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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 September 2021) | Viewed by 31166

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Dr. Cornelius Hess

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Department Clinical and Forensic Toxicology, MVZ Dr. Stein und Kollegen GbR Mönchengladbach, 41169 Mönchengladbach, Germany
Interests: chromatography; mass spectrometry; drugs of abuse; gamma hydroxy butyric acid; synthetic cannabinoids; enantioselective analysis
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Dear Colleagues,

The field of forensic toxicology has developed enormously within the last several decades. Methodological and technological developments in sample preparations, metabolite creation, analytical techniques (e.g., high-resolution mass spectrometry), data processing (e.g., metabolomics), and the examination of new sample specimens have generated previously unthinkable possibilities. Metabolite research reflects one of the most important fields in forensic toxicology, since the metabolites of well-known and new psychoactive substances can help in the interpretation of forensic cases in many ways (e.g., by allowing the detection of the abuse, by widening the detection window, by allowing the estimation of the time of use, or by estimation of the pharmacological effect at the time of sampling). This Special Issue of Metabolites, "Metabolite Analysis in Forensic Toxicology", is dedicated to metabolite research within this field. The topics that will be covered by this Special Issue include, but are not limited to: in vivo and in vitro techniques of metabolite synthesis; identification and/or quantification of metabolites with biological and/or forensic relevance—possibly in relation to functional genomics (pharmacogenomics); the pharmacokinetics of drugs of abuse and their metabolites; the pharmacological testing of metabolites; the detection of metabolites in different matrices (e.g., hair analysis); and forensic applications of the direct quantification of metabolites or untargeted metabolomic methods. Manuscripts dealing with other pertinent challenging issues are also highly desired.

Dr. Cornelius Hess
Guest Editor

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Keywords

Metabolites
Metabolomics
Drugs of abuse
New psychoactive substances
Toxicology
Pharmacogenomics
Pharmacokinetics
High-resolution mass spectrometry

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Related Special Issue

Metabolite Analysis in Forensic Toxicology Volume II in Metabolites (3 articles)

Published Papers (9 papers)

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12 pages, 706 KiB

Open AccessEditor’s ChoiceArticle

Significance of Metabolite Ratios in the Interpretation of Segmental Hair Testing Results—Differentiation of Single from Chronic Morphine Use in a Case Series

by Milena M. Madry, Sandra N. Poetzsch, Andrea E. Steuer, Thomas Kraemer and Markus R. Baumgartner

Metabolites 2021, 11(8), 557; https://doi.org/10.3390/metabo11080557 - 22 Aug 2021

Cited by 4 | Viewed by 2650

Abstract

In morphine intoxication cases, forensic toxicologists are frequently confronted with the question of if the individual was opioid-tolerant or opioid-naïve, which can be investigated by hair analysis. However, interpretation of results can be challenging. Here, we report on hair testing for morphine and its metabolite hydromorphone following morphine intoxication without tolerance and upon chronic use. Two consecutive hair samples were collected after a non-fatal intoxication. Analysis comprised short hair segments and their initial wash water solutions. In the intoxications, morphine and hydromorphone levels were 3.3 to 56 pg/mg and at maximum 9.8 pg/mg, respectively. Both levels and hydromorphone to morphine ratios were significantly lower compared to chronic morphine use. In the non-fatal intoxication, the highest hydromorphone to morphine ratio was obtained in the segment corresponding to the time of intoxication. Morphine ratios of wash to hair were significantly higher in the intoxications compared to chronic use, being indicative of sweat/sebum contamination. We recommend including the analysis of hydromorphone and the initial wash solution in cases of morphine intoxications. Our study demonstrates that hydromorphone to morphine ratios can help in distinguishing single from chronic morphine use and in estimating the period of exposure when a consecutive hair sample can be collected in survived intoxications. Full article

(This article belongs to the Special Issue Metabolite Analysis in Forensic Toxicology)

