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Pharmaceutics
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Membrane Transporters in Biomedicine and Drug Development
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Membrane Transporters in Biomedicine and Drug Development

A special issue of Pharmaceutics (ISSN 1999-4923). This special issue belongs to the section "Pharmacokinetics and Pharmacodynamics".

Deadline for manuscript submissions: closed (31 December 2022) | Viewed by 12191

Special Issue Editor

Prof. Dr. Balázs Sarkadi

E-Mail Website
Guest Editor
Membrane Transporter Laboratory, Research Centre for Natural Sciences, 1117 Budapest, Hungary
Interests: membrane transporters; ABC transporters; multidrug resistance; stem cell membrane transporters; drug development
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

This Special Issue of Pharmaceutics aims to cover the field of cellular membrane transporters in biomedical research, especially focusing on targeted and accidental drug effects, as well as the role of membrane transporters in the development of new pharmaceutical agents. While earlier concepts of drug permeation through tissue barriers emphasized the role of lipid solubility, by now it has become generally accepted that the transmembrane movement of most of the xenobiotics and pharmaceutical agents depends on the function of membrane transporters. Thus, in addition to drug-metabolizing enzymes, the in vivo ADME-tox parameters are crucially affected by the transporter-dependent entry or efflux of the clinically applied compounds. By a specific or non-specific modulation of these transporters may elicit, in some cases unexpected major effects on tissue-dependent efficacy and toxicity. New in vitro and in vivo techniques have been developed to study these phenomena, and regulatory agencies strongly emphasize the need for preclinical studies of transporters potentially involved in drug interactions. This Special Issue should help to provide a collection of original research and review papers covering this biomedically important field, further helping the advancement of clinical applications.

Prof. Dr. Sarkadi Balázs
Guest Editor

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Keywords

  • membrane transporters
  • transporter-drug interactions
  • regulation of transporter function
  • regulation of transporter expression
  • transporters in drug development

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Published Papers (3 papers)

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Research

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32 pages, 6066 KiB  
Article
Interaction of a Homologous Series of Amphiphiles with P-glycoprotein in a Membrane Environment—Contributions of Polar and Non-Polar Interactions
by Maria João Moreno, Hugo A. L. Filipe, Susana V. P. Cunha, Cristiana V. Ramos, Patrícia A. T. Martins, Biebele Abel, Luís M. S. Loura and Suresh V. Ambudkar
Pharmaceutics 2023, 15(1), 174; https://doi.org/10.3390/pharmaceutics15010174 - 3 Jan 2023
Cited by 5 | Viewed by 2744
Abstract
The transport of drugs by efflux transporters in biomembranes limits their bioavailability and is a major determinant of drug resistance development by cancer cells and pathogens. A large number of chemically dissimilar drugs are transported, and despite extensive studies, the molecular determinants of [...] Read more.
The transport of drugs by efflux transporters in biomembranes limits their bioavailability and is a major determinant of drug resistance development by cancer cells and pathogens. A large number of chemically dissimilar drugs are transported, and despite extensive studies, the molecular determinants of substrate specificity are still not well understood. In this work, we explore the role of polar and non-polar interactions on the interaction of a homologous series of fluorescent amphiphiles with the efflux transporter P-glycoprotein. The interaction of the amphiphiles with P-glycoprotein is evaluated through effects on ATPase activity, efficiency in inhibition of [125I]-IAAP binding, and partition to the whole native membranes containing the transporter. The results were complemented with partition to model membranes with a representative lipid composition, and details on the interactions established were obtained from MD simulations. We show that when the total concentration of amphiphile is considered, the binding parameters obtained are apparent and do not reflect the affinity for P–gp. A new formalism is proposed that includes sequestration of the amphiphiles in the lipid bilayer and the possible binding of several molecules in P–gp’s substrate-binding pocket. The intrinsic binding affinity thus obtained is essentially independent of amphiphile hydrophobicity, highlighting the importance of polar interactions. An increase in the lipophilicity and amphiphilicity led to a more efficient association with the lipid bilayer, which maintains the non-polar groups of the amphiphiles in the bilayer, while the polar groups interact with P–gp’s binding pocket. The presence of several amphiphiles in this orientation is proposed as a mechanism for inhibition of P-pg function. Full article
(This article belongs to the Special Issue Membrane Transporters in Biomedicine and Drug Development)
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14 pages, 1868 KiB  
Article
Comparison of the Blood–Brain Barrier Transport and Vulnerability to P-Glycoprotein-Mediated Drug–Drug Interaction of Domperidone versus Metoclopramide Assessed Using In Vitro Assay and PET Imaging
by Louise Breuil, Sébastien Goutal, Solène Marie, Antonio Del Vecchio, Davide Audisio, Amélie Soyer, Maud Goislard, Wadad Saba, Nicolas Tournier and Fabien Caillé
Pharmaceutics 2022, 14(8), 1658; https://doi.org/10.3390/pharmaceutics14081658 - 9 Aug 2022
Cited by 11 | Viewed by 4790
Abstract
Domperidone and metoclopramide are widely prescribed antiemetic drugs with distinct neurological side effects. The impact of P-glycoprotein (P-gp)-mediated efflux at the blood–brain barrier (BBB) on brain exposure and BBB permeation was compared in vitro and in vivo using positron emission tomography (PET) imaging [...] Read more.
Domperidone and metoclopramide are widely prescribed antiemetic drugs with distinct neurological side effects. The impact of P-glycoprotein (P-gp)-mediated efflux at the blood–brain barrier (BBB) on brain exposure and BBB permeation was compared in vitro and in vivo using positron emission tomography (PET) imaging in rats with the radiolabeled analogs [11C]domperidone and [11C]metoclopramide. In P-gp-overexpressing cells, the IC50 of tariquidar, a potent P-gp inhibitor, was drastically different using [11C]domperidone (221 nM [198–248 nM]) or [11C]metoclopramide (4 nM [2–8 nM]) as the substrate. Complete P-gp inhibition led to a 1.8-fold higher increase in the cellular uptake of [11C]domperidone compared with [11C]metoclopramide (p < 0.0001). Brain PET imaging revealed that the baseline brain exposure (AUCbrain) of [11C]metoclopramide was 2.4-fold higher compared with [11C]domperidone (p < 0.001), consistent with a 1.8-fold higher BBB penetration (AUCbrain/AUCplasma). The maximal increase in the brain exposure (2.9-fold, p < 0.0001) and BBB penetration (2.9-fold, p < 0.0001) of [11C]metoclopramide was achieved using 8 mg/kg of tariquidar. In comparison, neither 8 nor 15 mg/kg of tariquidar increased the brain exposure of [11C]domperidone (p > 0.05). Domperidone is an avid P-gp substrate that was in vitro compared with metoclopramide. Domperidone benefits from a lower brain exposure and a limited risk for P-gp-mediated drug–drug interaction involving P-gp inhibition at the BBB. Full article
(This article belongs to the Special Issue Membrane Transporters in Biomedicine and Drug Development)
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Review

