Polar molecular surface as a dominating determinant for oral absorption and brain penetration of drugs

Citation
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
Citations number
14
Categorie Soggetti
Pharmacology & Toxicology
Journal title
PHARMACEUTICAL RESEARCH
ISSN journal
07248741 → ACNP
Volume
16
Issue
10
Year of publication
1999
Pages
1514 - 1519
Database
ISI
SICI code
0724-8741(199910)16:10<1514:PMSAAD>2.0.ZU;2-T
Abstract
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.