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17 pages, 2265 KiB

Open AccessEditor’s ChoiceArticle

Enantioselective Quantification of Amphetamine and Metabolites in Serum Samples: Forensic Evaluation and Estimation of Consumption Time

by Moritz Losacker, Michael Kraemer, Alexandra Philipsen, Kristina Duecker, Nadine Dreimueller, Jan Engelmann, Joerg Roehrich and Cornelius Hess

Metabolites 2021, 11(8), 521; https://doi.org/10.3390/metabo11080521 - 6 Aug 2021

Cited by 13 | Viewed by 3594

Abstract

In forensic toxicology, amphetamine intoxications represent one of the most common case groups and present difficult questions for toxicologists. Estimating the time of consumption and the current influence of the stimulant is particularly difficult when only total amphetamine concentrations are considered. Stereoselective analysis and the consideration of metabolites can provide valuable information to facilitate interpretation. An enantioselective liquid chromatography−tandem mass spectrometry (LC-MS/MS) method for detection of amphetamine, norephedrine and 4-hydroxyamphetamine was developed. Validation showed satisfactory selectivity, sensitivity, linearity (0.5–250 ng/mL), precision and accuracy for all enantiomers. The method was applied to a collective of 425 forensic serum samples and 30 serum samples from psychiatric inpatients stating their last time of amphetamine consumption. Norephedrine and 4-hydroxyamphetamine were detected more frequently at higher amphetamine concentrations and at lower amphetamine (R)/(S) concentration ratios, possibly indicating recent consumption. Mean (R)/(S) ratio of amphetamine was 1.14, whereas higher ratios (mean 1.36) were found for amphetamine concentrations below 100 ng/mL. The (R)/(S) ratios of psychiatric inpatients significantly correlated with the reported time intervals to last consumption. The use of amphetamine (R)/(S) ratios and the simultaneous detection of metabolites are promising factors that can facilitate estimation of consumption time and current impairment. Full article

(This article belongs to the Special Issue Metabolite Analysis in Forensic Toxicology)

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14 pages, 3236 KiB

Open AccessEditor’s ChoiceArticle

In Vitro Metabolic Fate of the Synthetic Cannabinoid Receptor Agonists QMPSB and QMPCB (SGT-11) Including Isozyme Mapping and Esterase Activity

by Matthias J. Richter, Lea Wagmann, Tanja M. Gampfer, Simon D. Brandt and Markus R. Meyer

Metabolites 2021, 11(8), 509; https://doi.org/10.3390/metabo11080509 - 3 Aug 2021

Cited by 8 | Viewed by 2656

Abstract

Quinolin-8-yl 4-methyl-3-(piperidine-1-sulfonyl)benzoate (QMPSB) and quinolin-8-yl 4-methyl-3-(piperidine-1-carbonyl)benzoate (QMPCB, SGT-11) are synthetic cannabinoid receptor agonists (SCRAs). Knowing their metabolic fate is crucial for the identification of toxicological screening targets and to predict possible drug interactions. The presented study aimed to identify the in vitro phase I/II metabolites of QMPSB and QMPCB and to study the contribution of different monooxygenases and human carboxylesterases by using pooled human liver S9 fraction (pHLS9), recombinant human monooxygenases, three recombinant human carboxylesterases, and pooled human liver microsomes. Analyses were carried out by liquid chromatography high-resolution tandem mass spectrometry. QMPSB and QMPCB showed ester hydrolysis, and hydroxy and carboxylic acid products were detected in both cases. Mono/dihydroxy metabolites were formed, as were corresponding glucuronides and sulfates. Most of the metabolites could be detected in positive ionization mode with the exception of some QMPSB metabolites, which could only be found in negative mode. Monooxygenase activity screening revealed that CYP2B6/CYP2C8/CYP2C9/CYP2C19/CYP3A4/CYP3A5 were involved in hydroxylations. Esterase screening showed the involvement of all investigated isoforms. Additionally, extensive non-enzymatic ester hydrolysis was observed. Considering the results of the in vitro experiments, inclusion of the ester hydrolysis products and their glucuronides and monohydroxy metabolites into toxicological screening procedures is recommended. Full article

(This article belongs to the Special Issue Metabolite Analysis in Forensic Toxicology)

