scholarly journals 2C-B-Fly-NBOMe Metabolites in Rat Urine, Human Liver Microsomes and C. elegans: Confirmation with Synthesized Analytical Standards

Metabolites ◽  
2021 ◽  
Vol 11 (11) ◽  
pp. 775
Author(s):  
Jitka Nykodemová ◽  
Anna Šuláková ◽  
Petr Palivec ◽  
Hedvika Češková ◽  
Silvie Rimpelová ◽  
...  
Keyword(s):  
Phase I ◽  
Human Liver ◽  
Liver Microsomes ◽  
Human Liver Microsomes ◽  
Diagnostic Tools ◽  
Cunninghamella Elegans ◽  
Rat Urine ◽  
C Elegans ◽  
Fragmentation Patterns

Compounds from the N-benzylphenethylamine (NBPEA) class of novel psychoactive substances are being increasingly utilized in neurobiological and clinical research, as diagnostic tools, or for recreational purposes. To understand the pharmacology, safety, or potential toxicity of these substances, elucidating their metabolic fate is therefore of the utmost interest. Several studies on NBPEA metabolism have emerged, but scarce information about substances with a tetrahydrobenzodifuran (“Fly”) moiety is available. Here, we investigated the metabolism of 2-(8-bromo-2,3,6,7-tetrahydrobenzo[1,2-b:4,5-b’]difuran-4-yl)-N-(2-methoxybenzyl)ethan-1-amine (2C-B-Fly-NBOMe) in three different systems: isolated human liver microsomes, Cunninghamella elegans mycelium, and in rats in vivo. Phase I and II metabolites of 2C-B-Fly-NBOMe were first detected in an untargeted screening and identified by liquid chromatography–tandem mass spectrometry (LC–MS/MS). Several hypothesized metabolites were then synthesized as reference standards; knowledge of their fragmentation patterns was utilized for confirmation or tentative identification of isomers. Altogether, thirty-five phase I and nine phase II 2C-B-Fly-NBOMe metabolites were detected. Major detected metabolic pathways were mono- and poly-hydroxylation, O-demethylation, oxidative debromination, and to a lesser extent also N-demethoxybenzylation, followed by glucuronidation and/or N-acetylation. Differences were observed for the three used media. The highest number of metabolites and at highest concentration were found in human liver microsomes. In vivo metabolites detected from rat urine included two poly-hydroxylated metabolites found only in this media. Mycelium matrix contained several dehydrogenated, N-oxygenated, and dibrominated metabolites.

scholarly journals 25CN-NBOMe Metabolites in Rat Urine, Human Liver Microsomes and C.elegans—Structure Determination and Synthesis of the Most Abundant Metabolites

Metabolites ◽  
2021 ◽  
Vol 11 (4) ◽  
pp. 212
Author(s):  
Anna Šuláková ◽  
Jitka Nykodemová ◽  
Petr Palivec ◽  
Radek Jurok ◽  
Silvie Rimpelová ◽  
...  
Keyword(s):  
Human Liver ◽  
Liver Microsomes ◽  
Human Liver Microsomes ◽  
Cunninghamella Elegans ◽  
Rat Urine ◽  
C Elegans ◽  
Liquid Chromatography Tandem Mass ◽  
Phase Ii Metabolites

N-Benzylphenethylamines are novel psychedelic substances increasingly used for research, diagnostic, or recreational purposes. To date, only a few metabolism studies have been conducted for N-2-methoxybenzylated compounds (NBOMes). Thus, the available 2,5-dimethoxy-4-(2-((2-methoxybenzyl)amino)ethyl)benzonitrile (25CN-NBOMe) metabolism data are limited. Herein, we investigated the metabolic profile of 25CN-NBOMe in vivo in rats and in vitro in Cunninghamella elegans (C. elegans) mycelium and human liver microsomes. Phase I and phase II metabolites were first detected in an untargeted screening, followed by liquid chromatography-tandem mass spectrometry (LC-MS/MS) identification of the most abundant metabolites by comparison with in-house synthesized reference materials. The major metabolic pathways described within this study (mono- and bis-O-demethylation, hydroxylation at different positions, and combinations thereof, followed by the glucuronidation, sulfation, and/or N-acetylation of primary metabolites) generally correspond to the results of previously reported metabolism of several other NBOMes. The cyano functional group was either hydrolyzed to the respective amide or carboxylic acid or remained untouched. Differences between species should be taken into account in studies of the metabolism of novel substances.

