Comparison of blood-brain barrier permeability assays: in situ brain perfusion, MDR1-MDCKII and PAMPA-BBB.
Permeability data from MDR1-MDCKII and PAMPA-BBB assays were compared to data from in situ brain perfusion to evaluate the accuracy of in vitro assays in predicting in vivo blood-brain barrier (BBB) permeability. PAMPA-BBB significantly correlated to in situ brain perfusion, however, MDR1-MDCKII had no correlation with in situ brain perfusion. PAMPA-BBB also significantly correlated with MDR1-MDCKII. The differential correlation of PAMPA-BBB and MDR1-MDCKII to in situ brain perfusion appears to be mainly due to the difference in membrane characteristics rather than binding to brain tissue. The MDR1-MDCKII cell membrane has lower ratios of: phospholipid to cholesterol, unsaturated to saturated acyl chains, and phosphatidyl-choline (PC) to sphingomyelin (SM) than brain endothelial cells, making it a poor passive permeability model for BBB. The BBB is more hydrophobic, rigid, and less fluidic than MDR1-MDCKII cell membrane. PAMPA-BBB more closely matches the BBB membrane in these characteristics and is a more accurate passive diffusion permeability model for BBB than MDR1-MDCKII. PAMPA-BBB is high throughput, low cost and has good prediction of in vivo BBB permeability, and therefore, it is a valuable tool in drug discovery to screen compounds for the rate of brain penetration.
Chemical and Screening Sciences, Wyeth Research, Princeton, New Jersey, USA. dil@wyeth.com
Li
L
Di
Edward H
EH
Kerns
Ian F
IF
Bezar
Susan L
SL
Petusky
Youping
Y
Huang
D001692:Biological Transport; D001812:Blood-Brain Barrier / Q000378:metabolism*; D001921:Brain / Q000166:cytology / Q000378:metabolism*; D018929:Cell Culture Techniques; D002460:Cell Line; D055808:Drug Discovery / Q000191:economics / Q000379:methods; D006801:Humans; D008563:Membrane Lipids / Q000737:chemistry / Q000378:metabolism; D008567:Membranes, Artificial; D010477:Perfusion; D012680:Sensitivity and Specificity
D008563:Membrane Lipids; D008567:Membranes, Artificial