Assessment of blood-brain barrier permeability using the in situ mouse brain perfusion technique.
OBJECTIVE
To assess the blood-brain barrier (BBB) permeability of 12 clinically-used drugs in mdr1a(+/+) and mdr1a(-/-) mice, and investigate the influence of lipophilicity, nonspecific brain tissue binding, and P-gp-mediated efflux on the rate of brain uptake.


METHODS
The BBB partition coefficient (PS) was determined using the in situ mouse brain perfusion technique. The net brain uptake for 12 compounds, and the time course of brain uptake for selected compounds ranging in BBB equilibration kinetics from rapidly-equilibrating (e.g., alfentanil, sufentanil) to slowly-equilibrating (fexofenadine), was determined and compared.


RESULTS
There was a sigmoidal relationship in mdr1a(-/-) mice between the log-PS and clogD(7.4) in the range of 0-5. The brain uptake clearance was a function of both permeability and blood flow rate. The brain unbound fraction was inversely proportional to lipophilicity. Alfentanil achieved brain equilibrium approximately 4,000-fold faster than fexofenadine, based on the magnitude of PSxfu,brain.


CONCLUSIONS
In situ brain perfusion is a useful technique to determine BBB permeability. Lipophilicity, ionization state, molecular weight and polar surface area are all important determinants for brain penetration. The time to blood-to-brain equilibrium varies widely for different compounds, and is determined by a multiplicity of pharmacokinetic factors.
Zhao
Rong
R
Division of Pharmacotherapy and Experimental Therapeutics, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599-7360, USA.
Kalvass
J Cory
JC
Pollack
Gary M
GM
D018435:ATP Binding Cassette Transporter, Subfamily B / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D001783:Blood Flow Velocity; D001812:Blood-Brain Barrier / Q000378:metabolism*; D001921:Brain / Q000378:metabolism; D008055:Lipids / Q000737:chemistry; D051379:Mice; D018345:Mice, Knockout; D010477:Perfusion; D010539:Permeability; D004364:Pharmaceutical Preparations / Q000737:chemistry; D010599:Pharmacokinetics
D018435:ATP Binding Cassette Transporter, Subfamily B; D008055:Lipids; D004364:Pharmaceutical Preparations; C095122:multidrug resistance protein 3