Functional Group Biotransformations

Obach, R. Scott

doi:10.1002/9781118541203.xen0003

Cited by 3 publications

(6 citation statements)

References 74 publications

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“…For ketoconazole only one imidazole ring oxidation product was observed (KET_M565). These results also fit within expectations since the imidazole ring cleavage is known to be initiated by formation of an epoxide, , which is not possible for triazoles due to a lack of two adjacent carbon atoms in the triazole ring (see Figure ). In the case of triazoles, ring hydroxylation (for CP, EP, and TEB) represented the only change occurring at the active moiety.…”

Section: Resultssupporting

confidence: 87%

“…BTPs were formed without delay, i.e., no chronology of formation was observed, which would have assisted in pathway elucidation. We propose the biotransformation pathway of prochloraz depicted in Figure based on common drug biotransformation reactions, metabolic logic, and known reactions occurring at the imidazole ring. , The cascade of reactions taking place at the imidazole ring is described to start via an epoxide formation at the double bond between C4–C5. The proposed pathway was reviewed by model calibration and by profiling likelihoods to calculate robust confidence intervals for each parameter.…”

Section: Resultsmentioning

confidence: 99%

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How Biotransformation Influences Toxicokinetics of Azole Fungicides in the Aquatic Invertebrate Gammarus pulex

Rösch

Anliker

Hollender

2016

Environ. Sci. Technol.

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Biotransformation is a key process that can greatly influence the bioaccumulation potential and toxicity of organic compounds. In this study, biotransformation of seven frequently used azole fungicides (triazoles: cyproconazole, epoxiconazole, fluconazole, propiconazole, tebuconazole and imidazoles: ketoconazole, prochloraz) was investigated in the aquatic invertebrate Gammarus pulex in a 24 h exposure experiment. Additionally, temporal trends of the whole body internal concentrations of epoxiconazole, prochloraz, and their respective biotransformation products (BTPs) were studied to gain insight into toxicokinetic processes such as uptake, elimination and biotransformation. By the use of high resolution tandem mass spectrometry in total 37 BTPs were identified. Between one (ketoconazole) and six (epoxiconazole) BTPs were identified per parent compound except for prochloraz, which showed extensive biotransformation reactions with 18 BTPs detected that were mainly formed through ring cleavage or ring loss. In general, most BTPs were formed by oxidation and conjugation reactions. Ring loss or ring cleavage was only observed for the imidazoles as expected from the general mechanism of oxidative ring openings of imidazoles, likely affecting the bioactivity of these BTPs. Overall, internal concentrations of BTPs were up to 3 orders of magnitude lower than that of the corresponding parent compound. Thus, biotransformation did not dominate toxicokinetics and only played a minor role in elimination of the respective parent compound, with the exception of prochloraz.

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Section: Resultssupporting

confidence: 87%

Section: Resultsmentioning

confidence: 99%

How Biotransformation Influences Toxicokinetics of Azole Fungicides in the Aquatic Invertebrate Gammarus pulex

Rösch

Anliker

Hollender

2016

Environ. Sci. Technol.

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“…These include conjugation with glucuronic acid, glycine, glutamine, acyl coenzyme A and glutathione. The conjugation of carboxylic acids with glucuronic acid is a very common drug metabolism reaction (Obach, ). Acyl glucuronide metabolites have unique intrinsic properties that can make them of significant concern from a toxicological perspective.…”

Section: Acyl Glucuronidesmentioning

confidence: 99%

“…The primary organ for drug metabolism in the body is the liver. Metabolism in the liver occurs in two stages: phase I metabolism and Phase ii metabolism (Obach, ). In Phase I metabolism, enzymes such as cytochrome P450 oxidases introduce reactive or polar groups into xenobiotics.…”

Section: Introductionmentioning

confidence: 99%

“…Various enzymes catalyze the phase II biotransformation reactions. Specially, phase II conjugation reactions are catalyzed by uridine diphospho (UDP) glucuronosyltransferases (UGT), sulfotransferases, acetyl transferases, glutathione transferases, methyl transferases and aminoacyltransferases (Obach, ). The transferases that mediate phase II reactions are important not only for eliminating drugs but also for detoxifying reactive drug metabolites, which are mostly produced by phase I metabolism by cytochrome P450 enzymes (Leucuta & Vlase, ).…”