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25 pages, 1435 KiB

Open AccessArticle

Phase I In Vitro Metabolic Profiling of the Synthetic Cannabinoid Receptor Agonists CUMYL-THPINACA and ADAMANTYL-THPINACA

by Manuela Carla Monti, Eva Scheurer and Katja Mercer-Chalmers-Bender

Metabolites 2021, 11(8), 470; https://doi.org/10.3390/metabo11080470 - 21 Jul 2021

Cited by 3 | Viewed by 3351

Abstract

Synthetic cannabinoid receptor agonists (SCRAs) remain popular drugs of abuse. As many SCRAs are known to be mostly metabolized, in vitro phase I metabolic profiling was conducted of the two indazole-3-carboxamide SCRAs: CUMYL-THPINACA and ADAMANTYL-THPINACA. Both compounds were incubated using pooled human liver microsomes. The sample clean-up consisted of solid phase extraction, followed by analysis using liquid chromatography coupled to a high resolution mass spectrometer. In silico-assisted metabolite identification and structure elucidation with the data-mining software Compound Discoverer was applied. Overall, 28 metabolites were detected for CUMYL-THPINACA and 13 metabolites for ADAMATYL-THPINACA. Various mono-, di-, and tri-hydroxylated metabolites were detected. For each SCRA, an abundant and characteristic di-hydroxylated metabolite was identified as a possible in vivo biomarker for screening methods. Metabolizing cytochrome P450 isoenzymes were investigated via incubation of relevant recombinant liver enzymes. The involvement of mainly CYP3A4 and CYP3A5 in the metabolism of both substances were noted, and for CUMYL-THPINACA the additional involvement (to a lesser extent) of CYP2C8, CYP2C9, and CYP2C19 was observed. The results suggest that ADAMANTYL-THPINACA might be more prone to metabolic drug−drug interactions than CUMYL-THPINACA, when co-administrated with strong CYP3A4 inhibitors. Full article

(This article belongs to the Special Issue Metabolite Analysis in Forensic Toxicology)

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20 pages, 1252 KiB

Open AccessArticle

Identification of Potential Distinguishing Markers for the Use of Cannabis-Based Medicines or Street Cannabis in Serum Samples

by Anne Scheunemann, Katrin Elsner, Tanja Germerott, Sergiu Groppa, Cornelius Hess, Isabelle Miederer, Alicia Poplawski and Jörg Röhrich

Metabolites 2021, 11(5), 316; https://doi.org/10.3390/metabo11050316 - 13 May 2021

Cited by 4 | Viewed by 3315

Abstract

Increasing prescription numbers of cannabis-based medicines raise the question of whether uptake of these medicines can be distinguished from recreational cannabis use. In this pilot study, serum cannabinoid profiles after use of cannabis-based medicines were investigated, in order to identify potential distinguishing markers. Serum samples after use of Sativex^®, Dronabinol or medical cannabis were collected and analyzed for 18 different cannabinoids, using a validated liquid chromatography-tandem mass spectrometry (LC-MS/MS) method. Analytes included delta-9-tetrahydrocannabinol, 11-hydroxy-tetrahydrocannabinol, 11-nor-9-carboxy-tetrahydrocannabinol, cannabidiol, cannabinol, cannabigerol, cannabichromene, cannabicyclol, tetrahydrocannabivarin, cannabidivarin, tetrahydocannabinolic acid A, cannabidiolic acid, cannabinolic acid, cannabigerolic acid, cannabichromenic acid, cannabicyclolic acid, tetrahydrocannabivarinic acid and cannabidivarinic acid. Cannabinoid profiles of study samples were compared to profiles of street cannabis user samples via principal component analysis and Kruskal–Wallis test. Potential distinguishing markers for Dronabinol and Sativex^® intake were identified, including 11-hydroxy-tetrahydrocannabinol/delta-9-tetrahydrocannabinol ratios ≥1 and increased concentrations of 11-nor-9-carboxy-tetrahydrocannabinol, cannabidiol or cannabichromene. Larger quantities of minor cannabinoids suggested use of cannabis. Use of medical and street cannabis could not be distinguished, except for use of a cannabidiol-rich strain with higher cannabidiol/delta-9-tetrahydrocannabinol and cannabichromene/delta-9-tetrahydrocannabinol ratios. Findings of the study were used to classify forensic serum samples with self-reported use of cannabis-based medicines. Full article

