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Pharmaceutics
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Transport and Metabolism of Small-Molecule Drugs, 2nd Edition
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Transport and Metabolism of Small-Molecule Drugs, 2nd Edition

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

Deadline for manuscript submissions: closed (20 April 2024) | Viewed by 5198

Special Issue Editor

Prof. Dr. Gus Rosania

E-Mail Website
Guest Editor
Department of Pharmaceutical Sciences, College of Pharmacy, University of Michigan, 428 Church Street, Ann Arbor, MI 48109, USA
Interests: drug transport; cellular pharmacokinetics; computational modeling; systems biology; cheminformatics; microscopic imaging
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

This Special Issue will highlight studies centered on elucidating the biological processes and pathways that determine the absorption, distribution, metabolism, and excretion of drug-like chemical agents in the living organism. More specifically, we are seeking submissions related to studies of chemical agents with a molecular mass of <500 Daltons. Of special interest, we are seeking original research articles or reviews that present intellectually exciting and innovative ideas, including systems modeling and simulation approaches, or that offer unexpected insights into the pharmacokinetics of small drug-like molecules. We will also consider more traditional molecular-level studies looking at the interaction of small molecules with transporters, enzymes, membranes, and other macromolecular components that determine the distribution and disposition of chemical agents in cells, tissues, and organs. Hypothesis-driven and mechanistic studies related to regulatory science, such as the measurement and prediction of drug–drug interactions, the establishment of  in vitro–in vivo correlations, pharmacogenomics, interpatient variability, preclinical model systems (transgenic/knockout mice, isolated perfused organs, in vitro or in silico screening tools), or advanced computational approaches for modeling, simulating, or predicting pharmacokinetics at a multiscale level (from organelles to populations) are also welcome.

Prof. Dr. Gus Rosania
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

  • small molecules
  • pharmacokinetics
  • metabolism
  • drug–drug interactions
  • pharmacogenomics
  • drug targeting
  • drug delivery
  • in vitro–in vivo correlations
  • modeling and simulation

Related Special Issue

Published Papers (6 papers)

