Organic Cation Transporter (OCT/OCTN) Expression at Brain Barrier Sites: Focus on CNS Drug Delivery

Betterton, Robert D.; Davis, Thomas P.; Ronaldson, Patrick T.

doi:10.1007/164_2021_448

Cited by 22 publications

(18 citation statements)

References 139 publications

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“…These results are consistent with a previous study by Lin and colleagues that showed increased luminal expression of Oct1 and Oct2 in cultured rat brain endothelial cells [81]. Using fluorescent confocal microscopy, our laboratory has detected Oct1 in brain microvessels isolated from female Sprague-Dawley rats [5,134]. Similar to OATP isoforms, global proteomic analysis of human brain microvessels revealed detectable quantities of OCT1 and OCT3 protein [123].…”

Section: Role Of Uptake Transporters In Drug Disposition To the Ische...supporting

confidence: 91%

“…MATE1 functions to ensure the extrusion of cationic substrates into the urinary filtrate so that they can be efficiently excreted. At the BBB, current evidence suggests that OCTs/Octs are preferentially expressed at the luminal plasma membrane of endothelial cells (Figure 4) [134]. Functional expression of Octs has been demonstrated in brain microvessel endothelial cells as shown by OCT1/Oct1 and OCT2/Oct2-mediated uptake of N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) [81].…”

Section: Role Of Uptake Transporters In Drug Disposition To the Ische...mentioning

confidence: 99%

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Blood–Brain Barrier Transporters: Opportunities for Therapeutic Development in Ischemic Stroke

Nilles

Williams

Betterton

et al. 2022

IJMS

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Globally, stroke is a leading cause of death and long-term disability. Over the past decades, several efforts have attempted to discover new drugs or repurpose existing therapeutics to promote post-stroke neurological recovery. Preclinical stroke studies have reported successes in identifying novel neuroprotective agents; however, none of these compounds have advanced beyond a phase III clinical trial. One reason for these failures is the lack of consideration of blood–brain barrier (BBB) transport mechanisms that can enable these drugs to achieve efficacious concentrations in ischemic brain tissue. Despite the knowledge that drugs with neuroprotective properties (i.e., statins, memantine, metformin) are substrates for endogenous BBB transporters, preclinical stroke research has not extensively studied the role of transporters in central nervous system (CNS) drug delivery. Here, we review current knowledge on specific BBB uptake transporters (i.e., organic anion transporting polypeptides (OATPs in humans; Oatps in rodents); organic cation transporters (OCTs in humans; Octs in rodents) that can be targeted for improved neuroprotective drug delivery. Additionally, we provide state-of-the-art perspectives on how transporter pharmacology can be integrated into preclinical stroke research. Specifically, we discuss the utility of in vivo stroke models to transporter studies and considerations (i.e., species selection, co-morbid conditions) that will optimize the translational success of stroke pharmacotherapeutic experiments.

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Section: Role Of Uptake Transporters In Drug Disposition To the Ische...supporting

confidence: 91%

Section: Role Of Uptake Transporters In Drug Disposition To the Ische...mentioning

confidence: 99%

Blood–Brain Barrier Transporters: Opportunities for Therapeutic Development in Ischemic Stroke

Nilles

Williams

Betterton

et al. 2022

IJMS

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“…The SLC22A family consists of organic cation transporters (OCTs) and organic anion transporters (OATs) carrying anions, cations, or zwitterions. OCT1 (SLC22A1), OCT2 (SLC22A2), and OCT3 (SLC22A3) are expressed most likely both at the luminal and abluminal sides of the BBB endothelial cells, although more evidence of the exact localizations is needed [229]. Furthermore, OCT2-3 has been identified in neurons and OCT2 in microglia and astrocytes (Table 6, Figure 1g).…”

Section: Organic Cation/anion/zwitterion Transporter Family (Slc22a)mentioning

confidence: 98%

“…Furthermore, OCT2-3 has been identified in neurons and OCT2 in microglia and astrocytes (Table 6, Figure 1g). Similarly, OCTN1 (SLC22A4) and OCTN2 (SLC22A5) are most likely expressed at the BBB to some extent, but they are also found in parenchymal cells; OCTN1 in microglia and OCTN2 in neurons [229,230]. However, both OCTs and OCTNs are also expressed throughout the body, particularly in the kidneys and liver [194].…”

Section: Organic Cation/anion/zwitterion Transporter Family (Slc22a)mentioning

confidence: 99%

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

et al. 2022

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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.

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“…As with other SLC22 family members, the transporters all contain 12 transmembrane domains and a large extracellular loop between the first and second transmembrane domain. A few review articles about OCTNs have been recently published (Pochini et al, 2019;Betterton et al, 2021;Sweet, 2021). Below we briefly describe OCTN1, OCTN2 and SLC22A16.…”

Section: Slc22a15 Was Recently Deorphaned (See Section Recent Deorphaning Studies Of Transporters In the Slc22a Family)mentioning

confidence: 99%

Emerging Roles of the Human Solute Carrier 22 Family

Yee

Giacomini

2021

Drug Metab Dispos

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The human Solute Carrier 22 family (SLC22), also termed the organic ion transporter family, consists of 28 distinct multi-membrane spanning proteins, which phylogenetically cluster together according to their charge specificity for organic cations (OCTs), organic anions (OATs) and organic zwitterion/cations (OCTNs). Some SLC22 family members are well characterized in terms of their substrates, transport mechanisms and expression patterns, as well as their roles in human physiology and pharmacology, whereas others remain orphans with no known ligands. Pharmacologically, SLC22 family members play major roles as determinants of the absorption and disposition of many prescription drugs, and several including the renal transporters, OCT2, OAT1 and OAT3 are targets for many clinically important drug-drug interactions. In addition, mutations in some of these transporters (SLC22A5 (OCTN2) and SLC22A12 (URAT1) lead to rare monogenic disorders. Genetic polymorphisms in SLC22 transporters have been associated with common human disease, drug response and various phenotypic traits. Three members in this family were deorphaned in very recently: SLC22A14, SLC22A15 and SLC22A24, and found to transport specific compounds such as riboflavin (SLC22A14), anti-oxidant zwitterions (SLC22A15) and steroid conjugates (SLC22A24). Their physiologic and pharmacological roles need further investigation. This review aims to summarize the substrates, expression patterns and transporter mechanisms of individual SLC22 family members and their roles in human disease and drug disposition and response. Gaps in our understanding of SLC22 family members are described. SIGNIFICANCE STATEMENTIn recent years, three members of the SLC22 family of transporters have been deorphaned and found to play important roles in the transport of diverse solutes. New research has furthered our understanding of the mechanisms, pharmacological roles, and clinical impact of SLC22 transporters. This minireview provides overview of SLC22 family members of their physiologic and pharmacologic roles, the impact of genetic variants in the SLC22 family on disease and drug response, and summary of recent studies deorphaning SLC22 family members.

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Organic Cation Transporter (OCT/OCTN) Expression at Brain Barrier Sites: Focus on CNS Drug Delivery

Cited by 22 publications

References 139 publications

Blood–Brain Barrier Transporters: Opportunities for Therapeutic Development in Ischemic Stroke

Blood–Brain Barrier Transporters: Opportunities for Therapeutic Development in Ischemic Stroke

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

Emerging Roles of the Human Solute Carrier 22 Family

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