Section: Introductionmentioning

confidence: 99%

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Bioanalytical challenges and strategies for accurately measuring acyl glucuronide metabolites in biological fluids

Patel

2019

Biomedical Chromatography

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Bioanalysis of unstable compounds such as acyl glucuronide metabolites represents a great analytical challenge owing to poor analyte stability in biological matrices. The primary goal for bioanalytical assay development is to minimize the breakdown of acyl glucuronide metabolite into its parent aglycone during sample collection, transportation, storage and analysis. Samples need to be stabilized ex vivo immediately after sample collection to minimize potential breakdown and thus to ensure accurate concentration measurement of both acyl glucuronide metabolite and its parent aglycone. In this review paper, formation of acyl glucuronide metabolites, the importance of establishing acyl glucuronide exposure measurement and safety coverage, optimization of sample pretreatment to stabilize the acyl glucuronide metabolites, current analytical strategy of assaying them as well as considerations for regulatory filings are discussed. It is important to identify acyl glucuronide metabolites that are capable of undergoing hydrolysis and pH‐dependent intra‐molecular migration as well as covalently binding to plasma and tissue proteins which can cause toxicity in vivo in the early stages of drug development. Carefully planning analytical experiments, identifying structures of acyl glucuronides and monitoring their concentrations in early drug development can help assess the risks associated with their exposures and potentially predict their concentrations in human circulation.

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In Silico Toxicity of Anthocyanin Compounds (Cyanidin and Peonidin)

Susanti

Wisesa

Juwianti

2023

JPSA

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Backgrounds: Cyanidin and peonidin, anthocyanin compounds, have many in silico, in vitro, and in vivo activities, including antioxidant, anticancer, antihyperlipidemic, and antidiabetic. Toxicity testing is carried out to determine the potential hazard that may be produced by the test compound. Objective: This study was aimed to determine the in silico toxicity of anthocyanins (cyanidin and peonidin) using Toxtree v3.1.0 software. Methods: In silico toxicity testing was carried out using 2D structures of cyanidin and peonidin with Cramer rules, Verhaar scheme, Benigni/Bossa rulebase, Kroes TTC decision tree, Eye Irritation/Corrosion and Skin Irritation/Corrosion parameters. Data analysis on the results of the tested toxicity parameters was carried out descriptively. Results: The results showed that the two compounds have the same category for the toxicity parameters of Cramer Rules (class III), Kroes TTC Decision Tree (substance would not be expected to be safety concern), Benigni/Bossa Rulebase (Negatif for genotoxic and nongenotoxic carcinogenicity), Eye Irritation/Corrosion and Skin Irritation/Corrosion (not irritating or corrosive). Different results are shown in the parameters of the Verhaar Scheme, where cyanidin is included in class 5 (cannot be classified based on this parameter), while peonidin is included in class 1 (narcosis or basic toxicity). Conclusion: Based on in silico toxicity, cyanidin and peonidin have a chemical structure that has the potential for toxicity, but these compounds are neither potentially genotoxic nor non-genotoxic carcinogenicity, and are not potentially toxic to the skin and eyes. The toxicity mechanism of cyanidin cannot be classified based on the test parameters while peonidin is narcosis or basic toxicity.Keywords: Anthocyanin; Cyanidin; Peonidin; Toxicity; In Silico

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Functional Group Biotransformations

Cited by 3 publications

References 74 publications

How Biotransformation Influences Toxicokinetics of Azole Fungicides in the Aquatic Invertebrate Gammarus pulex

How Biotransformation Influences Toxicokinetics of Azole Fungicides in the Aquatic Invertebrate Gammarus pulex

Bioanalytical challenges and strategies for accurately measuring acyl glucuronide metabolites in biological fluids

In Silico Toxicity of Anthocyanin Compounds (Cyanidin and Peonidin)

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