Central Nervous System Drug Disposition: The Relationship between in Situ Brain Permeability and Brain Free Fraction

  1. Scott G. Summerfield,
  2. Kevin Read,
  3. David J. Begley,
  4. Tanja Obradovic,
  5. Ismael J. Hidalgo,
  6. Sara Coggon,
  7. Ann V. Lewis,
  8. Rod A. Porter and
  9. Phil Jeffrey
  1. Department of Drug Metabolism and Pharmacokinetics, Neurology and Gastrointestinal Centre of Excellence for Drug Discovery (S.G.S., A.V.L., P.J.), and Department of Medicinal Chemistry, Psychiatry Centre of Excellence for Drug Discovery (R.A.P.), GlaxoSmithKline R&D, Harlow, Essex, United Kingdom; Department of Drug Metabolism and Pharmacokinetics, Psychiatry Centre of Excellence for Drug Discovery, GlaxoSmithKline R&D, Verona, Italy (K.R.); Pharmaceutical Sciences Research Division and Wolfson Centre for Age-related Disease, Kings College London, London, United Kingdom (D.J.B.); Absorption Systems, Exton, Pennsylvania (T.O., I.J.H.); and Department of Drug Metabolism and Pharmacokinetics, UCB Celltech, Great Abington, Cambridge, United Kingdom (S.C.)
  1. Address correspondence to:
    Dr. Scott Summerfield, Department of Drug Metabolism and Pharmacokinetics, Neurology and Gastrointestinal Centre of Excellence for Drug Discovery, GlaxoSmithKline R&D, New Frontiers Science Park, Third Ave., Harlow, Essex CM19 5AW, UK. E-mail: scott.g.summerfield{at}gsk.com

Abstract

The dispositions of 50 marketed central nervous system (CNS) drugs into the brain have been examined in terms of their rat in situ (P) and in vitro apparent membrane permeability (Papp) alongside lipophilicity and free fraction in rat brain tissue. The inter-relationship between these parameters highlights that both permeability and brain tissue binding influence the uptake of drugs into the CNS. Hydrophilic compounds characterized by low brain tissue binding display a strong correlation (R2 = 0.82) between P and Papp, whereas the uptake of more lipophilic compounds seems to be influenced by both Papp and brain free fraction. A nonlinear relationship is observed between logPoct and P over the 6 orders of magnitude range in lipophilicity studied. These findings corroborate recent reports in the literature that brain penetration is a function of both rate and extent of drug uptake into the CNS.

Footnotes

  • Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.

  • doi:10.1124/jpet.107.121525.

  • ABBREVIATIONS: CNS, central nervous system; BBB, blood-brain barrier; P, in situ brain permeability; Papp, apparent membrane permeability; fu(brain), in vitro free fraction in brain tissue; clogPoct, log octanol/water partition coefficient; MDR, multidrug resistance; MDCK, Madin-Darby canine kidney; PBS, phosphate-buffered saline; TEER, transepithelial electrical resistance; P-gp, P-glycoprotein; HPLC, high-performance liquid chromatography; MS/MS, tandem mass spectrometry; GF120918A, N-(4-{2-[6,7-bis(methyloxy)-3,4-dihydro-2(1H)-isoquinolinyl]ethyl}phenyl)-5-(methyloxy)-9-oxo-9,10-dihydro-4-acridinecarboxamide hydrochloride.

  • ↵Graphic The online version of this article (available at http://jpet.aspetjournals.org) contains supplemental material.

    • Received February 15, 2007.
    • Accepted April 2, 2007.
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  1. doi: 10.1124/jpet.107.121525 JPET July 2007 vol. 322 no. 1 205-213
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