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Advance in Drug-Drug Interactions
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Advance in Drug-Drug Interactions

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 (31 December 2020) | Viewed by 23250

Special Issue Editors

Dr. Hassan Salhab

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Guest Editor
Department of Chemical and Pharmaceutical Sciences, School of Life Sciences, Pharmacy and Chemistry, Kingston University, Kingston upon Thames, London KT1 2EE, UK
Interests: high performance Liquid chromatography (HPLC); liquid chromatography mass spectrometry (LC-MS); drug-drug interactions; metabolites; Inhibition; Cytochrome CYP450; UGT enzymes
Special Issues, Collections and Topics in MDPI journals
Prof. Dr. James Barker

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Guest Editor
Department of Chemical and Pharmaceutical Sciences, School of Life Sciences, Pharmacy and Chemistry, Kingston University, Kingston upon Thames, London KT1 2EE, UK
Interests: pharmaceutical and forensic analysis; environmental analytical chemistry; drugs of abuse; drug/drug interactions; method development for enviro/bioanalysis; separation methods (GC, HPLC, LC–MS/MS); mass spectrometry and isotope ratio mass spectrometry; development and application of innovative sorbents for extraction of pollutants from water; fate and behaviour of organic contaminants, drugs, toxic metals, pesticides and emerging pollutants in the environment and during wastewater treatment; analysis of bioactive species from herbal matrices, application of nuclear instrumental methods for analysis
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Drug interactions occur when one drug interacts with another. The outcomes of these interactions can lead to adverse side effects and result in the altered activity of one or both drugs. Drug–drug interactions can occur at either pharmacokinetic or pharmacodynamic levels. Polytherapy is one of the major causes of drug–drug interactions in developing countries. Understanding the properties of adverse drug reactions (ADRs) gives a clear indication for the quantification of the side effects of a prospective drug and a good knowledge of the pathogenic pathways involved during the interaction.

At present, adverse drug reactions seem to be the main obstacle in clinical trials, slowing down the recovery of patients in hospitals.

This Special Issue on “Advances in Drug-Drug interactions” aims to provide a summary of the novel drugs inhibition or induction with other marketed drugs with an emphasis on their pharmacokinetic parameters. This Special Issue will publish original research articles as well as reviews, including aspects of current understanding the inhibition and induction process of the novel drugs and their effectiveness in clinical trials.

Dr. Hassan Salhab
Dr. James Barker
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. 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

  • cytochrome CYP450 activity
  • UGT enzymes
  • inhibition/induction
  • metabolites
  • rat/human liver microsomes
  • human suprasomes

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Published Papers (5 papers)

