Transport rankings of non-steroidal antiinflammatory drugs across blood-brain barrier in vitro models.
The aim of this work was to conduct a comprehensive study about the transport properties of NSAIDs across the blood-brain barrier (BBB) in vitro. Transport studies with celecoxib, diclofenac, ibuprofen, meloxicam, piroxicam and tenoxicam were accomplished across Transwell models based on cell line PBMEC/C1-2, ECV304 or primary rat brain endothelial cells. Single as well as group substance studies were carried out. In group studies substance group compositions, transport medium and serum content were varied, transport inhibitors verapamil and probenecid were added. Resulted permeability coefficients were compared and normalized to internal standards diazepam and carboxyfluorescein. Transport rankings of NSAIDs across each model were obtained. Single substance studies showed similar rankings as corresponding group studies across PBMEC/C1-2 or ECV304 cell layers. Serum content, glioma conditioned medium and inhibitors probenecid and verapamil influenced resulted permeability significantly. Basic differences of transport properties of the investigated NSAIDs were similar comparing all three in vitro BBB models. Different substance combinations in the group studies and addition of probenecid and verapamil suggested that transporter proteins are involved in the transport of every tested NSAID. Results especially underlined the importance of same experimental conditions (transport medium, serum content, species origin, cell line) for proper data comparison.
Department of Medicinal Chemistry, University of Vienna, Vienna, Austria.
Iveta
I
Novakova
Biopredic International, Rennes, France.
Eva-Anne
EA
Subileau
Department of Orthopedics, Medical University Vienna, Vienna, Austria.
Stefan
S
Toegel
Core Facility Cell Imaging and Ultrastructure Research, University of Vienna, Vienna, Austria.
Daniela
D
Gruber
Department of Medicinal Chemistry, University of Vienna, Vienna, Austria.
Bodo
B
Lachmann
Department of Medicinal Chemistry, University of Vienna, Vienna, Austria.
Ernst
E
Urban
Biopredic International, Rennes, France.
Christophe
C
Chesne
Department of Medicinal Chemistry, University of Vienna, Vienna, Austria.
Christian R
CR
Noe
Department of Medicinal Chemistry, University of Vienna, Vienna, Austria ; Department of Anesthesia and Critical Care, University Hospital Würzburg, Würzburg, Germany.
Winfried
W
Neuhaus
D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000493:pharmacokinetics*; D001253:Astrocytes / Q000166:cytology / Q000187:drug effects*; D001693:Biological Transport, Active; D001812:Blood-Brain Barrier / Q000187:drug effects* / Q000502:physiology*; D002463:Cell Membrane Permeability / Q000187:drug effects*; D002478:Cells, Cultured; D002851:Chromatography, High Pressure Liquid; D017077:Culture Media, Conditioned / Q000494:pharmacology; D055808:Drug Discovery; D004730:Endothelium, Vascular / Q000166:cytology / Q000187:drug effects*; D005910:Glioma / Q000188:drug therapy / Q000473:pathology; D008297:Male; D051381:Rats; D017208:Rats, Wistar; D013552:Swine; D014018:Tissue Distribution
D000894:Anti-Inflammatory Agents, Non-Steroidal; D017077:Culture Media, Conditioned