(This article belongs to the Special Issue Metabolite Analysis in Forensic Toxicology)

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23 pages, 1773 KiB

Open AccessArticle

The Role of Risk or Contributory Death Factors in Methadone-Related Fatalities: A Review and Pooled Analysis

by Arianna Giorgetti, Jennifer Pascali, Massimo Montisci, Irene Amico, Barbara Bonvicini, Paolo Fais, Alessia Viero, Raffaele Giorgetti, Giovanni Cecchetto and Guido Viel

Metabolites 2021, 11(3), 189; https://doi.org/10.3390/metabo11030189 - 22 Mar 2021

Cited by 4 | Viewed by 3385

Abstract

Methadone-related deaths are characterized by a wide range of post-mortem blood concentrations, due to the high pharmacokinetic/dynamic inter-individual variability, the potential subjective tolerance state and to other risk factors or comorbidities, which might enhance methadone acute toxicity. In the present study, the association among pre-existing and external conditions and diseases and the resultant methadone death capacity have been investigated. Beside a systematic literature review, a retrospective case-control study was done, dividing cases in which methadone was the only cause of death (controls), and those with associated clinical-circumstantial (naive/non-tolerant state), pathological (pulmonary or cardiovascular diseases) or toxicological (other drugs detected) conditions. Methadone concentrations were compared between the two groups and the association with conditions/diseases was assessed by multiple linear and binomial logistic regressions. Literature cases were 139, in house 35, consisting of 22 controls and 152 cases with associated conditions/diseases. Mean methadone concentrations were 2122 ng/mL and 715 ng/mL in controls and cases respectively, with a statistically significant difference (p < 0.05). Lower methadone concentrations (by 24, 19 and 33% respectively) were detected in association with naive/non-tolerant state, pulmonary diseases and presence of other drugs, and low levels of methadone (<600 ng/mL) might lead to death in the presence of the above conditions/diseases. Full article

(This article belongs to the Special Issue Metabolite Analysis in Forensic Toxicology)

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16 pages, 7394 KiB

Open AccessArticle

Towards Extending the Detection Window of Gamma-Hydroxybutyric Acid—An Untargeted Metabolomics Study in Serum and Urine Following Controlled Administration in Healthy Men

by Andrea E. Steuer, Justine Raeber, Fabio Simbuerger, Dario A. Dornbierer, Oliver G. Bosch, Boris B. Quednow, Erich Seifritz and Thomas Kraemer

Metabolites 2021, 11(3), 166; https://doi.org/10.3390/metabo11030166 - 12 Mar 2021

Cited by 15 | Viewed by 3517

Abstract

In forensic toxicology, gamma-hydroxybutyrate (GHB) still represents one of the most challenging drugs of abuse in terms of analytical detection and interpretation. Given its rapid elimination, the detection window of GHB in common matrices is short (maximum 12 h in urine). Additionally, the differentiation from naturally occurring endogenous GHB, is challenging. Thus, novel biomarkers to extend the detection window of GHB are urgently needed. The present study aimed at searching new potential biomarkers of GHB use by means of mass spectrometry (MS) metabolomic profiling in serum (up to 16.5 h) and urine samples (up to 8 h after intake) collected during a placebo-controlled crossover study in healthy men. MS data acquired by different analytical methods (reversed phase and hydrophilic interaction liquid chromatography; positive and negative electrospray ionization each) were filtered for significantly changed features applying univariate and mixed-effect model statistics. Complementary to a former study, conjugates of GHB with glycine, glutamate, taurine, carnitine and pentose (ribose) were identified in urine, with particularly GHB-pentose being promising for longer detection. None of the conjugates were detectable in serum. Therein, mainly energy metabolic substrates were identified, which may be useful for more detailed interpretation of underlying pathways but are too unspecific as biomarkers. Full article

