Transport Rankings of Non-Steroidal Antiinflammatory Drugs across Blood-Brain Barrier In Vitro Models

Abstract

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.

Establishment of a Human Blood-Brain Barrier Co-culture Model Mimicking the Neurovascular Unit Using Induced Pluri- and Multipotent Stem Cells

“…Moreover, transport of caffeine was significantly further decreased in the quadruple culture compared with the mono-culture, indicating an even more in vivo-like phenotype in the quadruple culture. In concordance with in vitro data obtained from BBB models based on rat primary cells, ibuprofen was also faster than diclofenac in our models (Novakova et al., 2014). Loratadine and rhodamine 123 are known to be strong substrates of the efflux pump P-glycoprotein and to permeate significantly slower than diazepam (Obradovic et al., 2007, Neuhaus et al., 2012).…”

Polymorphisms in ATP-binding cassette transporter genes and interaction with diet and life style factors in relation to colorectal cancer in a Danish prospective case-cohort study

“…Several studies have shown that NSAIDs modulate expression of the ABC transporters [30][31][32][33][34][35] and possibly functions as substrates [30]. The present study supports these findings and suggests that carriers of polymorphisms that are associated with lower ABC transport activity benefit from the anti-inflammatory effect of the NSAIDs.…”

“…We have previously found interaction between two polymorphisms in ABCB1 and red meat intake in relation to risk of CRC [29] which could be caused by a change in binding affinity or transport activity for PAHs and HCAs. Moreover, we found interaction between use of non-steroidal antiinflammatory drugs (NSAID) and an ABCB1 polymorphism which is in line with studies showing that several NSAIDs modulate expression of ABC transporters [30][31][32][33][34][35] or function as substrates for the ABC transporters [30]. In another study using the same study group as the present, we found interaction between several dietary factors and polymorphisms in genes encoding the cytokines interleukin 1-b (IL-1b) and IL-10 in relation to CRC risk [36].…”

Safety Issues of Pharmacological Acute Pain Treatment in Children

“…Ibuprofen, like several NSAIDs, is metabolized by CYP2C9, as well as CYP2C19. NSAIDs have a high liposolubility, and studies have shown that they easily cross the BBB . No information is available regarding their transport at the BBB, even if the role of multidrug resistance‐associated protein 1, organic anion transporter, and P‐gp is suggested …”

“…49 No information is available regarding their transport at the BBB, 50 even if the role of multidrug resistance-associated protein 1, organic anion transporter, and P-gp is suggested. 49 The incidence of ADRs associated with ibuprofen in children is low. 51,52 Rare but potentially severe ADRs in children are upper gastrointestinal complications and kidney injury ( Table 3).…”