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Revisited: Therapeutic and toxic blood concentrations of more than 1100 drugs and other xenobiotics.

ABSTRACT: In order to assess the significance of drug/substance levels measured in intensive care medicine and clinical and forensic toxicology as well as for therapeutic drug monitoring, it is essential that a comprehensive collection of data is readily available. We revisited and expanded our 2012 compilation of therapeutic and toxic plasma concentration ranges as well as half-lives of now more than 1100 drugs and other xenobiotics.Data have been abstracted from original papers, text books, and previous compilations and have been completed with data collected in our own forensic and clinical toxicology laboratories. We compiled the data presented in the table and the corresponding annotations over the past 30+ years. A previous compilation was completely double-checked, revised, and updated, if necessary. In addition, more than 200 substances, especially drugs who have been introduced since 2012 to the market as well as illegal drugs and other xenobiotics which became known to cause intoxications were added. We carefully referenced all data. Moreover, the annotations providing details were updated and revised, when necessary.For more than 1100 drugs and other xenobiotics, therapeutic ("normal") and, if data was available, toxic, and comatose-fatal plasma/blood concentrations as well as elimination half-lives were compiled in a table.In case of intoxications, the blood concentration of the substance and/or metabolite better predicts the clinical severity of the case when compared to the assumed amount and time of ingestion. Comparing and contrasting the clinical case against the data provided, including the half-life, may support the decision for or against further intensive care. In addition, the data provided are useful for the therapeutic monitoring of pharmacotherapies, to facilitate the diagnostic assessment and monitoring of acute and chronic intoxications as well as to support forensic and clinical expert opinions.

SUBMITTER: Schulz M

PROVIDER: S-EPMC7201985 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:IntroductionIn order to assess the significance of drug levels measured in intensive care medicine, clinical and forensic toxicology, as well as for therapeutic drug monitoring, it is essential that a comprehensive collection of data is readily available. Therefore, it makes sense to offer a carefully referenced compilation of therapeutic and toxic plasma concentration ranges, as well as half-lives, of a large number of drugs and other xenobiotics for quick and comprehensive information.MethodsData have been abstracted from original papers and text books, as well as from previous compilations, and have been completed with data collected in our own forensic and clinical toxicology laboratory. The data presented in the table and corresponding annotations have been developed over the past 20 years and longer. A previous compilation has been completely revised and updated. In addition, more than 170 substances, especially drugs that have been introduced to the market since 2003 as well as illegal drugs, which became known to cause intoxications, were added. All data were carefully referenced and more than 200 new references were included. Moreover, the annotations providing details were completely revised and more than 100 annotations were added.ResultsFor nearly 1,000 drugs and other xenobiotics, therapeutic ("normal") and, if data were available, toxic and comatose-fatal blood-plasma concentrations and elimination half-lives were compiled in a table.ConclusionsIn case of intoxications, the concentration of the ingested substances and/or metabolites in blood plasma better predicts the clinical severity of the case when compared to the assumed amount and time of ingestion. Comparing and contrasting the clinical case against the data provided, including the half-life, may support the decision for or against further intensive care. In addition, the data provided are useful for the therapeutic monitoring of pharmacotherapies, to facilitate the diagnostic assessment and monitoring of acute and chronic intoxications, and to support forensic and clinical expert opinions.

