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Drug Transporters
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Drug Transporters

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Pharmacology".

Deadline for manuscript submissions: closed (20 October 2020) | Viewed by 20910

Special Issue Editor

Prof. Dr. Marek Drozdzik

E-Mail Website
Guest Editor
Department of Experimental and Clinical Pharmacology, Pomeranian Medical University, Powstancow Wlkp. 72 Str., 70-111 Szczecin, Poland
Interests: molecular pharmacology; drug transporters; drug metabolizing enzymes; pharmacogenetics/pharmacogenomics; clinical pharmacology
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

The movement of many drugs and their metabolites, as well as endogenous molecules across cell membranes, is determined by protein transporters, providing both efflux and uptake functions. More than 400 transporters have been annotated in the human genome, but only few of them were defined for the biological role. Characterizing drug transporters, both structural and functional, is mandatory to improve efficacy and safety of drugs used in medicine. 

Novel findings contributing to our understanding of all aspects of the solute carrier (SLC) and ATP-binding case (ABC) families’ functions in physiological and pathological conditions are encouraged for submission to this Special Issue. Original investigations, review articles, and short communications are all welcome.

Topics of this Special Issue include but are not limited to:
Structure-based computational biology
Pharmacogenomics/pharmacogenetics
Expression and proteomic studies
In vitro models
In vivo models
Functional studies
Drug–drug interactions
Drug–endogenous substrate interactions

This Special Issue is jointly organized between the IJMS and Biomedicines journals. According to the Aims and Scope of these journals, articles showing basic studies in biochemistry, molecular biology, and molecular medicine can be submitted to IJMS, while articles presenting a more clinical content can be submitted to Biomedicines.

Prof. Marek Drozdzik
Guest Editor

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. International Journal of Molecular Sciences is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. There is an Article Processing Charge (APC) for publication in this open access journal. For details about the APC please see here. Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • solute carrier (SLC)
  • ATP-binding cassette (ABC) transporter
  • drug disposition
  • drug targets
  • interactions

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Related Special Issue

Published Papers (6 papers)

