Increased/Targeted Brain (Pro)Drug Delivery via Utilization of Solute Carriers (SLCs)

Abstract

Membrane transporters have a crucial role in compounds’ brain drug delivery. They allow not only the penetration of a wide variety of different compounds to cross the endothelial cells of the blood–brain barrier (BBB), but also the accumulation of them into the brain parenchymal cells. Solute carriers (SLCs), with nearly 500 family members, are the largest group of membrane transporters. Unfortunately, not all SLCs are fully characterized and used in rational drug design. However, if the structural features for transporter interactions (binding and translocation) are known, a prodrug approach can be utilized to temporarily change the pharmacokinetics and brain delivery properties of almost any compound. In this review, main transporter subtypes that are participating in brain drug disposition or have been used to improve brain drug delivery across the BBB via the prodrug approach, are introduced. Moreover, the ability of selected transporters to be utilized in intrabrain drug delivery is discussed. Thus, this comprehensive review will give insights into the methods, such as computational drug design, that should be utilized more effectively to understand the detailed transport mechanisms. Moreover, factors, such as transporter expression modulation pathways in diseases that should be taken into account in rational (pro)drug development, are considered to achieve successful clinical applications in the future.

Circulating (poly)phenol metabolites in the brain: unveiling in vitro and in vivo blood-brain barrier transport

“…( A ) Schematic representation of CMT and receptor-mediated transporters (RMT) predicted expression/localization in endothelial cells of the BBB based on literature revision[34–37]. Question marks (?)…”

“…We performed a literature revision of the most representative carrier-mediated (CMT) and receptor-mediated transporters (RMT) predicted to be present in brain microvascular endothelial cells [34][35][36][37][38] (Figure 4A). To assure which major BBB transporters are expressed in the HBMEC line, a RT-qPCR was performed.…”

Advanced Blood–Brain Barrier Drug Delivery

“…An alternative approach to the use of medicinal chemistry to enhance the BBB transport of small-molecule drugs is to modify the drug so that it both (a) retains pharmacologic activity, and (b) has a modest to high affinity for transport via one of several CMT systems at the BBB. In this Special Issue, the article by Huttunen et al [ 10 ] is the most comprehensive review, to date, on the use of medicinal chemistry for designing drugs that reach the brain via CMT across the BBB. All of the CMT systems reviewed by the authors [ 10 ] are members of the Solute Carrier (SLC) gene family.…”

“…In this Special Issue, the article by Huttunen et al [ 10 ] is the most comprehensive review, to date, on the use of medicinal chemistry for designing drugs that reach the brain via CMT across the BBB. All of the CMT systems reviewed by the authors [ 10 ] are members of the Solute Carrier (SLC) gene family. The problem lies in the complexity of the SLC family of transporters, as there are >400 genes in >60 families of SLC transporters [ 1 ].…”

“…Therefore, it is crucial to identify which SLC transporter functions at the luminal membrane of the brain capillary endothelium. Based on the available literature data, Huttunen et al [ 10 ] recommend targeting certain SLC transporters, including ASCT1; the alanine-serine-cysteine transporter (SLC1A); the GLUT1 glucose transporter (SLC2A); the CAT1 cationic amino acid transporter, the LAT1 large neutral amino acid transporter (SLC 7A); the MCT1 and MCT8 monocarboxylic acid transporters (SLC16A); the OATP2B1 and OATP1A2 organic anion transporters (SLC21A/SLCO); the OCT1-3 and OCTN1-2 organic anion and organic cation transporters (SLC22A); and the SNAT3 glutamine transporter (SLC38A). In addition, certain vitamins undergo CMT across the BBB via other members of the SLC gene family [ 1 ] and are potential targets for medicinal chemists [ 10 ].…”