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Pharmaceutics
Special Issues
ABC Transporter-Mediated Drug Disposition
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ABC Transporter-Mediated Drug Disposition

A special issue of Pharmaceutics (ISSN 1999-4923).

Deadline for manuscript submissions: closed (14 September 2018) | Viewed by 27954

Special Issue Editor

Dr. Qingcheng Mao

E-Mail Website
Guest Editor
Department of Pharmaceutics, School of Pharmacy, University of Washington, Seattle, Washington, USA
Interests: drug metabolism; distribution and transport; membrane transporters; pharmacokinetics/pharmacodynamics; pregnancy and fetal pharmacology

Special Issue Information

Dear Colleagues,

ATP-binding cassette (ABC) transporters are primarily efflux transporters that mediate active transport of drugs, xenobiotics and endogenous substances out of cells. P-glycoprotein (P-gp) is the first mammalian ABC transporter discovered about 40 years ago. Since then, ~50 ABC transporters have been found in humans alone. Studies have shown that ABC transporters play very important roles in the absorption, distribution and elimination of drugs and xenobiotics. Many ABC transporters including P-gp, BCRP and MRP2 are involved in clinically relevant drug disposition and drug-drug interactions (DDIs); investigating these transporters have become an integral part of drug discovery and development.

This Special Issue will cover a broad range of topics, including, but not limited to, roles of ABC transporters in absorption, distribution and elimination of drugs/xenobiotics, DDIs and xenobiotic toxicity,  in vitro transport characterization, ABC transporter-enzyme interplay, and new methods, such as physiologically based pharmacokinetics (PBPK) modeling and simulation to investigate ABC transporters in drug disposition.                        

Dr. Qingcheng Mao
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. Pharmaceutics 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 2900 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

  • ATP-binding cassette (ABC) transporter
  • P-glycoprotein/P-gp
  • P-gp/ABCB1
  • BCRP/ABCG2
  • MRP2/ABCC2
  • Drug Disposition
  • Absorption
  • Distribution
  • Elimination
  • Toxicity
  • Drug-drug interaction
  • Transporter-enzyme interplay
  • Pharmacokinetics

Published Papers (6 papers)