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16 pages, 374 KiB  
Review
Role of Hepatocyte Transporters in Drug-Induced Liver Injury (DILI)—In Vitro Testing
by Péter Tátrai, Franciska Erdő and Péter Krajcsi
Pharmaceutics 2023, 15(1), 29; https://doi.org/10.3390/pharmaceutics15010029 - 22 Dec 2022
Cited by 19 | Viewed by 3793
Abstract
Bile acids and bile salts (BA/BS) are substrates of both influx and efflux transporters on hepatocytes. Canalicular efflux transporters, such as BSEP and MRP2, are crucial for the removal of BA/BS to the bile. Basolateral influx transporters, such as NTCP, OATP1B1/1B3, and OSTα/β, [...] Read more.
Bile acids and bile salts (BA/BS) are substrates of both influx and efflux transporters on hepatocytes. Canalicular efflux transporters, such as BSEP and MRP2, are crucial for the removal of BA/BS to the bile. Basolateral influx transporters, such as NTCP, OATP1B1/1B3, and OSTα/β, cooperate with canalicular transporters in the transcellular vectorial flux of BA/BS from the sinusoids to the bile. The blockage of canalicular transporters not only impairs the bile flow but also causes the intracellular accumulation of BA/BS in hepatocytes that contributes to, or even triggers, liver injury. In the case of BA/BS overload, the efflux of these toxic substances back to the blood via MRP3, MRP4, and OST α/β is considered a relief function. FXR, a key regulator of defense against BA/BS toxicity suppresses de novo bile acid synthesis and bile acid uptake, and promotes bile acid removal via increased efflux. In drug development, the early testing of the inhibition of these transporters, BSEP in particular, is important to flag compounds that could potentially inflict drug-induced liver injury (DILI). In vitro test systems for efflux transporters employ membrane vesicles, whereas those for influx transporters employ whole cells. Additional in vitro pharmaceutical testing panels usually include cellular toxicity tests using hepatocytes, as well as assessments of the mitochondrial toxicity and accumulation of reactive oxygen species (ROS). Primary hepatocytes are the cells of choice for toxicity testing, with HepaRG cells emerging as an alternative. Inhibition of the FXR function is also included in some testing panels. The molecular weight and hydrophobicity of the drug, as well as the steady-state total plasma levels, may positively correlate with the DILI potential. Depending on the phase of drug development, the physicochemical properties, dosing, and cut-off values of BSEP IC50 ≤ 25–50 µM or total Css,plasma/BSEP IC50 ≥ 0.1 may be an indication for further testing to minimize the risk of DILI liability. Full article
(This article belongs to the Special Issue Membrane Transporters in Biomedicine and Drug Development)
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