title: Permeability analysis of neuroactive drugs through a dynamic microfluidic in vitro blood-brain barrier model.
abstract: This paper presents the permeability analysis of neuroactive drugs and correlation with in vivo brain/plasma ratios in a dynamic microfluidic blood-brain barrier (BBB) model. Permeability of seven neuroactive drugs (Ethosuximide, Gabapentin, Sertraline, Sunitinib, Traxoprodil, Varenicline, PF-304014) and trans-endothelial electrical resistance (TEER) were quantified in both dynamic (microfluidic) and static (transwell) BBB models, either with brain endothelial cells (bEnd.3) in monoculture, or in co-culture with glial cells (C6). Dynamic cultures were exposed to 15 dyn/cm(2) shear stress to mimic the in vivo environment. Dynamic models resulted in significantly higher average TEER (respective 5.9-fold and 8.9-fold increase for co-culture and monoculture models) and lower drug permeabilities (average respective decrease of 0.050 and 0.052 log(cm/s) for co-culture and monoculture) than static models; and co-culture models demonstrated higher average TEER (respective 90 and 25% increase for static and dynamic models) and lower drug permeability (average respective decrease of 0.063 and 0.061 log(cm/s) for static and dynamic models) than monoculture models. Correlation of the resultant logP e values [ranging from -4.06 to -3.63 log(cm/s)] with in vivo brain/plasma ratios (ranging from 0.42 to 26.8) showed highly linear correlation (R (2) > 0.85) for all model conditions, indicating the feasibility of the dynamic microfluidic BBB model for prediction of BBB clearance of pharmaceuticals.
authors.affiliation: Department of Bioengineering, University of Utah, SMBB 3100, 36 S. Wasatch Dr., Salt Lake City, UT, 84112, USA, Ross.Booth@utah.edu.
authors.forename: R
authors.initials: R
authors.lastname: Booth
authors.forename: H
authors.initials: H
authors.lastname: Kim
mesh_terms: D000588:Amines / Q000494:pharmacology; D000818:Animals; D001552:Benzazepines / Q000494:pharmacology; D001692:Biological Transport; D001812:Blood-Brain Barrier / Q000378:metabolism*; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D018920:Coculture Techniques; D003509:Cyclohexanecarboxylic Acids / Q000494:pharmacology; D042783:Endothelial Cells / Q000378:metabolism; D005013:Ethosuximide / Q000494:pharmacology; D000077206:Gabapentin; D007211:Indoles / Q000494:pharmacology; D007770:L-Lactate Dehydrogenase / Q000378:metabolism; D051379:Mice; D046210:Microfluidic Analytical Techniques; D009457:Neuroglia / Q000378:metabolism; D010539:Permeability; D010880:Piperidines / Q000494:pharmacology; D011758:Pyrroles / Q000494:pharmacology; D011810:Quinoxalines / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D020280:Sertraline / Q000494:pharmacology; D000077210:Sunitinib; D013764:Tetrahydronaphthalenes / Q000494:pharmacology; D014633:Valine / Q000031:analogs & derivatives / Q000494:pharmacology; D000068580:Varenicline; D005680:gamma-Aminobutyric Acid / Q000494:pharmacology
chemical_list: D000588:Amines; D001552:Benzazepines; D003509:Cyclohexanecarboxylic Acids; D007211:Indoles; D010880:Piperidines; D011758:Pyrroles; D011810:Quinoxalines; D013764:Tetrahydronaphthalenes; D005680:gamma-Aminobutyric Acid; D005013:Ethosuximide; D000077206:Gabapentin; C095106:traxoprodil mesylate; D007770:L-Lactate Dehydrogenase; D014633:Valine; D020280:Sertraline; C550722:nirogacestat; D000077210:Sunitinib; D000068580:Varenicline