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Research

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19 pages, 3905 KiB  
Article
Development of Novel Intramolecular FRET-Based ABC Transporter Biosensors to Identify New Substrates and Modulators
by Bremansu Osa-Andrews, Kee W. Tan, Angelina Sampson and Surtaj H. Iram
Pharmaceutics 2018, 10(4), 186; https://doi.org/10.3390/pharmaceutics10040186 - 13 Oct 2018
Cited by 6 | Viewed by 4045
Abstract
Multidrug resistance protein 1 (MRP1) can efflux a wide variety of molecules including toxic chemicals, drugs, and their derivatives out of cells. Substrates of MRP1 include anti-cancer agents, antibiotics, anti-virals, anti-human immunodeficiency virus (HIV), and many other drugs. To identify novel substrates and [...] Read more.
Multidrug resistance protein 1 (MRP1) can efflux a wide variety of molecules including toxic chemicals, drugs, and their derivatives out of cells. Substrates of MRP1 include anti-cancer agents, antibiotics, anti-virals, anti-human immunodeficiency virus (HIV), and many other drugs. To identify novel substrates and modulators of MRP1 by exploiting intramolecular fluorescence resonance energy transfer (FRET), we genetically engineered six different two-color MRP1 proteins by changing green fluorescent protein (GFP) insertion sites, while keeping the red fluorescent protein (RFP) at the C-terminal of MRP1. Four of six recombinant proteins showed normal expression, localization, and transport activity. We quantified intramolecular FRET using ensemble fluorescence spectroscopy in response to binding of known substrate or ATP alone, substrate/ATP, and trapping of the transporter in closed conformation by vanadate. Recombinant MRP1 proteins GR-881, GR-888, and GR-905 exhibited reproducible and higher FRET changes under all tested conditions and are very promising for use as MRP1 biosensors. Furthermore, we used GR-881 to screen 40 novel anti-cancer drugs and identified 10 hits that potentially directly interact with MRP1 and could be substrates or modulators. Profiling of drug libraries for interaction with MRP1 can provide very useful information to improve the efficacy and reduce the toxicity of various therapies. Full article
(This article belongs to the Special Issue ABC Transporter-Mediated Drug Disposition)
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15 pages, 1908 KiB  
Article
In Vitro Stimulation of Multidrug Resistance-Associated Protein 2 Function Is Not Reproduced In Vivo in Rats
by Ravindranath Reddy Gilibili, Vishwanath Kurawattimath, Bokka Venkata Murali, Yurong Lai, T. Thanga Mariappan, Hong Shen and Sagnik Chatterjee
Pharmaceutics 2018, 10(3), 125; https://doi.org/10.3390/pharmaceutics10030125 - 08 Aug 2018
Cited by 5 | Viewed by 3193
Abstract
Previously we reported that coproporphyrin-I (CP-I) is an optimal probe substrate for multidrug resistance-associated protein 2 (MRP2), and stimulation of MRP2-mediated transport is probe substrate-dependent. In the present investigation, we assessed if the in vitro stimulation is physiologically relevant. Similar to human MRP2 [...] Read more.
Previously we reported that coproporphyrin-I (CP-I) is an optimal probe substrate for multidrug resistance-associated protein 2 (MRP2), and stimulation of MRP2-mediated transport is probe substrate-dependent. In the present investigation, we assessed if the in vitro stimulation is physiologically relevant. Similar to human MRP2 transport, CP-I was transported by rat Mrp2 in a typical Michaelis-Menten kinetics with apparent Km and Vmax values of 15 ± 6 µM and 161 ± 20 pmol/min/mg protein, respectively. In vivo Mrp2 functions were monitored by biliary and renal secretion of CP-I and its isomer CP-III, in bile-duct cannulated rats before and after treatment with mitoxantrone, progesterone, and verapamil. These compounds stimulated Mrp2-mediated CP-I transport in vitro. No significant increase in biliary or renal clearances, as well as in the cumulative amount of CP-I or CP-III eliminated in bile, were detected following treatment with the in vitro stimulators, indicating an in vitro to in vivo disconnect. In presence of 10 µM bilirubin, the in vitro stimulation was suppressed. We concluded that the in vitro stimulation of CP-I transport mediated by Mrp2 is not translatable in vivo, and proposed that the presence of endogenous compounds such as bilirubin in the liver may contribute to the in vitro to in vivo disconnect. Full article
(This article belongs to the Special Issue ABC Transporter-Mediated Drug Disposition)
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13 pages, 750 KiB  
Article
New ABCC2 rs3740066 and rs2273697 Polymorphisms Identified in a Healthy Colombian Cohort
by Rosa Helena Bustos-Cruz, Luis Rafael Martínez, Julio César García, George E. Barreto and Fernando Suárez
Pharmaceutics 2018, 10(3), 93; https://doi.org/10.3390/pharmaceutics10030093 - 17 Jul 2018
Cited by 4 | Viewed by 3492
Abstract
Multidrug resistance-associated proteins (MRP) 1 and 2 belong to the ABC (ATP-Binding Cassette) transporters. These transport proteins are involved in the removal of various drugs and xenobiotics, as well as in multiple physiological, pathological, and pharmacological processes. There is a strong correlation between [...] Read more.
Multidrug resistance-associated proteins (MRP) 1 and 2 belong to the ABC (ATP-Binding Cassette) transporters. These transport proteins are involved in the removal of various drugs and xenobiotics, as well as in multiple physiological, pathological, and pharmacological processes. There is a strong correlation between different polymorphisms and their clinical implication in resistance to antiepileptic drugs, anticancer, and anti-infective agents. In our study, we evaluated exon regions of MRP1 (ABCC1)/MRP2 (ABCC2) in a Colombian cohort of healthy subjects to determine single nucleotide polymorphisms (SNPs) and to determine the allelic and genomic frequency. Results showed there are SNPs in our population that have been previously reported for both MRP1/ABCC1 (rs200647436, rs200624910, rs150214567) and MRP2/ABCC2 (rs2273697, rs3740066, rs142573385, rs17216212). Additionally, 13 new SNPs were identified. Evidence also shows a significant clinical correlation for polymorphisms rs3740066 and rs2273697 in the transport of multiple drugs, which suggests a genetic variability in regards to that reported in other populations. Full article
(This article belongs to the Special Issue ABC Transporter-Mediated Drug Disposition)
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Review