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Research

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14 pages, 5146 KiB  
Article
Apical Sodium-Dependent Bile Acid Cotransporter, A Novel Transporter of Indocyanine Green, and Its Application in Drug Screening
by Menq-Rong Wu and Jong-Kai Hsiao
Int. J. Mol. Sci. 2020, 21(6), 2202; https://doi.org/10.3390/ijms21062202 - 23 Mar 2020
Cited by 3 | Viewed by 3546
Abstract
Bile acid plays critical roles in the elimination of inorganic compounds such as bilirubin, heavy metals, and drug metabolites. Apical sodium-dependent bile acid cotransporter (ASBT), a solute carrier membrane transport protein, transports bile acids. Several inhibitors of ASBT have been evaluated in clinical [...] Read more.
Bile acid plays critical roles in the elimination of inorganic compounds such as bilirubin, heavy metals, and drug metabolites. Apical sodium-dependent bile acid cotransporter (ASBT), a solute carrier membrane transport protein, transports bile acids. Several inhibitors of ASBT have been evaluated in clinical trials. Sodium taurocholate cotransporting polypeptide (NTCP), belonging to the same family as ASBT, has fluorescein 5(6)-isothiocyanate (FITC) and indocyanine green (ICG) transportability. ICG, a Food and Drug Administration-approved fluorophore at near-infrared range, has perfect optical characteristics, so it can be applied in cell tracking and drug screening. In this study, ASBT and NTCP were transduced into the HT-1080 cell line. Nude mice were subcutaneously xenografted with control and ASBT-expressing cells. ICG transportability was observed through flow cytometry, fluorescent microscopy, multi-mode plate readers, and an in vivo imaging system. Several molecules, including taurocholate, sodium deoxycholate, cyclosporine A, nifedipine, and Primovist, were used to evaluate an in vitro drug-screening platform by using the combination of ICG and ASBT through flow cytometry. ICG and FITC were validated and shown to be transported by ASBT. NTCP had a higher ICG intensity compared with ASBT. For cell tracking, the ASBT xenograft had similar ICG signals as the control. For a drug-screening platform, the ICG intensity decreased with 186 μM taurocholate (56.8%), deoxycholate (83.8%), and increased with nifedipine (133.2%). These findings are suggestive of opportunities for the high-throughput drug screening of cholestasis and other diseases that are related to the dynamics of bile acid reabsorption. Full article
(This article belongs to the Special Issue Drug Transporters)
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12 pages, 3406 KiB  
Article
Monocarboxylate Transporter 1 (MCT1) in Liver Pathology
by Marek Droździk, Sylwia Szeląg-Pieniek, Justyna Grzegółkowska, Joanna Łapczuk-Romańska, Mariola Post, Pawel Domagała, Janusz Miętkiewski, Stefan Oswald and Mateusz Kurzawski
Int. J. Mol. Sci. 2020, 21(5), 1606; https://doi.org/10.3390/ijms21051606 - 26 Feb 2020
Cited by 16 | Viewed by 3585
Abstract
Membrane monocarboxylate transporter 1 (SLC16A1/MCT1) plays an important role in hepatocyte homeostasis, as well as drug handling. However, there is no available information about the impact of liver pathology on the transporter levels and function. The study was aimed to quantify [...] Read more.
Membrane monocarboxylate transporter 1 (SLC16A1/MCT1) plays an important role in hepatocyte homeostasis, as well as drug handling. However, there is no available information about the impact of liver pathology on the transporter levels and function. The study was aimed to quantify SLC16A1 mRNA (qRT-PCR) and MCT1 protein abundance (liquid chromatography–tandem mass spectrometry (LC¬¬–MS/MS)) in the livers of patients diagnosed, according to the standard clinical criteria, with hepatitis C, primary biliary cirrhosis, primary sclerosing hepatitis, alcoholic liver disease (ALD), and autoimmune hepatitis. The stage of liver dysfunction was classified according to Child–Pugh score. Downregulation of SLC16A1/MCT1 levels was observed in all liver pathology states, significantly for ALD. The progression of liver dysfunction, from Child–Pugh class A to C, involved the gradual decline in SLC16A1 mRNA and MCT1 protein abundance, reaching a clinically significant decrease in class C livers. Reduced levels of MCT1 were associated with significant intracellular lactate accumulation. The MCT1 transcript and protein did not demonstrate significant correlations regardless of the liver pathology analyzed, as well as the disease stage, suggesting posttranscriptional regulation, and several microRNAs were found as potential regulators of MCT1 abundance. MCT1 membrane immunolocalization without cytoplasmic retention was observed in all studied liver pathologies. Overall, the study demonstrates that SLC16A1/MCT1 is involved in liver pathology, especially in ALD. Full article
(This article belongs to the Special Issue Drug Transporters)
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15 pages, 2777 KiB  
Article
A Miniaturized Pump Out Method for Characterizing Molecule Interaction with ABC Transporters
by Emmanuel Sevin, Lucie Dehouck, Romain Versele, Maxime Culot and Fabien Gosselet
Int. J. Mol. Sci. 2019, 20(22), 5529; https://doi.org/10.3390/ijms20225529 - 6 Nov 2019
Cited by 10 | Viewed by 2532
Abstract
Characterizing interaction of newly synthetized molecules with efflux pumps remains essential to improve their efficacy and safety. Caco-2 cell line cultivated on inserts is widely used for measuring apparent permeability of drugs across biological barriers, and for estimating their interaction with efflux pumps [...] Read more.
Characterizing interaction of newly synthetized molecules with efflux pumps remains essential to improve their efficacy and safety. Caco-2 cell line cultivated on inserts is widely used for measuring apparent permeability of drugs across biological barriers, and for estimating their interaction with efflux pumps such as P-gp, BCRP and MRPs. However, this method remains time consuming and expensive. In addition, detection method is required for measuring molecule passage across cell monolayer and false results can be generated if drugs concentrations used are too high as demonstrated with quinidine. For this reason, we developed a new protocol based on the use of Caco-2 cell directly seeded on 96- or 384-well plates and the use of fluorescent substrates for efflux pumps. We clearly observed that the new method reduces costs for molecule screening and leads to higher throughput compared to traditional use of Caco-2 cell model. This accelerated model could provide quick feedback regarding the molecule design during the early stage of drug discovery and therefore reduce the number of compounds to be further evaluated using the traditional Caco-2 insert method. Full article
(This article belongs to the Special Issue Drug Transporters)
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20 pages, 2903 KiB  
Article
Coix Seed Extract Enhances the Anti-Pancreatic Cancer Efficacy of Gemcitabine through Regulating ABCB1- and ABCG2-Mediated Drug Efflux: A Bioluminescent Pharmacokinetic and Pharmacodynamic Study
by Yifan Qian, Yang Xiong, Di Feng, Yali Wu, Xu Zhang, Liping Chen and Mancang Gu
Int. J. Mol. Sci. 2019, 20(21), 5250; https://doi.org/10.3390/ijms20215250 - 23 Oct 2019
Cited by 25 | Viewed by 3502
Abstract
A deep insight into the function and kinetics of ATP-binding cassette (ABC) transporters may aid in the development of pharmaceutics that can minimize the particular facet of chemo-resistance. We utilized bioluminescence imaging to monitor the ABC transporter mediated intracellular drug efflux function. We [...] Read more.
A deep insight into the function and kinetics of ATP-binding cassette (ABC) transporters may aid in the development of pharmaceutics that can minimize the particular facet of chemo-resistance. We utilized bioluminescence imaging to monitor the ABC transporter mediated intracellular drug efflux function. We also investigated the potential association between the intracellular bioluminescent pharmacokinetic profiles and the anti-tumor efficacy of the coix seed extract and gemcitabine against pancreatic cancer cells in vitro and in vivo. The bioluminescent pharmacokinetic parameters and pharmacodynamic index (IC50 and TGI) were determined. The expression levels ABCB1 and ABCG2 were assessed. Results showed that coix seed extract could synergistically enhance the anti-cancer efficacy of gemcitabine (p < 0.05). Meanwhile coix seed extract alone or in combination with gemcitabine could significantly increase the AUCluc while decreasing the Kluc (p < 0.01). Western blot and immunohistochemistry assay demonstrated that coix seed extract could significantly mitigate gemcitabine-induced upregulation of ABCB1 and ABCG2 protein. The Pearson correlation analysis demonstrated that the bioluminescent pharmacokinetic parameters and pharmacodynamic index have strong association in vitro and in vivo. In conclusion coix seed extract could augment the efficacy of gemcitabine therapy in pancreatic cancer cells may at least partly due to the alteration of ABC transporter-mediated drug efflux function. Full article
(This article belongs to the Special Issue Drug Transporters)
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Review

