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Drugs of Abuse and New Psychoactive Substances – Toxicokinetics Revealed...
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Drugs of Abuse and New Psychoactive Substances – Toxicokinetics Revealed by In Vitro / In Vivo Tools

A special issue of Metabolites (ISSN 2218-1989). This special issue belongs to the section "Pharmacology and Drug Metabolism".

Deadline for manuscript submissions: closed (30 June 2022) | Viewed by 9054

Special Issue Editors

Prof. Dr. Markus R. Meyer

E-Mail Website
Guest Editor
Department of Experimental and Clinical Toxicology, Institute of Experimental and Clinical Pharmacology and Toxicology, Center for Molecular Signaling (PZMS), Saarland University, 66421 Homburg, Germany
Interests: hyphenated mass spectrometry; drugs of abuse; new psychoactive substances; toxicokinetics
Special Issues, Collections and Topics in MDPI journals
Dr. Lea Wagmann

E-Mail Website
Guest Editor
Department of Experimental and Clinical Toxicology, Institute of Experimental and Clinical Pharmacology and Toxicology, Center for Molecular Signaling (PZMS), Saarland University, Homburg, Germany
Interests: hyphenated mass spectrometry; drugs of abuse; new psychoactive substances; toxicokinetics

Special Issue Information

Dear Colleagues,

A non-reflected intake of traditional drugs of abuse (DOA) or new psychoactive substances (NPS) may lead to serious health issues such as arrythmia, seizures, or acute psychosis. Possible risks also include drug-drug or drug-food interactions and are hardly to predict without any knowledge about the toxicokinetics. Unfortunately, such data are usually not available when the DOA/NPS are sold and consumed.

This Special Issue of Metabolites, "Drugs of Abuse and New Psychoactive Substances - Toxicokinetics Revealed by in vitro / in vivo Tools ", will be dedicated to in vitro and/or in vivo studies dealing with the elucidation of the toxicokinetics of traditional DOA but also of emerging NPS. This includes – but is not limited to - metabolism of DOA/NPS, isozyme mapping, formation of reactive metabolites, or interaction with transporter proteins.

Prof. Dr. Markus R. Meyer
Dr. Lea Wagmann
Guest Editors

Manuscript Submission Information

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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. Metabolites 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 2700 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

  • new psychoactive substances
  • drugs of abuse
  • toxicokinetics
  • metabolism
  • in vivo / in vitro

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Published Papers (3 papers)