(This article belongs to the Special Issue Metabolite Analysis in Forensic Toxicology)

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19 pages, 3861 KiB

Open AccessArticle

Structure Assignment of Seized Products Containing Cathinone Derivatives Using High Resolution Analytical Techniques

by João L. Gonçalves, Vera L. Alves, Joselin Aguiar, Maria J. Caldeira, Helena M. Teixeira and José S. Câmara

Metabolites 2021, 11(3), 144; https://doi.org/10.3390/metabo11030144 - 27 Feb 2021

Cited by 9 | Viewed by 3077

Abstract

The innovation of the new psychoactive substances (NPS) market requires the rapid identification of new substances that can be a risk to public health, in order to reduce the damage from their use. Twelve seized products suspected to contain illicit substances were analyzed by attenuated total reflectance Fourier transform infrared spectroscopy (ATR-FTIR), gas chromatography coupled to mass spectrometry (GC-MS), and nuclear magnetic resonance spectroscopy (NMR). Synthetic cathinones (SCat) were found in all products, either as a single component or in mixtures. Infrared spectra of all products were consistent with the molecular structure of SCat, showing an intense absorption band at 1700–1674 cm⁻¹, corresponding to the carbonyl stretching, a medium/strong peak at 1605–1580 cm⁻¹, indicating stretching vibrations in the aromatic ring (C=C) and bands with relative low intensity at frequencies near 2700–2400 cm⁻¹, corresponding to an amine salt. It was possible to identify a total of eight cathinone derivatives by GC-MS and NMR analysis: 4′-methyl-α-pyrrolidinohexanophenone (MPHP), α-pyrrolidinohexanophenone (α-PHP), 3-fluoromethcathinone (3-FMC), methedrone, methylone, buphedrone, N-ethylcathinone, and pentedrone. Among the adulterants found in these samples, caffeine was the most frequently detected substance, followed by ethylphenidate. These results highlight the prevalence of SCat in seized materials of the Portuguese market. Reference standards are usually required for confirmation, but when reference materials are not available, the combination of complementary techniques is fundamental for a rapid and an unequivocal identification of such substances. Full article

(This article belongs to the Special Issue Metabolite Analysis in Forensic Toxicology)

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28 pages, 1331 KiB

Open AccessSystematic Review

A Systematic Review of Metabolite-to-Drug Ratios of Pharmaceuticals in Hair for Forensic Investigations

by Karen Rygaard, Kristian Linnet and Sys Stybe Johansen

Metabolites 2021, 11(10), 686; https://doi.org/10.3390/metabo11100686 - 6 Oct 2021

Cited by 10 | Viewed by 3387

Abstract

After ingestion, consumed drugs and their metabolites are incorporated into hair, which has a long detection window, ranging up to months. Therefore, in addition to conventional blood and urine analyses, hair analysis can provide useful information on long-term drug exposure. Meta-bolite-to-drug (MD) ratios are helpful in interpreting hair results, as they provide useful information on drug metabolism and can be used to distinguish drug use from external contamination, which is otherwise a limitation in hair analysis. Despite this, the MD ratios of a wide range of pharmaceuticals have scarcely been explored. This review aims to provide an overview of MD ratios in hair in a range of pharmaceuticals of interest to forensic toxicology, such as antipsychotic drugs, antidepressant drugs, benzodiazepines, common opiates/opioids, etc. The factors influencing the ratio were evaluated. MD ratios of 41 pharmaceuticals were reported from almost 100 studies. MD ratios below 1 were frequently reported, indicating higher concentrations of the parent pharmaceutical than of its metabolite in hair, but wide-ranging MD ratios of the majority of pharmaceuticals were found. Intra- and interindividual differences and compound properties were variables possibly contributing to this. This overview presents guidance for future comparison and evaluation of MD ratios of pharmaceuticals. Full article

(This article belongs to the Special Issue Metabolite Analysis in Forensic Toxicology)

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