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Vol. 303, Issue 3, 1029-1037, December 2002
Preclinical Drug Metabolism and Pharmacokinetics, GlaxoSmithKline,
Research Triangle Park, North Carolina
Membrane permeability and P-glycoprotein (Pgp) can be limiting
factors for blood-brain barrier penetration. The objectives of this
study were to determine whether there are differences in the in vitro
permeability, Pgp substrate profiles, and physicochemical properties of
drugs for central nervous system (CNS) and non-CNS indications, and
whether these differences are useful criteria in selecting compounds
for drug development. Apparent permeability (Papp) and Pgp substrate profiles for 93 CNS
(n = 48) and non-CNS (n = 45)
drugs were determined by monolayer efflux. Calcein-AM inhibition assays
were used to supplement the efflux results. The CNS set (2 of 48, 4.2%) had a 7-fold lower incidence of passive permeability values
<150 nm/s compared with the non-CNS set (13 of 45, 28.9%). The
majority of drugs (72.0%, 67 of 93) were not Pgp substrates; however,
49.5% (46 of 93) were positive in the calcein-AM assay when tested at
100 µM. The CNS drug set (n = 7 of 48, 14.6%)
had a 3-fold lower incidence of Pgp-mediated efflux than the non-CNS
drug set (n = 19 of 45, 42.2%). Analysis of 18 physicochemical properties revealed that the CNS drug set had fewer
hydrogen bond donors, fewer positive charges, greater lipophilicity, lower polar surface area, and reduced flexibility compared with the
non-CNS group (p < 0.05), properties that enhance
membrane permeability. This study on a large, diverse set of marketed
compounds clearly demonstrates that permeability, Pgp-mediated efflux,
and certain physicochemical properties are factors that differentiate CNS and non-CNS drugs. For CNS delivery, a drug should ideally have an
in vitro passive permeability >150 nm/s and not be a good (B 
A/A
B ratio <2.5) Pgp substrate.
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