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20 pages, 1087 KiB  
Review
Modulation of Opioid Transport at the Blood-Brain Barrier by Altered ATP-Binding Cassette (ABC) Transporter Expression and Activity
by Junzhi Yang, Bianca G. Reilly, Thomas P. Davis and Patrick T. Ronaldson
Pharmaceutics 2018, 10(4), 192; https://doi.org/10.3390/pharmaceutics10040192 - 18 Oct 2018
Cited by 19 | Viewed by 6563
Abstract
Opioids are highly effective analgesics that have a serious potential for adverse drug reactions and for development of addiction and tolerance. Since the use of opioids has escalated in recent years, it is increasingly important to understand biological mechanisms that can increase the [...] Read more.
Opioids are highly effective analgesics that have a serious potential for adverse drug reactions and for development of addiction and tolerance. Since the use of opioids has escalated in recent years, it is increasingly important to understand biological mechanisms that can increase the probability of opioid-associated adverse events occurring in patient populations. This is emphasized by the current opioid epidemic in the United States where opioid analgesics are frequently abused and misused. It has been established that the effectiveness of opioids is maximized when these drugs readily access opioid receptors in the central nervous system (CNS). Indeed, opioid delivery to the brain is significantly influenced by the blood-brain barrier (BBB). In particular, ATP-binding cassette (ABC) transporters that are endogenously expressed at the BBB are critical determinants of CNS opioid penetration. In this review, we will discuss current knowledge on the transport of opioid analgesic drugs by ABC transporters at the BBB. We will also examine how expression and trafficking of ABC transporters can be modified by pain and/or opioid pharmacotherapy, a novel mechanism that can promote opioid-associated adverse drug events and development of addiction and tolerance. Full article
(This article belongs to the Special Issue ABC Transporter-Mediated Drug Disposition)
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20 pages, 1420 KiB  
Review
The Effects of Synthetically Modified Natural Compounds on ABC Transporters
by Daniel Dantzic, Pawan Noel, Fabrice Merien, Dong-Xu Liu, Jun Lu, Haiyong Han, Mark J. McKeage and Yan Li
Pharmaceutics 2018, 10(3), 127; https://doi.org/10.3390/pharmaceutics10030127 - 09 Aug 2018
Cited by 18 | Viewed by 5087
Abstract
Multidrug resistance (MDR) is a major hurdle which must be overcome to effectively treat cancer. ATP-binding cassette transporters (ABC transporters) play pivotal roles in drug absorption and disposition, and overexpression of ABC transporters has been shown to attenuate cellular/tissue drug accumulation and thus [...] Read more.
Multidrug resistance (MDR) is a major hurdle which must be overcome to effectively treat cancer. ATP-binding cassette transporters (ABC transporters) play pivotal roles in drug absorption and disposition, and overexpression of ABC transporters has been shown to attenuate cellular/tissue drug accumulation and thus increase MDR across a variety of cancers. Overcoming MDR is one desired approach to improving the survival rate of patients. To date, a number of modulators have been identified which block the function and/or decrease the expression of ABC transporters, thereby restoring the efficacy of a range of anticancer drugs. However, clinical MDR reversal agents have thus far proven ineffective and/or toxic. The need for new, effective, well-tolerated and nontoxic compounds has led to the development of natural compounds and their derivatives to ameliorate MDR. This review evaluates whether synthetically modifying natural compounds is a viable strategy to generate potent, nontoxic, ABC transporter inhibitors which may potentially reverse MDR. Full article
(This article belongs to the Special Issue ABC Transporter-Mediated Drug Disposition)
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14 pages, 1227 KiB  
Review
Alterations in Expression and Function of ABC Family Transporters at Blood-Brain Barrier under Liver Failure and Their Clinical Significances
by Yilin Fan and Xiaodong Liu
Pharmaceutics 2018, 10(3), 102; https://doi.org/10.3390/pharmaceutics10030102 - 23 Jul 2018
Cited by 13 | Viewed by 4619
Abstract
Liver failure is often associated with hepatic encephalopathy, due to dyshomeostasis of the central nervous system (CNS). Under physiological conditions, the CNS homeostasis is precisely regulated by the blood-brain barrier (BBB). The BBB consists of brain microvessel endothelial cells connected with a junctional [...] Read more.
Liver failure is often associated with hepatic encephalopathy, due to dyshomeostasis of the central nervous system (CNS). Under physiological conditions, the CNS homeostasis is precisely regulated by the blood-brain barrier (BBB). The BBB consists of brain microvessel endothelial cells connected with a junctional complex by the adherens junctions and tight junctions. Its main function is to maintain brain homoeostasis via limiting the entry of drugs/toxins to brain. The brain microvessel endothelial cells are characterized by minimal pinocytotic activity, absent fenestrations, and highly expressions of ATP-binding cassette (ABC) family transporters (such as P-glycoprotein, breast cancer resistance protein and multidrug resistance-associated proteins). These ABC transporters prevent brain from toxin accumulation by pumping toxins out of brain. Accumulating evidences demonstrates that liver failure diseases altered the expression and function of ABC transporters at The BBB, indicating that the alterations subsequently affect drugs’ brain distribution and CNS activity/neurotoxicity. ABC transporters also mediate the transport of endogenous substrates across the BBB, inferring that ABC transporters are also implicated in some physiological processes and the development of hepatic encephalopathy. This paper focuses on the alteration in the BBB permeability, the expression and function of ABC transporters at the BBB under liver failure status and their clinical significances. Full article
(This article belongs to the Special Issue ABC Transporter-Mediated Drug Disposition)
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