Project description:IntroductionEpigenetic marks have been proposed as early changes, at the subcellular level, in disease development. To find more specific biomarkers of effect in occupational exposures to toxicants, DNA methylation studies in peripheral blood cells have been performed. The goal of this review is to summarize and contrast findings about DNA methylation in blood cells from workers exposed to toxicants.MethodsA literature search was performed using PubMed and Web of Science. After first screening, we discarded all studies performed in vitro and in experimental animals, as well as those performed in other cell types other than peripheral blood cells. Results: 116 original research papers met the established criteria, published from 2007 to 2022. The most frequent investigated exposures/labor group were for benzene (18.9%) polycyclic aromatic hydrocarbons (15.5%), particulate matter (10.3%), lead (8.6%), pesticides (7.7%), radiation (4.3%), volatile organic compound mixtures (4.3%), welding fumes (3.4%) chromium (2.5%), toluene (2.5%), firefighters (2.5%), coal (1.7%), hairdressers (1.7%), nanoparticles (1.7%), vinyl chloride (1.7%), and others. Few longitudinal studies have been performed, as well as few of them have explored mitochondrial DNA methylation. Methylation platforms have evolved from analysis in repetitive elements (global methylation), gene-specific promoter methylation, to epigenome-wide studies. The most reported observations were global hypomethylation as well as promoter hypermethylation in exposed groups compared to controls, while methylation at DNA repair/oncogenes genes were the most studied; studies from genome-wide studies detect differentially methylated regions, which could be either hypo or hypermethylated.DiscussionSome evidence from longitudinal studies suggest that modifications observed in cross-sectional designs may be transitory; then, we cannot say that DNA methylation changes are predictive of disease development due to those exposures.ConclusionDue to the heterogeneity in the genes studied, and scarcity of longitudinal studies, we are far away from considering DNA methylation changes as biomarkers of effect in occupational exposures, and nor can we establish a clear functional or pathological correlate for those epigenetic modifications associated with the studied exposures.

Project description:Bacteria in the gut can modulate the availability and efficacy of therapeutic drugs. Interactions at this level have only recently started to being systematically mapped and the main underlying mechanism proposed is chemical transformation of drugs by microbes (biotransformation). Here, we investigated the depletion of 15 structurally diverse drugs by 25 representative gut bacterial strains. This revealed 70 bacteria-drug interactions, 29 of which had not been reported before.Over half of the new interactions can be ascribed to bioaccumulation, that is bacteria storing the drug without chemically modifying it, and in most cases without their growth being affected. As a case in point, we studied the molecular basis of bioaccumulation of the widely used antidepressant duloxetine by using click-chemistry, thermal proteome profiling and metabolomics. We find that duloxetine binds to several metabolic enzymes and changes metabolite secretion of the respective bacteria. When tested in a defined microbial community of accumulators and non-accumulators, duloxetine markedly altered the community composition through metabolic cross-feeding. We further validated our findings in an animal model, showing that bioaccumulating bacteria attenuate the behavioral response of Caenorhabditis elegans to duloxetine.Taken together, bioaccumulation by gut bacteria might be a common mechanism that alters drug availability and bacterial metabolism, with implications for microbiota composition, pharmacokinetics, side effects and drug responses, likely in an individual manner. Linked studies;UPLC-MS/MS assays of Bifidobacterium animalis subsp. lactis are reported in <a href='https://www.ebi.ac.uk/metabolights/MTBLS1264' rel='noopener noreferrer' target='_blank'>MTBLS1264</a>.UPLC-MS/MS assays of Escherichia coli ED1a, Clostridium saccharolyticum, Escherichia coli IAI1, Streptococcus salivarius, Eubacterium rectale, Lactobacillus plantarum WCFS1 and Lactococcus lactis subsp. lactis Il1403 are reported in <a href='https://www.ebi.ac.uk/metabolights/MTBLS1627' rel='noopener noreferrer' target='_blank'>MTBLS1627</a>.UPLC-MS/MS assay of Bacteroides uniformis and Clostridium saccharolyticum is reported in <a href='https://www.ebi.ac.uk/metabolights/MTBLS1757' rel='noopener noreferrer' target='_blank'>MTBLS1757</a>.UPLC-MS/MS assay of Clostridium saccharolyticum, Escherichia coli ED1a, Escherichia coli IAI1, Lactobacillus plantarum WCFS1, Lactococcus lactis subsp. lactis Il1403 and Streptococcus salivarius is reported in <a href='https://www.ebi.ac.uk/metabolights/MTBLS1791' rel='noopener noreferrer' target='_blank'>MTBLS1791</a>.UPLC-MS/MS assay of Eubacterium rectale and Streptococcus salivarius is reported in <a href='https://www.ebi.ac.uk/metabolights/MTBLS1792' rel='noopener noreferrer' target='_blank'>MTBLS1792</a>.UPLC-MS/MS assay of Lacrimispora saccharolytica and standards is reported in <a href='https://www.ebi.ac.uk/metabolights/MTBLS2885' rel='noopener noreferrer' target='_blank'>MTBLS2885</a>.

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Revisited: Therapeutic and toxic blood concentrations of more than 1100 drugs and other xenobiotics.

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