In vitro blood-brain barrier permeability predictions for GABA_A receptor modulating piperine analogs

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• 作者：Daniela Elisabeth Eigenmann^a ; Carmen Dü ; rig^a ; Evelyn Andrea Jä ; hne^a ; Martin Smie&scaron ; ko^b ; Maxime Culot^c ; Fabien Gosselet^c ; Romeo Cecchelli^c ; Hans Christian Cederberg Helms^d ; Birger Brodin^d ; Laurin Wimmer^e ; Marko D. Mihovilovic^e ; Matthias Hamburger^a ; Mouhssin Oufir^a ; ^{mouhssin.oufir@unibas.ch" class="auth_mail" title="E-mail the corresponding author}
• 关键词：BBB ; blood&ndash ; brain barrier ; BLEC ; human brain-like endothelial cells ; BSA ; bovine serum albumin ; CCL ; cell layer capacitance ; CNS ; central nervous system ; CV ; coefficient of variation ; DMEM ; Dulbecco&rsquo ; s Modified Eagle Medium ; ER ; efflux ratio ; FA ; formic acid ; FBS ; fetal bovine serum ; GABAA receptor ; γ-aminobutyric acid type A receptor ; hBMEC ; human brain microvascular endothelial cell line ; I.S. ; internal standard ; LLOQ ; lower limit of quantification ; MRM ; multiple reaction monitoring
• 刊名：European Journal of Pharmaceutics and Biopharmaceutics
• 出版年：2016
• 出版时间：June 2016
• 年：2016
• 卷：103
• 期：Complete
• 页码：118-126
• 全文大小：970 K

文摘

The alkaloid piperine from black pepper (Piper nigrum L.) and several synthetic piperine analogs were recently identified as positive allosteric modulators of γ-aminobutyric acid type A (GABA_A) receptors. In order to reach their target sites of action, these compounds need to enter the brain by crossing the blood–brain barrier (BBB). We here evaluated piperine and five selected analogs (SCT-66, SCT-64, SCT-29, LAU397, and LAU399) regarding their BBB permeability. Data were obtained in three in vitro BBB models, namely a recently established human model with immortalized hBMEC cells, a human brain-like endothelial cells (BLEC) model, and a primary animal (bovine endothelial/rat astrocytes co-culture) model. For each compound, quantitative UHPLC-MS/MS methods in the range of 5.00–500 ng/mL in the corresponding matrix were developed, and permeability coefficients in the three BBB models were determined. In vitro predictions from the two human BBB models were in good agreement, while permeability data from the animal model differed to some extent, possibly due to protein binding of the screened compounds. In all three BBB models, piperine and SCT-64 displayed the highest BBB permeation potential. This was corroborated by data from in silico prediction. For the other piperine analogs (SCT-66, SCT-29, LAU397, and LAU399), BBB permeability was low to moderate in the two human BBB models, and moderate to high in the animal BBB model. Efflux ratios (ER) calculated from bidirectional permeability experiments indicated that the compounds were likely not substrates of active efflux transporters.