Rapid screening of blood-brain barrier penetration of drugs using the immobilized artificial membrane phosphatidylcholine column chromatography

The chromatographic capacity factors (k_IAM) of 23 structurally diverse drugs were measured by the immobilized artificial membrane (kIAM) phosphatidylcholine chromatography for the prediction of blood-brain barrier (BBB) penetration. The k_IAM was determined using themobile phase consisting of acetonitrile:DPBS (20:80 v/v) and corrected for the molar volume of the solutes (k_IAM/MWⁿ). The correlation between k _IAM/MWⁿ and CNS penetration was highest when measured at pH 5.5 with the power function of n = 4. This in vitro predictionmethod was validated with 7 newly synthesized PDE-4 inhibitors. The relationship between in vivo plasma-to-brain concentration ratios and in vitro CNS penetration was excellent (r= 0.959). The developed in vitro prediction method may be used as a rapid screening tool for BBB penetration of drugs with passive transport mechanism, with high success, low cost, and reproducibility.