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Personalized Medicine Based on Drug Transporter Genetic Heterogeneity

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

Deadline for manuscript submissions: closed (15 February 2019) | Viewed by 35716

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Special Issue Editors

Prof. Dr. Marçal Pastor-Anglada

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Guest Editor

1. Department of Biochemistry and Molecular Biomedicine, Institute of Biomedicine (IBUB), University of Barcelona, Barcelona, Spain
2. Pediatric Oncology Program, Institut de Recerca Sant Joan de Déu (IR SJD), Esplugues de Llobregat, Barcelona, Spain
3. Oncology Program, National Biomedical Research Institute of Liver and Gastrointestinal Diseases (CIBER EHD), Instituto de Salud Carlos III, Madrid, Spain
Interests: drug transporters; nucleoside analogs; anticancer therapy; antiviral therapy; mechanisms of drug action; nucleotide metabolism; oncogenesis
Special Issues, Collections and Topics in MDPI journals

Prof. Dr. Matthias Schwab

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Guest Editor

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
Interests: pharmacogenomics/epigenetics of drug metabolizing enzymes; drug transporters and nuclear receptors; pharmacogenomics of anticancer and immunosuppressive drugs; drug interaction
Special Issues, Collections and Topics in MDPI journals

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. Dr. Marçal Pastor-Anglada

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 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. Journal of Personalized Medicine is an international peer-reviewed open access monthly 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 2600 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 (5 papers)

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Research

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11 pages, 247 KiB

Open AccessArticle

Metformin Pharmacogenetics: Effects of SLC22A1, SLC22A2, and SLC22A3 Polymorphisms on Glycemic Control and HbA1c Levels

by Laith N. AL-Eitan, Basima A. Almomani, Ahmad M. Nassar, Barakat Z. Elsaqa and Nesreen A. Saadeh

J. Pers. Med. 2019, 9(1), 17; https://doi.org/10.3390/jpm9010017 - 25 Mar 2019

Cited by 29 | Viewed by 7331

Abstract

Type 2 diabetes mellitus (T2DM) constitutes a major portion of Jordan’s disease burden, and incidence rates are rising at a rapid rate. Due to variability in the drug’s response between ethnic groups, it is imperative that the pharmacogenetics of metformin be investigated in the Jordanian population. The objective of this study was to investigate the relationship between twenty-one single nucleotide polymorphisms (SNPs) in the SLC22A1, SLC22A2, and SLC22A3 genes and their effects on metformin pharmacogenetics in Jordanian patients diagnosed with type 2 diabetes mellitus. Blood samples were collected from 212 Jordanian diabetics who fulfilled the inclusion criteria, which were then used in SNP genotyping and determination of HbA1c levels. The rs12194182 SNP in the SLC22A3 gene was found to have a significant association (p < 0.05) with lower mean HbA1c levels, and this association more pronounced in patients with the CC genotype (i.e., p-value was significant before correcting for multiple testing). Moreover, the multinomial logistic regression analysis showed that SNP genotypes within the SLC22A1, SLC22A2, and SLC22A3 genes, body mass index (BMI) and age of diagnosis were significantly associated with glycemic control (p < 0.05). The results of this study can be used to predict response to metformin and other classes of T2DM drugs, making treatment more individualized and resulting in better clinical outcomes. Full article

(This article belongs to the Special Issue Personalized Medicine Based on Drug Transporter Genetic Heterogeneity)

16 pages, 3051 KiB

Open AccessArticle

Impact of Promoter Polymorphisms on the Transcriptional Regulation of the Organic Cation Transporter OCT1 (SLC22A1)

by Kristin Bokelmann, Jürgen Brockmöller and Mladen V. Tzvetkov

J. Pers. Med. 2018, 8(4), 42; https://doi.org/10.3390/jpm8040042 - 11 Dec 2018

Cited by 5 | Viewed by 6727

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, 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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11 pages, 638 KiB

Open AccessArticle

The Impact of Potassium Channel Gene Polymorphisms on Antiepileptic Drug Responsiveness in Arab Patients with Epilepsy

by Laith N. AL-Eitan, Islam M. Al-Dalalah, Afrah K. Elshammari, Wael H. Khreisat and Ayah Y. Almasri

J. Pers. Med. 2018, 8(4), 37; https://doi.org/10.3390/jpm8040037 - 14 Nov 2018

Cited by 11 | Viewed by 6133

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 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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12 pages, 298 KiB

Open AccessReview

ATP-Binding Cassette Transporters in the Clinical Implementation of Pharmacogenetics

by Luis A. López-Fernández

J. Pers. Med. 2018, 8(4), 40; https://doi.org/10.3390/jpm8040040 - 05 Dec 2018

Cited by 8 | Viewed by 5844

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 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)

27 pages, 2759 KiB

Open AccessFeature PaperReview

Genetic Heterogeneity of SLC22 Family of Transporters in Drug Disposition

by Elisa Lozano, Oscar Briz, Rocio I. R. Macias, Maria A. Serrano, Jose J. G. Marin and Elisa Herraez

J. Pers. Med. 2018, 8(2), 14; https://doi.org/10.3390/jpm8020014 - 16 Apr 2018

Cited by 28 | Viewed by 8908

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 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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