International Journal of Molecular Sciences Review Disease-Induced Modulation of Drug Transporters at the Blood–Brain Barrier Level Sweilem B. Al Rihani 1 , Lucy I. Darakjian 1, Malavika Deodhar 1 , Pamela Dow 1 , Jacques Turgeon 1,2 and Veronique Michaud 1,2,* 1 Tabula Rasa HealthCare, Precision Pharmacotherapy Research and Development Institute, Orlando, FL 32827, USA; [email protected] (S.B.A.R.); [email protected] (L.I.D.); [email protected] (M.D.); [email protected] (P.D.); [email protected] (J.T.) 2 Faculty of Pharmacy, Université de Montréal, Montreal, QC H3C 3J7, Canada * Correspondence: [email protected]; Tel.: +1-856-938-8697 Abstract: The blood–brain barrier (BBB) is a highly selective and restrictive semipermeable network of cells and blood vessel constituents. All components of the neurovascular unit give to the BBB its crucial and protective function, i.e., to regulate homeostasis in the central nervous system (CNS) by removing substances from the endothelial compartment and supplying the brain with nutrients and other endogenous compounds. Many transporters have been identified that play a role in maintaining BBB integrity and homeostasis. As such, the restrictive nature of the BBB provides an obstacle for drug delivery to the CNS. Nevertheless, according to their physicochemical or pharmacological properties, drugs may reach the CNS by passive diffusion or be subjected to putative influx and/or efflux through BBB membrane transporters, allowing or limiting their distribution to the CNS. Drug transporters functionally expressed on various compartments of the BBB involve numerous proteins from either the ATP-binding cassette (ABC) or the solute carrier (SLC) superfamilies. Pathophysiological stressors, Citation: Al Rihani, S.B.; Darakjian, age, and age-associated disorders may alter the expression level and functionality of transporter L.I.; Deodhar, M.; Dow, P.; Turgeon, J.; protein elements that modulate drug distribution and accumulation into the brain, namely, drug Michaud, V. Disease-Induced efficacy and toxicity. This review focuses and sheds light on the influence of inflammatory conditions Modulation of Drug Transporters at and diseases such as Alzheimer’s disease, epilepsy, and stroke on the expression and functionality of the Blood–Brain Barrier Level. Int. J. the BBB drug transporters, the consequential modulation of drug distribution to the brain, and their Mol. Sci. 2021, 22, 3742. https:// impact on drug efficacy and toxicity. doi.org/10.3390/ijms22073742 Keywords: the blood–brain barrier; drug transporters; Alzheimer’s disease; stroke; epilepsy; neu- Academic Editor: Ryszard Pluta roinflammation Received: 3 February 2021 Accepted: 1 April 2021 Published: 3 April 2021 1. The Blood–Brain Barrier The blood–brain barrier (BBB) is a complex cellular barrier composed of a tightly sealed Publisher’s Note: MDPI stays neutral monolayer of specialized brain capillary endothelial cells lined on a basement membrane with regard to jurisdictional claims in published maps and institutional affil- and surrounded by adjacent perivascular astrocytes, pericytes, and microglia. The major iations. function of the BBB is to separate the circulating blood from the brain extracellular fluid and maintain homeostasis in the central nervous system (CNS) (Figure1). 1.1. BBB Facts and Figures For an average adult, the human brain represents 2% of total body mass. Remarkably, Copyright: © 2021 by the authors. despite this relatively small contribution to total body weight, the brain is composed of Licensee MDPI, Basel, Switzerland. ~170 billion neuronal, glial, or non-neuronal cells [1]. Under resting conditions, about 20% This article is an open access article distributed under the terms and of total blood flow from the heart is received by the brain in healthy adults [2,3]. The BBB 2 conditions of the Creative Commons has a large surface area of almost 15 to 25 m , a total length of capillaries of ~400 miles, Attribution (CC BY) license (https:// microcapillaries with a diameter of 7–10 µm, and an average inter-capillary distance of creativecommons.org/licenses/by/ ~40 µm [1,4–6]. These characteristics allow very selective diffusion and penetration of 4.0/). compounds [1,4]. The large BBB surface area and its critical role in maintaining homeostasis Int. J. Mol. Sci. 2021, 22, 3742. https://doi.org/10.3390/ijms22073742 https://www.mdpi.com/journal/ijms Int. J. Mol. Sci. 2021, 22, 3742 2 of 29 Int. J. Mol. Sci. 2021, 22, x FOR PEER REVIEW 2 of 30 of the brain require regulation and support from accompanying brain cells, which all together form the neurovascular unit (NVU). Figure 1.1. The blood–brainblood–brain barrier.barrier. (Created withwith BioRender,BioRender, accessedaccessed onon 2727 JanuaryJanuary 2021).2021). 