Special Issue "Personalized Medicine Based on Drug Transporter Genetic Heterogeneity"

A special issue of Journal of Personalized Medicine (ISSN 2075-4426).

Deadline for manuscript submissions: closed (15 February 2019)

Special Issue Editors

Guest Editor
Prof. Dr. Marçal Pastor-Anglada

Molecular Pharmacology and Experimental Therapeutics, Department of Biochemistry and Molecular Biomedicine, Institute of Biomedicine (IBUB), University of Barcelona, Oncology Program, National Biomedical Research Institute on Liver and Gastrointestinal Diseases (CIBER EHD) and Institut de Recerca Sant Joan de Déu (IR SJD), Av. Diagonal 643, E-08028 Barcelona, Spain
Website | E-Mail
Interests: drug transporters; nucleoside analogs; anticancer therapy; antiviral therapy; mechanisms of drug action; nucleotide metabolism; oncogenesis
Guest Editor
Prof. Dr. Matthias Schwab

Dr. Margarete Fischer-Bosch Institute of Clinical Pharmacology, Stuttgart and Department of Clinical Pharmacology, Institute of Experimental and Clinical Pharmacology and Toxicology and Interfaculty Center for Pharmacogenomics and Drug Research (ICEPHA), University Hospital, Tuebingen Auerbachstrasse 112, 70376 Stuttgart, Germany
E-Mail
Phone: +49 711 8101 3700
Fax: +49-711-8592 95
Interests: pharmacogenomics/epigenetics of drug metabolizing enzymes; drug transporters and nuclear receptors; pharmacogenomics of anticancer and immunosuppressive drugs; drug interaction

Special Issue Information

Dear Colleagues,

The International Transporter Consortium (ITC) has indicated the need to implement easy and reproducible preclinical assays suitable for the analysis of drug-transporter interactions and drug–drug interactions likely to compromise drug pharmacokinetics and pharmacodynamics. These cross-interactions have been shown, in some cases, to have a clinical impact and may be also modulated by genetic polymorphisms in the transporter-encoding genes. The two major transporter-encoding gene superfamilies in humans, SLC and ABC, include paradigms of genetic heterogeneity, although their impact on drug action and their suitability as biomarkers of individual drug-response heterogeneity have not been properly addressed thus far. The Journal of Personalized Medicine is now opening a Special Issue that is fully devoted to drug transporter functional heterogeneity, with a call for papers involving basic, translational, and clinical research on this topic.

Prof. Marçal Pastor-Anglada and Prof. Matthias Schwab
Guest Editors

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 papers will be 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. Journal of Personalized Medicine is an international peer-reviewed open access quarterly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 550 CHF (Swiss Francs). 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

  • Drug
  • Transporters
  • Pharmacogenetics
  • Therapy
  • Cancer
  • AIDS
  • Immunosuppression
  • Diabetes
  • Neurological Diseases

Published Papers (4 papers)

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Research

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Open AccessArticle Impact of Promoter Polymorphisms on the Transcriptional Regulation of the Organic Cation Transporter OCT1 (SLC22A1)
J. Pers. Med. 2018, 8(4), 42; https://doi.org/10.3390/jpm8040042
Received: 14 September 2018 / Revised: 20 November 2018 / Accepted: 5 December 2018 / Published: 11 December 2018
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Abstract
The organic cation transporter 1 (OCT1, SLC22A1) is strongly expressed in the human liver and facilitates the hepatic uptake of drugs such as morphine, metformin, tropisetron, sumatriptan and fenoterol and of endogenous substances such as thiamine. OCT1 expression is inter-individually highly variable. Here, [...] Read more.
The organic cation transporter 1 (OCT1, SLC22A1) is strongly expressed in the human liver and facilitates the hepatic uptake of drugs such as morphine, metformin, tropisetron, sumatriptan and fenoterol and of endogenous substances such as thiamine. OCT1 expression is inter-individually highly variable. Here, we analyzed SNPs in the OCT1 promoter concerning their potential contribution to the variability in OCT1 expression. Using electrophoretic mobility shift and luciferase reporter gene assays in HepG2, Hep3B, and Huh7 cell lines, we identified the SNPs −1795G>A (rs6935207) and −201C>G (rs58812592) as having effects on transcription factor binding and/or promoter activity. The A-allele of the −1795G>A SNP showed allele-specific binding of the transcription factor NF-Y leading to 2.5-fold increased enhancer activity of the artificial SV40 promoter. However, the −1795G>A SNP showed no significant effects on the native OCT1 promoter activity. Furthermore, the −1795G>A SNP was not associated with the pharmacokinetics of metformin, fenoterol, sumatriptan and proguanil in healthy individuals or tropisetron efficacy in patients undergoing chemotherapy. Allele-dependent differences in USF1/2 binding and nearly total loss in OCT1 promoter activity were detected for the G-allele of −201C>G, but the SNP is apparently very rare. In conclusion, common OCT1 promoter SNPs have only minor effects on OCT1 expression. Full article
(This article belongs to the Special Issue Personalized Medicine Based on Drug Transporter Genetic Heterogeneity)
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Open AccessArticle The Impact of Potassium Channel Gene Polymorphisms on Antiepileptic Drug Responsiveness in Arab Patients with Epilepsy
J. Pers. Med. 2018, 8(4), 37; https://doi.org/10.3390/jpm8040037
Received: 13 October 2018 / Revised: 27 October 2018 / Accepted: 8 November 2018 / Published: 14 November 2018
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Abstract
This study aims to investigate the effects of the three potassium channel genes KCNA1, KCNA2, and KCNV2 on increased susceptibility to epilepsy as well as on responsiveness to antiepileptic drugs (AEDs). The pharmacogenetic and case-control cohort (n = 595) consisted [...] Read more.
This study aims to investigate the effects of the three potassium channel genes KCNA1, KCNA2, and KCNV2 on increased susceptibility to epilepsy as well as on responsiveness to antiepileptic drugs (AEDs). The pharmacogenetic and case-control cohort (n = 595) consisted of 296 epileptic patients and 299 healthy individuals. Epileptic patients were recruited from the Pediatric Neurology clinic at the Queen Rania Al Abdullah Hospital (QRAH) in Amman, Jordan. A custom platform array search for genetic association in Jordanian-Arab epileptic patients was undertaken. The MassARRAY system (iPLEX GOLD) was used to genotype seven single nucleotide polymorphisms (SNPs) within three candidate genes (KCNA1, KCNA2, and KCNV2). Only one SNP in KCNA2, rs3887820, showed significant association with increased risk of susceptibility to generalized myoclonic seizure (p-value < 0.001). Notably, the rs112561866 polymorphism of the KCNA1 gene was non-polymorphic, but no significant association was found between the KCNA1 (rs2227910, rs112561866, and rs7974459) and KCNV2 (rs7029012, rs10967705, and rs10967728) polymorphisms and disease susceptibility or drug responsiveness among Jordanian patients. This study suggests that a significant association exists between the KCNA2 SNP rs3887820 and increased susceptibility to generalized myoclonic seizure. However, the present findings indicate that the KCNA1 and KCNV2 SNPs do not influence disease susceptibility and drug responsiveness in epileptic patients. Pharmacogenetic and case-control studies involving a multicenter and multiethnic approach are needed to confirm our results. To improve the efficacy and safety of epilepsy treatment, further studies are required to identify other genetic factors that contribute to susceptibility and treatment outcome. Full article
(This article belongs to the Special Issue Personalized Medicine Based on Drug Transporter Genetic Heterogeneity)
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Review