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Research

11 pages, 2714 KiB  
Article
Novel Fluorescent Strategy for Discriminating T and B Lymphocytes Using Transport System
by Heewon Cho, Na-Kyeong Hong and Young-Tae Chang
Pharmaceutics 2024, 16(3), 424; https://doi.org/10.3390/pharmaceutics16030424 - 19 Mar 2024
Viewed by 677
Abstract
Fluorescent bioprobes are invaluable tools for visualizing live cells and deciphering complex biological processes by targeting intracellular biomarkers without disrupting cellular functions. In addition to protein-binding concepts, fluorescent probes utilize various mechanisms, including membrane, metabolism, and gating-oriented strategies. This study introduces a novel [...] Read more.
Fluorescent bioprobes are invaluable tools for visualizing live cells and deciphering complex biological processes by targeting intracellular biomarkers without disrupting cellular functions. In addition to protein-binding concepts, fluorescent probes utilize various mechanisms, including membrane, metabolism, and gating-oriented strategies. This study introduces a novel fluorescent mechanism distinct from existing ways. Here, we developed a B cell selective probe, CDrB, with unique transport mechanisms. Through SLC-CRISPRa screening, we identified two transporters, SLCO1B3 and SLC25A41, by sorting out populations exhibiting higher and lower fluorescence intensities, respectively, demonstrating contrasting activities. We confirmed that SLCO1B3, with comparable expression levels in T and B cells, facilitates the transport of CDrB into cells, while SLC25A41, overexpressed in T lymphocytes, actively exports CDrB. This observation suggests that SLC25A41 plays a crucial role in discriminating between T and B lymphocytes. Furthermore, it reveals the potential for the reversible localization of SLC25A41 to demonstrate its distinct activity. This study is the first report to unveil a novel strategy of SLC by exporting the probe. We anticipate that this research will open up new avenues for developing fluorescent probes. Full article
(This article belongs to the Special Issue Transport and Metabolism of Small-Molecule Drugs, 2nd Edition)
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16 pages, 2726 KiB  
Article
Metabolic Stability and Metabolite Identification of N-Ethyl Pentedrone Using Rat, Mouse and Human Liver Microsomes
by Alexandre Barcia Godoi, Natalícia de Jesus Antunes, Kelly Francisco Cunha, Aline Franco Martins, Marilyn A. Huestis and Jose Luiz Costa
Pharmaceutics 2024, 16(2), 257; https://doi.org/10.3390/pharmaceutics16020257 - 09 Feb 2024
Viewed by 893
Abstract
New Psychoactive Substances (NPSs) are defined as a group of substances produced from molecular modifications of traditional drugs. These molecules represent a public health problem since information about their metabolites and toxicity is poorly understood. N-ethyl pentedrone (NEP) is an NPS that was [...] Read more.
New Psychoactive Substances (NPSs) are defined as a group of substances produced from molecular modifications of traditional drugs. These molecules represent a public health problem since information about their metabolites and toxicity is poorly understood. N-ethyl pentedrone (NEP) is an NPS that was identified in the illicit market for the first time in the mid-2010s, with four intoxication cases later described in the literature. This study aims to evaluate the metabolic stability of NEP as well as to identify its metabolites using three liver microsomes models. To investigate metabolic stability, NEP was incubated with rat (RLM), mouse (MLM) and human (HLM) liver microsomes and its concentration over time evaluated by liquid chromatography–mass spectrometry. For metabolite identification, the same procedure was employed, but the samples were analyzed by liquid chromatography–high resolution mass spectrometry. Different metabolism profiles were observed depending on the model employed and kinetic parameters were determined. The in vitro NEP elimination half-lives (t1/2) were 12.1, 187 and 770 min for the rat, mouse and human models, respectively. Additionally, in vitro intrinsic clearances (Cl int, in vitro) were 229 for rat, 14.8 for mouse, and 3.6 μL/min/mg in the human model, and in vivo intrinsic clearances (Cl int, in vivo) 128, 58.3, and 3.7 mL/min/kg, respectively. The HLM model had the lowest rate of metabolism when compared to RLM and MLM. Also, twelve NEP metabolites were identified from all models, but at different rates of production. Full article
(This article belongs to the Special Issue Transport and Metabolism of Small-Molecule Drugs, 2nd Edition)
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18 pages, 4810 KiB  
Article
Higher Brain Uptake of Gentamicin and Ceftazidime under Isoflurane Anesthesia Compared to Ketamine/Xylazine