1.2.1.1. TheBBB Neurovascular Facts and Figures Unit TheFor an NVU average is a relativelyadult, the newhuman concept brain inrepresents neuroscience. 2% of total The NVUbody mass. was originally Remarkably, de- scribeddespite inthis 1996 relatively as a three-party small contribution unit composed to total of body neurons, weight, cerebral the brain blood is composed vessels, and of astrocytes,~170 billion collectivelyneuronal, glial regulating, or non-neuronal cerebral bloodcells [1] flow. Under [7,8 ].resting In 2001, conditions, during theabout Stroke 20% Progress Review Group meeting of the National Institute of Neurological Disorders and of total blood flow from the heart is received by the brain in healthy adults [2,3]. The BBB Stroke, endothelial cells were recognized as the NVU blood vessel component to empha- has a large surface area of almost 15 to 25 m2, a total length of capillaries of ~400 miles, sizes the unique relationship between brain cells and cerebral vasculature [9,10]. Since microcapillaries with a diameter of 7–10 µm, and an average inter-capillary distance of then, the NVU has gained much interest from the neuroscience community and provided a ~40 µm [1,4–6]. These characteristics allow very selective diffusion and penetration of better understanding of the inter-play and signaling between these different cell types. The compounds [1,4]. The large BBB surface area and its critical role in maintaining homeo- gate function of the BBB is mainly due to the tightly sealed monolayer of endothelial cells stasis of the brain require regulation and support from accompanying brain cells, which lining the brain capillaries but the interaction of these endothelial cells with surrounding all together form the neurovascular unit (NVU). neurons, astrocytes, microglia, and pericytes is key to maintaining proper integrity and function of the BBB [11]. Furthermore, the NVU has become the center of attention for our 1.2. The Neurovascular Unit understanding of the pathology of several neurodegenerative diseases and, consequently, may representThe NVU ais potential a relativel therapeuticy new concept target in [12 neuroscience.]. The NVU was originally de- scribed in 1996 as a three-party unit composed of neurons, cerebral blood vessels, and 1.3.astrocytes, Movement collectively across the regulating BBB cerebral blood flow [7,8]. In 2001, during the Stroke Pro- gressThe Review BBB playsGroup an meeting essential of role the in National maintaining Institute proper of CNSNeurological functions Disorders by selectively and regulatingStroke, endothelial movement cells of were essential recogni nutrientszed as the and NVU toxins blood into vessel and out component of the CNS. to empha- While severalsizes the molecules unique relationship are restricted between from entering brain thecells brain, and cerebral many molecules vasculature can move[9,10]. across Since thethen, BBB the membrane NVU has gained using fourmuch basic interest mechanisms, from the neuroscience namely, passive community diffusion, and endocytosis, provided anda better carrier-mediated understanding transport of the inter or active-play transport,and signaling depending between on these the characteristics different cell oftypes. the moleculeThe gate function and the directionof the BBB of is the mainly transport due (Figureto the tightly2)[13]. sealed monolayer of endothelial cells lining the brain capillaries but the interaction of these endothelial cells with sur- rounding neurons, astrocytes, microglia, and pericytes is key to maintaining proper integ- rity and function of the BBB [11]. Furthermore, the NVU has become the center of attention for our understanding of the pathology of several neurodegenerative diseases and, con- sequently, may represent a potential therapeutic target [12]. Int. J. Mol. Sci. 2021, 22, x FOR PEER REVIEW 3 of 30 1.3. Movement across the BBB The BBB plays an essential role in maintaining proper CNS functions by selectively regulating movement of essential nutrients and toxins into and out of the CNS. While several molecules are restricted from entering the brain, many molecules can move across Int. J. Mol. Sci. 2021, 22, 3742 the BBB membrane using four basic mechanisms, namely, passive diffusion, endocytosis,3 of 29 and carrier-mediated transport or active transport, depending on the characteristics of the molecule and the direction of the transport (Figure 2) [13]. Figure 2.2. Transport pathwayspathways acrossacross thethe blood–brainblood–brain barrier (BBB).(BBB). The passagepassage of variousvarious molecules through the brain implies four basic mechanisms allowing specific molecules to move across the BBB membrane including: (1) the passive implies four basic mechanisms allowing specific molecules to move