Relevance of ABC Transporters in Drug Development

Nwabufo, Chukwunonso K

doi:10.2174/1389200223666220621113524

Cited by 9 publications

(7 citation statements)

References 126 publications

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“…The translation of these compounds from bench to bedside is primarily dependent on their ability to demonstrate sufficient clinical efficacy and safety profile. Drug metabolizing enzymes and membrane-associated drug transporters are important modulators of the efficacy and safety profile of drugs and their effect on the disposition of these potential neuroprotective agents should be investigated at the early discovery stage to avoid costly clinical development failures [ 195 – 197 ].…”

Section: Management Of Parkinson’s Diseasementioning

confidence: 99%

“…P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP) are two important efflux transporters that play a critical role in limiting the CNS activity of some neurotherapeutic agents by preventing their penetration across the BBB [ 197 , 198 ]. In fact, P-gp and BCRP are also implicated in the neuropathology of PD [ 199 , 200 ].…”

Section: Management Of Parkinson’s Diseasementioning

confidence: 99%

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Diagnostic and therapeutic agents that target alpha-synuclein in Parkinson’s disease

Nwabufo

Aigbogun

2022

J Neurol

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The development of disease-modifying drugs and differential diagnostic agents is an urgent medical need in Parkinson’s disease. Despite the complex pathophysiological pathway, the misfolding of alpha-synuclein has been identified as a putative biomarker for detecting the onset and progression of the neurodegeneration associated with Parkinson’s disease. Identifying the most appropriate alpha-synuclein-based diagnostic modality with clinical translation will revolutionize the diagnosis of Parkinson’s. Likewise, molecules that target alpha-synuclein could alter the disease pathway that leads to Parkinson’s and may serve as first-in class therapeutics compared to existing treatment options such as levodopa and dopamine agonist that do not necessarily modify the disease pathway. Notwithstanding the promising benefits that alpha-synuclein presents to therapeutics and diagnostics development for Parkinson’s disease, finding ways to address potential challenges such as inadequate preclinical models, safety and efficacy will be paramount to achieving clinical translation. In this comprehensive review paper, we described the role of alpha-synuclein in the pathogenesis of Parkinson’s disease, as well as how its structure and function relationship delineate disease onset and progression. We further discussed different alpha-synuclein-based diagnostic modalities including biomolecular assays and molecular imaging. Finally, we presented current small molecules and biologics that are being developed as disease-modifying drugs or positron emission tomography imaging probes for Parkinson’s disease.

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Section: Management Of Parkinson’s Diseasementioning

confidence: 99%

Section: Management Of Parkinson’s Diseasementioning

confidence: 99%

Diagnostic and therapeutic agents that target alpha-synuclein in Parkinson’s disease

Nwabufo

Aigbogun

2022

J Neurol

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“…Efflux transporters export the drug out of cells into blood vessels or excretory vessels by utilizing an ATP energy source. Most of the efflux transporters belong to ATP binding cassette (ABC) transporters family [85] except multidrug and toxin extrusions (MATEs/SLC47As), which belong to the SLC family. Among the ABC transporters, multidrug resistance (MDR), P-gp and BCRP are majorly involved in the excretion of drugs and A d v n c e d o n l i n e a r t i c l e their metabolites from hepatocytes to bile and renal epithelial cells to lumen.…”

Section: Excretionmentioning

confidence: 99%

Role of in vitro two-dimensional (2D) and three-dimensional (3D) cell culture systems for ADME-Tox screening in drug discovery and development: a comprehensive review

Chunduri¹,

Maddi²

2022

ADMET DMPK

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Drug discovery and development have become a very time-consuming and expensive process. Preclinical animal models have become the gold standard for studying drug pharmacokinetic and toxicity parameters. However, the involvement of a huge number of animal subjects and inter-species pathophysiological variations between animals and humans has provoked a lot of debate, particularly because of ethical concerns. Although many efforts are being established by biotech and pharmaceutical companies for screening new chemical entities in vitro before preclinical trials, failures during clinical trials are still involved. Currently, a large number of two- dimensional (2D) in vitro assays have been developed and are being developed by researchers for the screening of compounds. Although these assays are helpful in screening a huge library of compounds and have shown perception, there is a significant lack in predicting human Absorption, Distribution, Metabolism, Excretion and Toxicology (ADME-Tox). As a result, these assays cannot completely replace animal models. The recent inventions in three-dimensional (3D) cell culture-based assays like organoids and micro-physiological systems have shown great potential alternative tools for predicting the compound pharmacokinetic and pharmacodynamic fate in humans. In this comprehensive review, we have summarized some of the most commonly used 2D in vitro assays and emphasized the achievements in next-generation 3D cell culture-based systems for predicting the compound ADME-Tox.

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“…Transport proteins are often categorized by their mechanism of transport. ATP-binding cassette (ABC) transporters are primary active transporters that, in higher organisms, use ATP hydrolysis to drive the transport of solutes across the membrane and typically out of cells [ 2 , 3 ]. Secondary active transporters couple solute translocation to the cotransport or counter-transport of either inorganic ions or other solutes; in the latter case, they are often called exchangers.…”

Section: Introductionmentioning

confidence: 99%

Transporter-Mediated Drug Delivery

Gyimesi

Hediger

2023

Molecules

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Transmembrane transport of small organic and inorganic molecules is one of the cornerstones of cellular metabolism. Among transmembrane transporters, solute carrier (SLC) proteins form the largest, albeit very diverse, superfamily with over 400 members. It was recognized early on that xenobiotics can directly interact with SLCs and that this interaction can fundamentally determine their efficacy, including bioavailability and intertissue distribution. Apart from the well-established prodrug strategy, the chemical ligation of transporter substrates to nanoparticles of various chemical compositions has recently been used as a means to enhance their targeting and absorption. In this review, we summarize efforts in drug design exploiting interactions with specific SLC transporters to optimize their therapeutic effects. Furthermore, we describe current and future challenges as well as new directions for the advanced development of therapeutics that target SLC transporters.

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Relevance of ABC Transporters in Drug Development

Cited by 9 publications

References 126 publications

Diagnostic and therapeutic agents that target alpha-synuclein in Parkinson’s disease

Diagnostic and therapeutic agents that target alpha-synuclein in Parkinson’s disease

Role of in vitro two-dimensional (2D) and three-dimensional (3D) cell culture systems for ADME-Tox screening in drug discovery and development: a comprehensive review

Transporter-Mediated Drug Delivery

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