by Yeseul Ahn, Chanakya D. Patil, Ehsan Nozohouri, Sumaih Zoubi, Dhavalkumar Patel and Ulrich Bickel
Pharmaceutics 2024, 16(1), 135; https://doi.org/10.3390/pharmaceutics16010135 - 19 Jan 2024
Viewed by 906
Abstract
We have recently shown that the volatile anesthetics isoflurane and sevoflurane acutely enhance the brain uptake of the hydrophilic markers sucrose and mannitol about two-fold from an awake condition, while the combined injection of the anesthetic agents ketamine and xylazine has no effect. [...] Read more.
We have recently shown that the volatile anesthetics isoflurane and sevoflurane acutely enhance the brain uptake of the hydrophilic markers sucrose and mannitol about two-fold from an awake condition, while the combined injection of the anesthetic agents ketamine and xylazine has no effect. The present study investigated two small-molecule hydrophilic drugs with potential neurotoxicity, the antibiotic agents ceftazidime and gentamicin. Transport studies using an in vitro blood–brain barrier (BBB) model, a monolayer of induced pluripotent stem cell-derived human brain microvascular endothelial cells seeded on Transwells, and LC-MS/MS analysis demonstrated the low permeability of both drugs in the range of sucrose, with permeability coefficients of 6.62 × 10−7 ± 2.34 × 10−7 cm/s for ceftazidime and 7.38 × 10−7 ± 2.29 × 10−7 cm/s for gentamicin. In vivo brain uptake studies of ceftazidime or gentamicin after IV doses of 25 mg/kg were performed in groups of 5–6 mice anesthetized at typical doses for surgical procedures with either isoflurane (1.5–2% v/v) or ketamine/xylazine (100:10 mg/kg I.P.). The brain uptake clearance, Kin, for ceftazidime increased from 0.033 ± 0.003 μL min−1 g−1 in the ketamine/xylazine group to 0.057 ± 0.006 μL min−1 g−1 in the isoflurane group (p = 0.0001), and from 0.052 ± 0.016 μL min−1 g−1 to 0.101 ± 0.034 μL min−1 g−1 (p = 0.0005) for gentamicin. We did not test the dose dependency of the uptake, because neither ceftazidime nor gentamicin are known substrates of any active uptake or efflux transporters at the BBB. In conclusion, the present study extends our previous findings with permeability markers and suggests that inhalational anesthetic isoflurane increases the BBB permeability of hydrophilic small-molecule endobiotics or xenobiotics when compared to the injection of ketamine/xylazine. This may be of clinical relevance in the case of potential neurotoxic substances. Full article
(This article belongs to the Special Issue Transport and Metabolism of Small-Molecule Drugs, 2nd Edition)
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15 pages, 479 KiB  
Article
Effects of Aqueous Boundary Layers and Paracellular Transport on the Efflux Ratio as a Measure of Active Transport Across Cell Layers
by Soné Kotze, Andrea Ebert and Kai-Uwe Goss
Pharmaceutics 2024, 16(1), 132; https://doi.org/10.3390/pharmaceutics16010132 - 19 Jan 2024
Viewed by 731
Abstract
The efflux ratio (ER), determined by Caco-2/MDCK assays, is the standard in vitro metric to establish qualitatively whether a compound is a substrate of an efflux transporter. However, others have also enabled the utilisation of this metric quantitatively by deriving a relationship that [...] Read more.
The efflux ratio (ER), determined by Caco-2/MDCK assays, is the standard in vitro metric to establish qualitatively whether a compound is a substrate of an efflux transporter. However, others have also enabled the utilisation of this metric quantitatively by deriving a relationship that expresses the ER as a function of the intrinsic membrane permeability of the membrane (P0) as well as the permeability of carrier-mediated efflux (Ppgp). As of yet, Ppgp cannot be measured directly from transport experiments or otherwise, but the ER relationship provides easy access to this value if P0 is known. However, previous derivations of this relationship failed to consider the influence of additional transport resistances such as the aqueous boundary layers (ABLs) and the filter on which the monolayer is grown. Since single fluxes in either direction can be heavily affected by these experimental artefacts, it is crucial to consider the potential impact on the ER. We present a model that includes these factors and show both mathematically and experimentally that this simple ER relationship also holds for the more realistic scenario that does not neglect the ABLs/filter. Furthermore, we also show mathematically how paracellular transport affects the ER, and we experimentally confirm that paracellular dominance reduces the ER to unity and can mask potential efflux. Full article
(This article belongs to the Special Issue Transport and Metabolism of Small-Molecule Drugs, 2nd Edition)
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14 pages, 1585 KiB  
Article
