Computation of log BB values for compounds transported through carrier-mediated mechanisms using in vitro permeability data from brain microvessel endothelial cell (BMEC) monolayers.
OBJECTIVE
To explore the possibility of determining in vivo log BB values (the logarithm value of brain to plasma concentration ratio) from in vitro permeability data measured in brain microvessel endothelial cell (BMEC) monolayers.


METHODS
An equilibrium mathematical model was developed: log BB = log(Ca/Cb) + log Kbr:pl, where Cb and Ca are the drug concentrations at equilibrium in the basolateral (B) and apical (A) sides of BMECs in an A-to-B directional diffusion system and Kbr:pl is the brain-plasma partition coefficient. With this model, murine log BB values were calculated for 24 pharmaceutical compounds, mostly Pgp substrates.


RESULTS
Calculated log BB values correlated well to experimental values (r2 = 0.854, slope = 0.907 +/- 0.080), demonstrating that the model could reasonably predict brain penetration for compounds that are involved in carrier-mediated transport mechanisms. For a second data set that included volatile organic compounds (log BB = log Kbr:pl), log Kbr:pl values were also shown to correlate well with their respective experimental log BB values (r2 = 0.876, slope = 0.973 +/- 0.082), demonstrating that log Kbr:pl is an excellent descriptor for log BB when a compound penetrates the blood-brain barrier by passive diffusion only.


CONCLUSIONS
The equilibrium model demonstrated a reasonable ability to compute in vivo log BB values, regardless of the involvement or mechanisms of carrier-mediated transport.
Usansky
Helen H
HH
Department of Pharmaceutics, Ernest Mario School of Pharmacy, Rutgers University, Piscataway, New Jersey 08854-8022, USA.
Sinko
Patrick J
PJ
D000818:Animals; D001692:Biological Transport; D001812:Blood-Brain Barrier / Q000502:physiology*; D001921:Brain / Q000098:blood supply*; D004337:Drug Carriers; D004730:Endothelium, Vascular / Q000378:metabolism / Q000502:physiology*; D005544:Forecasting; D066298:In Vitro Techniques; D016014:Linear Models; D051379:Mice; D008833:Microcirculation; D008954:Models, Biological; D010539:Permeability; D004364:Pharmaceutical Preparations / Q000378:metabolism; D010599:Pharmacokinetics
D004337:Drug Carriers; D004364:Pharmaceutical Preparations