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Research

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17 pages, 4343 KiB  
Article
Interaction of Cucurbit[7]uril with Oxime K027, Atropine, and Paraoxon: Risky or Advantageous Delivery System?
by Jana Zdarova Karasova, Martin Mzik, Tomas Kucera, Zbynek Vecera, Jiri Kassa and Vit Sestak
Int. J. Mol. Sci. 2020, 21(21), 7883; https://doi.org/10.3390/ijms21217883 - 23 Oct 2020
Cited by 10 | Viewed by 2036
Abstract
Antidotes against organophosphates often possess physicochemical properties that mitigate their passage across the blood–brain barrier. Cucurbit[7]urils may be successfully used as a drug delivery system for bisquaternary oximes and improve central nervous system targeting. The main aim of these studies was to elucidate [...] Read more.
Antidotes against organophosphates often possess physicochemical properties that mitigate their passage across the blood–brain barrier. Cucurbit[7]urils may be successfully used as a drug delivery system for bisquaternary oximes and improve central nervous system targeting. The main aim of these studies was to elucidate the relationship between cucurbit[7]uril, oxime K027, atropine, and paraoxon to define potential risks or advantages of this delivery system in a complex in vivo system. For this reason, in silico (molecular docking combined with umbrella sampling simulation) and in vivo (UHPLC—pharmacokinetics, toxicokinetics; acetylcholinesterase reactivation and functional observatory battery) methods were used. Based on our results, cucurbit[7]urils affect multiple factors in organophosphates poisoning and its therapy by (i) scavenging paraoxon and preventing free fraction of this toxin from entering the brain, (ii) enhancing the availability of atropine in the central nervous system and by (iii) increasing oxime passage into the brain. In conclusion, using cucurbit[7]urils with oximes might positively impact the overall treatment effectiveness and the benefits can outweigh the potential risks. Full article
(This article belongs to the Special Issue Advance in Drug-Drug Interactions)
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16 pages, 3830 KiB  
Article
Cytotoxic and Senolytic Effects of Methadone in Combination with Temozolomide in Glioblastoma Cells
by Bernd Kaina, Lea Beltzig, Andrea Piee-Staffa and Bodo Haas
Int. J. Mol. Sci. 2020, 21(19), 7006; https://doi.org/10.3390/ijms21197006 - 23 Sep 2020
Cited by 10 | Viewed by 3077
Abstract
Methadone is an analgesic drug used for pain treatment and heroin substitution. Recently, methadone has been proposed to be useful also for cancer therapy, including glioblastoma multiforme (GBM), the most severe form of brain cancer, because experiments on cultured glioma cells treated with [...] Read more.
Methadone is an analgesic drug used for pain treatment and heroin substitution. Recently, methadone has been proposed to be useful also for cancer therapy, including glioblastoma multiforme (GBM), the most severe form of brain cancer, because experiments on cultured glioma cells treated with doxorubicin showed promising results. Doxorubicin, however, is not used first-line in GBM therapy. Therefore, we analyzed the cytotoxic effect of methadone alone and in combination with temozolomide, a DNA-alkylating drug that is first-line used in GBM treatment, utilizing GBM-derived cell lines and a human fibroblast cell line. We show that methadone is cytotoxic on its own, inducing apoptosis and necrosis, which was observed at a concentration above 20 µg/mL. Methadone was similar toxic in isogenic MGMT expressing and non-expressing cells, and in LN229 glioblastoma and VH10T human fibroblasts. The apoptosis-inducing activity of methadone is not bound on the opioid receptor (OR), since naloxone, a competitive inhibitor of OR, did not attenuate methadone-induced apoptosis/necrosis. Administrating methadone and temozolomide together, temozolomide had no impact on methadone-induced apoptosis (which occurred 3 days after treatment), while temozolomide-induced apoptosis (which occurred 5 days after treatment) was unaffected at low (non-toxic) methadone concentration (5 µg/mL), and at high (toxic) methadone concentration (20 µg/mL) the cytotoxic effects of methadone and temozolomide were additive. Methadone is not genotoxic, as revealed by comet and γH2AX assay, and did not ameliorate the genotoxic effect of temozolomide. Further, methadone did not induce cellular senescence and had no effect on temozolomide-induced senescence. Although methadone was toxic on senescent cells, it cannot be considered a senolytic drug since cytotoxicity was not specific for senescent cells. Finally, we show that methadone had no impact on the MGMT promoter methylation. Overall, the data show that methadone on glioblastoma cells in vitro is cytotoxic and induces apoptosis/necrosis at doses that are above the level that can be achieved in vivo. It is not genotoxic, and does not ameliorate the cell killing or the senescence-inducing effect of temozolomide (no synergistic effect), indicating it has no impact on temozolomide-induced signaling pathways. The data do not support the notion that concomitant methadone treatment supports temozolomide-based chemotherapy. Full article
(This article belongs to the Special Issue Advance in Drug-Drug Interactions)
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Review

