Improving the prediction of the brain disposition for orally administered drugs using BDDCS. Academic Article Book Review uri icon

start page

  • 95

end page

  • 109

abstract

  • In modeling blood-brain barrier (BBB) passage, in silico models have yielded ~80% prediction accuracy, and are currently used in early drug discovery. Being derived from molecular structural information only, these models do not take into account the biological factors responsible for the in vivo outcome. Passive permeability and P-glycoprotein (Pgp, ABCB1) efflux have been successfully recognized to impact xenobiotic extrusion from the brain, as Pgp is known to play a role in limiting the BBB penetration of oral drugs in humans. However, these two properties alone fail to explain the BBB penetration for a significant number of marketed central nervous system (CNS) agents. The Biopharmaceutics Drug Disposition Classification System (BDDCS) has proved useful in predicting drug disposition in the human body, particularly in the liver and intestine. Here we discuss the value of using BDDCS to improve BBB predictions of oral drugs. BDDCS class membership was integrated with in vitro Pgp efflux and in silico permeability data to create a simple 3-step classification tree that accurately predicted CNS disposition for more than 90% of 153 drugs in our data set. About 98% of BDDCS class 1 drugs were found to markedly distribute throughout the brain; this includes a number of BDDCS class 1 drugs shown to be Pgp substrates. This new perspective provides a further interpretation of how Pgp influences the sedative effects of H1-histamine receptor antagonists.Copyright © 2012 Elsevier B.V. All rights reserved.

date/time value

  • 2012
  • 2012

Digital Object Identifier (DOI)

  • 10.1016/j.addr.2011.12.008

PubMed Identifier

  • 22261306

volume

  • 64

number

  • 1

keywords

  • Administration, Oral
  • Animals
  • Biopharmaceutics
  • Blood-Brain Barrier
  • Central Nervous System Agents
  • Drug Delivery Systems
  • Humans
  • Models, Neurological
  • P-Glycoproteins
  • Permeability
  • Pharmacokinetics