.forename: Maria
authors.initials: M
authors.lastname: del Carmen Osuna
authors.forename: Beverley
authors.initials: B
authors.lastname: Hammond
authors.forename: Sac-Pham
authors.initials: SP
authors.lastname: Tang
authors.forename: Ann
authors.initials: A
authors.lastname: Hersey
authors.forename: David J
authors.initials: DJ
authors.lastname: Spalding
authors.forename: Phil
authors.initials: P
authors.lastname: Jeffrey
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism*; D000818:Animals; D001812:Blood-Brain Barrier; D001921:Brain / Q000378:metabolism*; D003956:Dialysis; D004285:Dogs; D008297:Male; D051379:Mice; D010539:Permeability; D051381:Rats; D012995:Solubility; D013045:Species Specificity
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1