ACD/Blood Brain Barrier Permeation

Predict the extent of BBB permeability, brain/plasma permeation rate, and the rate of passive diffusion from structure

The blood-brain barrier (BBB) permeation model in ACD/Labs software provides a comprehensive evaluation of the permeation potential of candidate compounds. While prediction cannot replace experimentation, this module allows compounds to be ranked according to their passive transport across the BBB, based on the following information:

  • Predictions of:
    • Rate of passive diffusion/permeability (logPS)
    • Extent of BBB permeation (logBB)—steady-state distribution ratio of a compound between brain tissue and plasma
    • Brain/plasma equilibration rate (PS * fu, brain)
  • Alerts for compounds likely to undergo transport across the BBB barrier by carrier mediated mechanisms

About the Models

Calculated Quantitative Parameters

The quantitative characteristics of drug transport across blood-brain barrier, calculated by the BBB model, are:

  • Rate of brain penetration (logPS). PS stands for Permeability-Surface area product and is defined from the kinetic equation of capillary transport (PS = -F * (1 – e-Kin/F)). By definition, PS is equal to the influx rate constant Kin corrected for blood flow rate in cerebral microcapillaries denoted as F
  • Extent of brain penetration (logBB) determined by ratio of total drug concentrations in tissue and plasma at steady-state conditions (logBB = log(cbrainSS/cbloodSS)
  • Fraction of drug that is unbound, i.e., pharmacologically active, in brain tissue (fu, brain)
  • Brain/plasma equilibration rate given by log(PS * fu, brain)—combination of permeation rate and fraction unbound in brain, according to Liu X. et al. J Pharmacol Exp Ther., 313(3):1254–62, 2005

Data Source

The data sets used for modeling were compiled from original literature publications of BBB permeation studies in rodents. Quantitative logPS data (determined by one of the experimental methods below) was collected for more than 250 compounds:

  • Intravenous administration (IV)
  • Brain uptake index (BUI)
  • In situ brain perfusion
Analysis and evaluation of published brain/plasma distribution studies of drugs after intravenous, intraperitoneal, and oral administration to rats and mice yielded more than 600 logBB values. After thorough data verification, entries supposedly affected by carrier-mediated processes were removed, leaving us with a data set of 180 logPS and 470 logBB values (representing BBB transport by passive diffusion).

Descriptors

Descriptors used for modeling included key physicochemical properties:

  • Octanol/water logP of neutral species as a determinant of lipophilicity
  • Ion form fractions at pH 7.4 calculated from the respective pKa values
  • Number of hydrogen bond donors and acceptors in the molecule
  • McGowan characteristic volume reflecting molecular size

Transport Mechanism Alerts

Special alerts are provided for compounds that cross the BBB by enzymatic efflux or influx, indicating that the observed parameters for these molecules may be considerably higher or lower than values predicted by our BBB model, due to the presence of carrier-mediated processes, such as facilitated diffusion or P-gp efflux. Considered influx transporters include:

  • Amino-acid transport systems (System A, L, y+, x-)
  • Glucose carrier GLUT1
  • Organic cation/carnitine transporters (OCTN)
  • Organic anion transporting polypeptide (OATP)
  • Various other carriers specific for nucleotides and other endogenous substances

Read about the prediction accuracy of the model

ACD/Labs Product Suites

The Percepta prediction modules are available as bundles to offer cost savings for multiple modules, and provide related modules as a package.

Other Products

ACD/Blood Brain Barrier Permeation Model predictions are available as a browser-based thin client application on ACD/Percepta Portal; a thick client product (ACD/Percepta for the Desktop); and a batch calculator (ACD/Percepta Batch).