Electrochemical Simulation of Phase I Hepatic Metabolism of Voriconazole Using a Screen-Printed Iron(II) Phthalocyanine Electrode
by Michał Wroński, Jakub Trawiński and Robert Skibiński
Pharmaceutics 2023, 15(11), 2586; https://doi.org/10.3390/pharmaceutics15112586 - 04 Nov 2023
Viewed by 629
Abstract
Understanding the metabolism of pharmaceutical compounds is a fundamental prerequisite for ensuring their safety and efficacy in clinical use. However, conventional methods for monitoring drug metabolism often come with the drawbacks of being time-consuming and costly. In an ongoing quest for innovative approaches, [...] Read more.
Understanding the metabolism of pharmaceutical compounds is a fundamental prerequisite for ensuring their safety and efficacy in clinical use. However, conventional methods for monitoring drug metabolism often come with the drawbacks of being time-consuming and costly. In an ongoing quest for innovative approaches, the application of electrochemistry in metabolism studies has gained prominence as a promising approach for the synthesis and analysis of drug transformation products. In this study, we investigated the hepatic metabolism of voriconazole, an antifungal medication, by utilizing human liver microsomes (HLM) assay coupled with LC-MS. Based on the obtained results, the electrochemical parameters were optimized to simulate the biotransformation reactions. Among the various electrodes tested, the chemometric analysis revealed that the iron(II) phthalocyanine electrode was the most effective in catalyzing the formation of all hepatic voriconazole metabolites. These findings exemplify the potential of phthalocyanine electrodes as an efficient and cost-effective tool for simulating the intricate metabolic processes involved in drug biotransformation, offering new possibilities in the field of pharmaceutical research. Additionally, in silico analysis showed that two detected metabolites may exhibit significantly higher acute toxicity and mutagenic potential than the parent compound. Full article
(This article belongs to the Special Issue Transport and Metabolism of Small-Molecule Drugs, 2nd Edition)
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13 pages, 3656 KiB  
Article
Distinguishing the Concentration- vs. Bioaccumulation-Dependent Immunological and Metabolic Effects of Clofazimine
by Andrew R. Willmer, Jennifer Diaz-Espinosa, Austin Zhou, Kathleen A. Stringer and Gus R. Rosania
Pharmaceutics 2023, 15(9), 2350; https://doi.org/10.3390/pharmaceutics15092350 - 20 Sep 2023
Viewed by 840
Abstract
The antimycobacterial drug clofazimine (CFZ) is used as a single agent at high doses, to suppress the exaggerated inflammation associated with leprosy. Paradoxically, increasing doses of CFZ leads to bioaccumulation of CFZ in the spleen and other organs under physiologically relevant dosing regimens, [...] Read more.
The antimycobacterial drug clofazimine (CFZ) is used as a single agent at high doses, to suppress the exaggerated inflammation associated with leprosy. Paradoxically, increasing doses of CFZ leads to bioaccumulation of CFZ in the spleen and other organs under physiologically relevant dosing regimens, without accompanying dose-dependent elevation in the concentrations of the circulating drug in the blood. In long-term oral dosing regimens, CFZ induces immunological and metabolic changes resulting in splenomegaly, while the mass of other organs decreases or remains unchanged. As an organ that extensively sequesters CFZ as insoluble drug precipitates, the spleen likely influences drug-induced inflammatory signaling. To probe the role of systemic drug concentrations vs. drug bioaccumulation in the spleen, healthy mice were treated with six different dosing regimens. A subgroup of these mice underwent surgical splenectomies prior to drug treatment to assess the bioaccumulation-dependent changes in immune system signaling and immune-system-mediated drug distribution. Under increasing drug loading, the spleen was observed to grow up to six times in size, sequestering over 10% of the total drug load. Interestingly, when the spleen was removed prior to CFZ administration, drug distribution in the rest of the organism was unaffected. However, there were profound cytokine elevations in the serum of asplenic CFZ-treated mice, indicating that the spleen is primarily involved in suppressing the inflammatory signaling mechanisms that are upregulated during CFZ bioaccumulation. Thus, beyond its role in drug sequestration, the spleen actively modulates the systemic effect of CFZ on the immune system, without impacting its blood concentrations or distribution to the rest of the organism. Full article
(This article belongs to the Special Issue Transport and Metabolism of Small-Molecule Drugs, 2nd Edition)
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