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20 pages, 2458 KiB  
Review
Impacts of Drug Interactions on Pharmacokinetics and the Brain Transporters: A Recent Review of Natural Compound-Drug Interactions in Brain Disorders
by Bikram Khadka, Jae-Young Lee, Eui Kyun Park, Ki-Taek Kim and Jong-Sup Bae
Int. J. Mol. Sci. 2021, 22(4), 1809; https://doi.org/10.3390/ijms22041809 - 11 Feb 2021
Cited by 5 | Viewed by 3337
Abstract
Natural compounds such as herbal medicines and/or phyto-compounds from foods, have frequently been used to exert synergistic therapeutic effects with anti-brain disorder drugs, supplement the effects of nutrients, and boost the immune system. However, co-administration of natural compounds with the drugs can cause [...] Read more.
Natural compounds such as herbal medicines and/or phyto-compounds from foods, have frequently been used to exert synergistic therapeutic effects with anti-brain disorder drugs, supplement the effects of nutrients, and boost the immune system. However, co-administration of natural compounds with the drugs can cause synergistic toxicity or impeditive drug interactions due to changes in pharmacokinetic properties (e.g., absorption, metabolism, and excretion) and various drug transporters, particularly brain transporters. In this review, natural compound–drug interactions (NDIs), which can occur during the treatment of brain disorders, are emphasized from the perspective of pharmacokinetics and cellular transport. In addition, the challenges emanating from NDIs and recent approaches are discussed. Full article
(This article belongs to the Special Issue Advance in Drug-Drug Interactions)
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19 pages, 1703 KiB  
Review
The Interactions of Nintedanib and Oral Anticoagulants—Molecular Mechanisms and Clinical Implications
by Grzegorz Grześk, Anita Woźniak-Wiśniewska, Jan Błażejewski, Bartosz Górny, Łukasz Wołowiec, Daniel Rogowicz and Alicja Nowaczyk
Int. J. Mol. Sci. 2021, 22(1), 282; https://doi.org/10.3390/ijms22010282 - 30 Dec 2020
Cited by 27 | Viewed by 5482
Abstract
Nintedanib is a synthetic orally active tyrosine kinase inhibitor, whose main action is to inhibit the receptors of the platelet-derived growth factor, fibroblast growth factor and vascular endothelial growth factor families. The drug also affects other kinases, including Src, Flt-3, LCK, LYN. Nintedanib [...] Read more.
Nintedanib is a synthetic orally active tyrosine kinase inhibitor, whose main action is to inhibit the receptors of the platelet-derived growth factor, fibroblast growth factor and vascular endothelial growth factor families. The drug also affects other kinases, including Src, Flt-3, LCK, LYN. Nintedanib is used in the treatment of idiopathic pulmonary fibrosis, chronic fibrosing interstitial lung diseases and lung cancer. The mechanism of action suggests that nintedanib should be considered one of the potential agents for inhibiting and revising the fibrosis process related to COVID-19 infections. Due to the known induction of coagulation pathways during COVID-19 infections, possible interaction between nintedanib and anticoagulant seems to be an extremely important issue. In theory, nintedanib could increase the bleeding risk, thrombosis and lead to thrombocytopenia. The data from clinical trials on the concomitant use of nintedanib and antithrombotic agents is very limited as this patient group was within the standard exclusion criteria. Nintedanib is an important therapeutic option, despite its interaction with anticoagulants. If anticoagulant therapy is necessary, the more effective and safer option is the concomitant administration of DOACs and nintedanib, especially when drug-monitored therapy will be used in patients at high risk of bleeding complications. Full article
(This article belongs to the Special Issue Advance in Drug-Drug Interactions)
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21 pages, 3957 KiB  
Review
Pharmaceutical Excipients and Drug Metabolism: A Mini-Review
by Rahul Patel, James Barker and Amr ElShaer
Int. J. Mol. Sci. 2020, 21(21), 8224; https://doi.org/10.3390/ijms21218224 - 3 Nov 2020
Cited by 39 | Viewed by 8325
Abstract
Conclusions from previously reported articles have revealed that many commonly used pharmaceutical excipients, known to be pharmacologically inert, show effects on drug transporters and/or metabolic enzymes. Thus, the pharmacokinetics (absorption, distribution, metabolism and elimination) of active pharmaceutical ingredients are possibly altered because of [...] Read more.
Conclusions from previously reported articles have revealed that many commonly used pharmaceutical excipients, known to be pharmacologically inert, show effects on drug transporters and/or metabolic enzymes. Thus, the pharmacokinetics (absorption, distribution, metabolism and elimination) of active pharmaceutical ingredients are possibly altered because of their transport and metabolism modulation from the incorporated excipients. The aim of this review is to present studies on the interaction of various commonly-used excipients on pre-systemic metabolism by CYP450 enzymes. Excipients such as surfactants, polymers, fatty acids and solvents are discussed. Based on all the reported outcomes, the most potent inhibitors were found to be surfactants and the least effective were organic solvents. However, there are many factors that can influence the inhibition of CYP450, for instance type of excipient, concentration of excipient, type of CYP450 isoenzyme, incubation condition, etc. Such evidence will be very useful in dosage form design, so that the right formulation can be designed to maximize drug bioavailability, especially for poorly bioavailable drugs. Full article
(This article belongs to the Special Issue Advance in Drug-Drug Interactions)
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