Rapid screening of blood-brain barrier penetration of drugs using the immobilized artificial membrane phosphatidylcholine column chromatography.
The chromatographic capacity factors (kIAM) of 23 structurally diverse drugs were measured by the immobilized artificial membrane (IAM) phosphatidylcholine chromatography for the prediction of blood-brain barrier (BBB) penetration. The kIAM was determined using the mobile phase consisting of acetonitrile:DPBS (20:80 v/v) and corrected for the molar volume of the solutes (kIAM/MWn). The correlation between kIAM/MWn and CNS penetration was highest when measured at pH 5.5 with the power function of n = 4. This in vitro prediction method 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.
Yoon
Chi Ho
CH
College of Pharmacy, Sungkyunkwan University, Gyeonggi-do, Korea.
Kim
Soo Jin
SJ
Shin
Beom Soo
BS
Lee
Kang Choon
KC
Yoo
Sun Dong
SD
D015105:3',5'-Cyclic-AMP Phosphodiesterases / Q000037:antagonists & inhibitors; D000818:Animals; D001681:Biological Assay; D001812:Blood-Brain Barrier / Q000378:metabolism*; D002490:Central Nervous System; D002845:Chromatography / Q000295:instrumentation* / Q000379:methods*; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4; D004353:Drug Evaluation, Preclinical / Q000295:instrumentation / Q000379:methods*; D006801:Humans; D008567:Membranes, Artificial; D010539:Permeability; D004364:Pharmaceutical Preparations / Q000378:metabolism*; D010713:Phosphatidylcholines / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D015203:Reproducibility of Results; D013223:Statistics as Topic
D008567:Membranes, Artificial; D004364:Pharmaceutical Preparations; D010713:Phosphatidylcholines; D015105:3',5'-Cyclic-AMP Phosphodiesterases; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4