Purpose: To study oral absorption and brain penetration as a function of polar molecular surface area.
Methods: Measured brain penetration data of 45 drug molecules were investigated. The dynamic polar surface areas were calculated and correlated with the brain penetration data. Also the static polar surface areas of 776 orally administered CNS drugs that have reached at least Phase II efficacy studies were calculated. The same was done for a series of 1590 orally administered non-CNS drugs that have reached at least Phase II efficacy studies.
Results: A linear relationship between brain penetration and dynamic polar surface area (A2) was found (n = 45, R = 0.917, F1,43 = 229). Brain penetration decreases with increasing polar surface area. A clear difference between the distribution of the polar surface area of the 776 CNS and 1590 non-CNS drugs was found. It was deduced that orally active drugs that are transported passively by the transcellular route should not exceed a polar surface area of about 120 A2. They can be tailored to brain penetration by decreasing the polar surface to <60-70 A2. This conclusion is supported by the inverse linear relationship between experimental brain penetration data and the dynamic polar surface area of 45 drug molecules.
Conclusions: The polar molecular surface area is a dominating determinant for oral absorption and brain penetration of drugs that are transported by the transcellular route. This property should be considered in the early phase of drug screening.