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Research

16 pages, 1760 KiB  
Article
Similar 5F-APINACA Metabolism between CD-1 Mouse and Human Liver Microsomes Involves Different P450 Cytochromes
by Samantha V. Crosby, Izzeldin Y. Ahmed, Laura R. Osborn, Zeyuan Wang, Mary A. Schleiff, William E. Fantegrossi, Swati Nagar, Paul L. Prather, Gunnar Boysen and Grover P. Miller
Metabolites 2022, 12(8), 773; https://doi.org/10.3390/metabo12080773 - 22 Aug 2022
Viewed by 2410
Abstract
In 2019, synthetic cannabinoids accounted for more than one-third of new drugs of abuse worldwide; however, assessment of associated health risks is not ethical for controlled and often illegal substances, making CD-1 mouse exposure studies the gold standard. Interpretation of those findings then [...] Read more.
In 2019, synthetic cannabinoids accounted for more than one-third of new drugs of abuse worldwide; however, assessment of associated health risks is not ethical for controlled and often illegal substances, making CD-1 mouse exposure studies the gold standard. Interpretation of those findings then depends on the similarity of mouse and human metabolic pathways. Herein, we report the first comparative analysis of steady-state metabolism of N-(1-adamantyl)-1-(5-pentyl)-1H-indazole-3-carboxamide (5F-APINACA/5F-AKB48) in CD-1 mice and humans using hepatic microsomes. Regardless of species, 5F-APINACA metabolism involved highly efficient sequential adamantyl hydroxylation and oxidative defluorination pathways that competed equally. Secondary adamantyl hydroxylation was less efficient for mice. At low 5F-APINACA concentrations, initial rates were comparable between pathways, but at higher concentrations, adamantyl hydroxylations became less significant due to substrate inhibition likely involving an effector site. For humans, CYP3A4 dominated both metabolic pathways with minor contributions from CYP2C8, 2C19, and 2D6. For CD-1 mice, Cyp3a11 and Cyp2c37, Cyp2c50, and Cyp2c54 contributed equally to adamantyl hydroxylation, but Cyp3a11 was more efficient at oxidative defluorination than Cyp2c members. Taken together, the results of our in vitro steady-state study indicate a high conservation of 5F-APINACA metabolism between CD-1 mice and humans, but deviations can occur due to differences in P450s responsible for the associated reactions. Full article
(This article belongs to the Special Issue Drugs of Abuse and New Psychoactive Substances – Toxicokinetics Revealed by In Vitro / In Vivo Tools)
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11 pages, 1537 KiB  
Article
Human Hepatocyte 4-Acetoxy-N,N-Diisopropyltryptamine Metabolite Profiling by Reversed-Phase Liquid Chromatography Coupled with High-Resolution Tandem Mass Spectrometry
by Sara Malaca, Marilyn A. Huestis, Leonardo Lattanzio, Luigi T. Marsella, Adriano Tagliabracci, Jeremy Carlier and Francesco P. Busardò
Metabolites 2022, 12(8), 705; https://doi.org/10.3390/metabo12080705 - 29 Jul 2022
Cited by 4 | Viewed by 2697
Abstract
Tryptamine intoxications and fatalities are increasing, although these novel psychoactive substances (NPS) are not controlled in most countries. There are few data on the metabolic pathways and enzymes involved in tryptamine biotransformation. 4-acetoxy-N,N-diisopropyltryptamine (4-AcO-DiPT) is a synthetic tryptamine related [...] Read more.
Tryptamine intoxications and fatalities are increasing, although these novel psychoactive substances (NPS) are not controlled in most countries. There are few data on the metabolic pathways and enzymes involved in tryptamine biotransformation. 4-acetoxy-N,N-diisopropyltryptamine (4-AcO-DiPT) is a synthetic tryptamine related to 4-hydroxy-N,N-diisopropyltryptamine (4-OH-DiPT), 4-acetyloxy-N,N-dipropyltryptamine (4-AcO-DPT), and 4-acetoxy-N,N-dimethyltryptamine (4-AcO-DMT). The aim of this study was to determine the best 4-AcO-DiPT metabolites to identify 4-AcO-DiPT consumption through human hepatocyte metabolism and high-resolution mass spectrometry. 4-AcO-DiPT metabolites were predicted in silico with GLORYx freeware to assist in metabolite identification. 4-AcO-DiPT was incubated with 10-donor-pooled human hepatocytes and sample analysis was performed with reversed-phase liquid chromatography coupled with high-resolution tandem mass spectrometry (LC-HRMS/MS) in positive- and negative-ion modes. Software-assisted LC-HRMS/MS raw data mining was performed. A total of 47 phase I and II metabolites were predicted, and six metabolites were identified after 3 h incubation following ester hydrolysis, O-glucuronidation, O-sulfation, N-oxidation, and N-dealkylation. All second-generation metabolites were derived from the only first-generation metabolite detected after ester hydrolysis (4-OH-DiPT). The metabolite with the second-most-intense signal was 4-OH-iPT-sulfate followed by 4-OH-DiPT-glucuronide, indicating that glucuronidation and sulfation are common in this tryptamine’s metabolic pathway. 4-OH-DiPT, 4-OH-iPT, and 4-OH-DiPT-N-oxide are suggested as optimal biomarkers to identify 4-AcO-DiPT consumption. Full article
(This article belongs to the Special Issue Drugs of Abuse and New Psychoactive Substances – Toxicokinetics Revealed by In Vitro / In Vivo Tools)
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13 pages, 869 KiB  
Article
Human In Vivo Metabolism and Elimination Behavior of Micro-Dosed Selective Androgen Receptor Modulator RAD140 for Doping Control Purposes
by Felicitas Wagener, Luisa Euler, Christian Görgens, Sven Guddat and Mario Thevis
Metabolites 2022, 12(7), 666; https://doi.org/10.3390/metabo12070666 - 20 Jul 2022
Cited by 9 | Viewed by 3209
Abstract
RAD140 is a selective androgen receptor modulator which has been abused in sporting competitions. Its use is prohibited by the World Anti-Doping Agency (WADA) for athletes at all times. In addition to its illicit use, adverse analytical findings of RAD140 in doping control [...] Read more.
RAD140 is a selective androgen receptor modulator which has been abused in sporting competitions. Its use is prohibited by the World Anti-Doping Agency (WADA) for athletes at all times. In addition to its illicit use, adverse analytical findings of RAD140 in doping control samples might result from other scenarios, e.g., the ingestion of contaminated dietary supplements. The differentiation between samples resulting from such contamination scenarios and intentional doping presents a considerable challenge, as little is known about the metabolism and elimination behavior of RAD140 in humans. In this study, six micro-dose excretion studies with five adult male volunteers each were conducted, and urine samples were analyzed by means of LC-HRMS/MS. Multiple metabolites, firstly detected in human urine, are described in this study. The sample preparation included an enzymatic hydrolysis step, which facilitated the estimation of RAD140 concentrations in urine. The elimination profiles and detection times for six metabolites as well as the intact drug are presented. The method was extensively characterized and deemed fit-for-purpose. The metabolite ratios were investigated for their predictive power in estimating the dose of RAD140 intake. The presented data will aid in better case result management in future doping cases involving RAD140. Full article
(This article belongs to the Special Issue Drugs of Abuse and New Psychoactive Substances – Toxicokinetics Revealed by In Vitro / In Vivo Tools)
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