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Open AccessReview ATP-Binding Cassette Transporters in the Clinical Implementation of Pharmacogenetics
J. Pers. Med. 2018, 8(4), 40; https://doi.org/10.3390/jpm8040040
Received: 31 August 2018 / Revised: 3 December 2018 / Accepted: 3 December 2018 / Published: 5 December 2018
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Abstract
ATP-binding cassette (ABC) transporters are involved in a large number of processes and contribute to various human genetic diseases. Among other functions, ABC proteins are involved in the transport of multiple drugs through cells. Most of the genes coding for these transporters are [...] Read more.
ATP-binding cassette (ABC) transporters are involved in a large number of processes and contribute to various human genetic diseases. Among other functions, ABC proteins are involved in the transport of multiple drugs through cells. Most of the genes coding for these transporters are highly polymorphic and DNA variants in these genes can affect the normal functioning of these proteins, affecting the way drugs are transported, increasing or decreasing drug levels. These changes in the intracellular and extracellular drug levels may be associated with altered drug effectiveness or severe drug-induced adverse events. This review presents a state-of-art of the most pharmacogenetics clinically relevant ABC transporters closed to the clinical implementation. Full article
(This article belongs to the Special Issue Personalized Medicine Based on Drug Transporter Genetic Heterogeneity)
Open AccessFeature PaperReview Genetic Heterogeneity of SLC22 Family of Transporters in Drug Disposition
J. Pers. Med. 2018, 8(2), 14; https://doi.org/10.3390/jpm8020014
Received: 28 February 2018 / Revised: 4 April 2018 / Accepted: 10 April 2018 / Published: 16 April 2018
Cited by 2 | PDF Full-text (2759 KB) | HTML Full-text | XML Full-text
Abstract
An important aspect of modern medicine is its orientation to achieve more personalized pharmacological treatments. In this context, transporters involved in drug disposition have gained well-justified attention. Owing to its broad spectrum of substrate specificity, including endogenous compounds and xenobiotics, and its strategical [...] Read more.
An important aspect of modern medicine is its orientation to achieve more personalized pharmacological treatments. In this context, transporters involved in drug disposition have gained well-justified attention. Owing to its broad spectrum of substrate specificity, including endogenous compounds and xenobiotics, and its strategical expression in organs accounting for drug disposition, such as intestine, liver and kidney, the SLC22 family of transporters plays an important role in physiology, pharmacology and toxicology. Among these carriers are plasma membrane transporters for organic cations (OCTs) and anions (OATs) with a marked overlap in substrate specificity. These two major clades of SLC22 proteins share a similar membrane topology but differ in their degree of genetic variability. Members of the OCT subfamily are highly polymorphic, whereas OATs have a lower number of genetic variants. Regarding drug disposition, changes in the activity of these variants affect intestinal absorption and target tissue uptake, but more frequently they modify plasma levels due to enhanced or reduced clearance by the liver and secretion by the kidney. The consequences of these changes in transport-associated function markedly affect the effectiveness and toxicity of the treatment in patients carrying the mutation. In solid tumors, changes in the expression of these transporters and the existence of genetic variants substantially determine the response to anticancer drugs. Moreover, chemoresistance usually evolves in response to pharmacological and radiological treatment. Future personalized medicine will require monitoring these changes in a dynamic way to adapt the treatment to the weaknesses shown by each tumor at each stage in each patient. Full article
(This article belongs to the Special Issue Personalized Medicine Based on Drug Transporter Genetic Heterogeneity)
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