Central nervous system drug disposition: The relationship between in situ brain permeability and brain free fraction

S G Summerfield, K Read, D J Begley, T Obradovic, I J Hidalgo, S Coggon, A V Lewis, R A Porter, P Jeffrey

Research output: Contribution to journalArticlepeer-review

243 Citations (Scopus)

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 ( P app) 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 ( R-2 = 0.82) between P and P-app, whereas the uptake of more lipophilic compounds seems to be influenced by both P-app and brain free fraction. A nonlinear relationship is observed between logP(oct) 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
Original languageEnglish
Pages (from-to)205 - 213
Number of pages9
JournalJournal of Pharmacology and Experimental Therapeutics
Volume322
Issue number1
DOIs
Publication statusPublished - Jul 2007

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