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Permeability Analysis of Neuroactive Drugs Through a Dynamic Microfluidic In Vitro Blood–Brain Barrier Model

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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/cm2 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.

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Abbreviations

μBBB:

Microfluidic blood–brain barrier

CAN:

Acetonitrile

APTES:

3-aminopropyltriethoxysilane

AUC:

Area under the curve

B/P:

Brain/plasma ratio

BBB:

Blood–brain barrier

CNS:

Central nervous system

DAPI:

4′,6-Diamidino-2-phenylindole

DMSO:

Dimethylsiloxane

HPLC:

High performance liquid chromatography

LC–MS:

Liquid chromatography-mass spectrometry

LDH:

Lactate dehydrogenase

OPA:

ο-Phthalaldehyde

PBS:

Phosphate buffered saline

PC:

Polycarbonate

PDMS:

Polydimethylsiloxane

PK:

Pharmacokinetic

TEER:

Trans-endothelial electrical resistance

ZO-1:

Zonal occludin-1

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Acknowledgements

This project has been supported by the Utah Science Technology and Research Initiative (USTAR). Microfabrication was performed at the University of Utah Nano Fabrication Facility located in the Sorenson Molecular Biotechnology Building. CNS drugs were provided by Pfizer through the compound transfer program. LC–MS and HPLC–UV was performed at the University of Utah Health Sciences Center (HSC) Core Lab.

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  1. Department of Bioengineering, University of Utah, SMBB 3100, 36 S. Wasatch Dr., Salt Lake City, UT, 84112, USA

    R. Booth & H. Kim

  2. Department of Electrical and Computer Engineering, University of Utah, MEB 3280, 50 S. Central Campus Dr., Salt Lake City, UT, 84112, USA

    R. Booth & H. Kim

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Correspondence to R. Booth.

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Associate Editor Sriram Neelamegham oversaw the review of this article.

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Booth, R., Kim, H. Permeability Analysis of Neuroactive Drugs Through a Dynamic Microfluidic In Vitro Blood–Brain Barrier Model. Ann Biomed Eng 42, 2379–2391 (2014). https://doi.org/10.1007/s10439-014-1086-5

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