J. Kelder et al., Polar molecular surface as a dominating determinant for oral absorption and brain penetration of drugs, PHARM RES, 16(10), 1999, pp. 1514-1519
Purpose. To study oral absorption and brain penetration as a function of po
lar molecular surface area.
Methods. Measured brain penetration data of 45 drug molecules were investig
ated. The dynamic polar surface areas were calculated and correlated with t
he brain penetration data. Also the static polar surface areas of 776 orall
y administered CNS drugs that have reached at least Phase II efficacy studi
es were calculated. The same was done for a series of 1590 orally administe
red non-CNS drugs that have reached at least Phase II efficacy studies.
Results. A linear relationship between brain penetration and dynamic polar
surface area (Angstrom(2)) was found (n = 45, R = 0.917, F-1,F-43 = 229). B
rain penetration decreases with increasing polar surface area. A clear diff
erence between the distribution of the polar surface area of the 776 CNS an
d 1590 non-CNS drugs was found. It was deduced that orally active drugs tha
t are transported passively by the transcellular route should not exceed a
polar surface area of about 120 Angstrom(2). They can be tailored to brain
penetration by decreasing the polar surface to <60-70 Angstrom(2). This con
clusion is supported by the inverse linear relationship between experimenta
l brain penetration data and the dynamic polar surface area of 45 drug mole
cules.
Conclusions. The polar molecular surface area is a dominating determinant f
ar oral absorption and brain penetration of drugs that are transported by t
he transcellular route. This property should be considered in the early pha
se of drug screening.