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16 pages, 1258 KiB  
Review
KV11.1, NaV1.5, and CaV1.2 Transporter Proteins as Antitarget for Drug Cardiotoxicity
by Magdalena Kowalska, Jacek Nowaczyk and Alicja Nowaczyk
Int. J. Mol. Sci. 2020, 21(21), 8099; https://doi.org/10.3390/ijms21218099 - 30 Oct 2020
Cited by 14 | Viewed by 3313
Abstract
Safety assessment of pharmaceuticals is a rapidly developing area of pharmacy and medicine. The new advanced guidelines for testing the toxicity of compounds require specialized tools that provide information on the tested drug in a quick and reliable way. Ion channels represent the [...] Read more.
Safety assessment of pharmaceuticals is a rapidly developing area of pharmacy and medicine. The new advanced guidelines for testing the toxicity of compounds require specialized tools that provide information on the tested drug in a quick and reliable way. Ion channels represent the third-largest target. As mentioned in the literature, ion channels are an indispensable part of the heart’s work. In this paper the most important information concerning the guidelines for cardiotoxicity testing and the way the tests are conducted has been collected. Attention has been focused on the role of selected ion channels in this process. Full article
(This article belongs to the Special Issue Drug Transporters)
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17 pages, 970 KiB  
Review
Extrahepatic Drug Transporters in Liver Failure: Focus on Kidney and Gastrointestinal Tract
by Marek Droździk, Stefan Oswald and Agnieszka Droździk
Int. J. Mol. Sci. 2020, 21(16), 5737; https://doi.org/10.3390/ijms21165737 - 10 Aug 2020
Cited by 11 | Viewed by 3763
Abstract
Emerging information suggests that liver pathological states may affect the expression and function of membrane transporters in the gastrointestinal tract and the kidney. Altered status of the transporters could affect drug as well as endogenous compounds handling with subsequent clinical consequences. It seems [...] Read more.
Emerging information suggests that liver pathological states may affect the expression and function of membrane transporters in the gastrointestinal tract and the kidney. Altered status of the transporters could affect drug as well as endogenous compounds handling with subsequent clinical consequences. It seems that changes in intestinal and kidney transporter functions provide the compensatory activity of eliminating endogenous compounds (e.g., bile acids) generated and accumulated due to liver dysfunction. A literature search was conducted on the Ovid and PubMed databases to select relevant in vitro, animal and human studies that have reported expression, protein abundance and function of the gastrointestinal and kidney operating ABC (ATP-binding cassette) transporters and SLC (solute carriers) carriers. The accumulated data suggest that liver failure-associated transporter alterations in the gastrointestinal tract and kidney may affect drug pharmacokinetics. The altered status of drug transporters in those organs in liver dysfunction conditions may provide compensatory activity in handling endogenous compounds, affecting local drug actions as well as drug pharmacokinetics. Full article
(This article belongs to the Special Issue Drug Transporters)
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