Predictions of the In Vivo Clearance of Drugs from Rate of Loss Using Human Liver Microsomes for Phase I and Phase II Biotransformations

2006 ◽  
Vol 23 (4) ◽  
pp. 654-662 ◽  
Author(s):  
Michael A. Mohutsky ◽  
Jenny Y. Chien ◽  
Barbara J. Ring ◽  
Steven A. Wrighton
Keyword(s):  
Phase I ◽  
Phase Ii ◽  
Human Liver ◽  
Liver Microsomes ◽  
Human Liver Microsomes

scholarly journals Characterization of CYPs and UGTs Involved in Human Liver Microsomal Metabolism of Osthenol

Pharmaceutics ◽  
2018 ◽  
Vol 10 (3) ◽  
pp. 141 ◽  
Author(s):  
Pil Cho ◽  
Sanjita Paudel ◽  
Doohyun Lee ◽  
Yun Jin ◽  
GeunHyung Jo ◽  
...  
Keyword(s):  
Metabolic Pathway ◽  
Human Liver ◽  
Liver Microsomes ◽  
Nicotinamide Adenine Dinucleotide Phosphate ◽  
Human Liver Microsomes ◽  
Rat Urine ◽  
Human Cytochrome ◽  
Orbitrap Mass Spectrometer ◽  
Metabolic Products

Osthenol is a prenylated coumarin isolated from the root of Angelica koreana and Angelica dahurica, and is an O-demethylated metabolite of osthole in vivo. Its various pharmacological effects have been reported previously. The metabolic pathway of osthenol was partially confirmed in rat osthole studies, and 11 metabolic products were identified in rat urine. However, the metabolic pathway of osthenol in human liver microsomes (HLM) has not been reported. In this study, we elucidated the structure of generated metabolites using a high-resolution quadrupole-orbitrap mass spectrometer (HR-MS/MS) and characterized the major human cytochrome P450 (CYP) and uridine 5′-diphospho-glucuronosyltransferase (UGT) isozymes involved in osthenol metabolism in human liver microsomes (HLMs). We identified seven metabolites (M1-M7) in HLMs after incubation in the presence of nicotinamide adenine dinucleotide phosphate (NADPH) and uridine 5′-diphosphoglucuronic acid (UDPGA). As a result, we demonstrated that osthenol is metabolized to five mono-hydroxyl metabolites (M1-M5) by CYP2D6, 1A2, and 3A4, respectively, a 7-O-glucuronide conjugate (M6) by UGT1A9, and a hydroxyl-glucuronide (M7) from M5 by UGT1A3 in HLMs. We also found that glucuronidation is the dominant metabolic pathway of osthenol in HLMs.

scholarly journals Effect of a New Prokinetic Agent DA-9701 Formulated with Corydalis Tuber and Pharbitidis Semen on Cytochrome P450 and UDP-Glucuronosyltransferase Enzyme Activities in Human Liver Microsomes

2012 ◽  
Vol 2012 ◽  
pp. 1-7 ◽  
Author(s):  
Hye Young Ji ◽  
Kwang Hyeon Liu ◽  
Ji Hyeon Jeong ◽  
Dae-Young Lee ◽  
Hyun Joo Shim ◽  
...  
Keyword(s):  
Cytochrome P450 ◽  
Human Liver ◽  
Liver Microsomes ◽  
Human Liver Microsomes ◽  
Udp Glucuronosyltransferase ◽  
Index Value ◽  
Tuber Extract ◽  
Corydalis Tuber

DA-9701 is a new botanical drug composed of the extracts of Corydalis tuber and Pharbitidis semen, and it is used as an oral therapy for the treatment of functional dyspepsia in Korea. The inhibitory potentials of DA-9701 and its component herbs, Corydalis tuber and Pharbitidis semen, on the activities of seven major human cytochrome P450 (CYP) enzymes and four UDP-glucuronosyltransferase (UGT) enzymes in human liver microsomes were investigated using liquid chromatography-tandem mass spectrometry. DA-9701 and Corydalis tuber extract slightly inhibited UGT1A1-mediated etoposide glucuronidation, with 50% inhibitory concentration (IC50) values of 188 and 290 μg/mL, respectively. DA-9701 inhibited CYP2D6-catalyzed bufuralol1′-hydroxylation with an inhibition constant (Ki) value of 6.3 μg/mL in a noncompetitive manner. Corydalis tuber extract competitively inhibited CYP2D6-mediated bufuralol1′-hydroxylation, with aKivalue of 3.7 μg/mL, whereas Pharbitidis semen extract showed no inhibition. The volume in which the dose could be diluted to generate an IC50equivalent concentration (volume per dose index) value of DA-9701 for inhibition of CYP2D6 activity was 1.16 L/dose, indicating that DA-9701 may not be a potent CYP2D6 inhibitor. Further clinical studies are warranted to evaluate thein vivoextent of the observedin vitrointeractions.

Metabolism of 4,4′-methylene-bis-2-chloroaniline (MOCA) by rats in vivo and formation of N-hydroxy MOCA by rat and human liver microsomes

1988 ◽  
Vol 9 (5) ◽  
pp. 731-739 ◽  
Author(s):  
Kenneth C. Morton ◽  
Mei-Sie Lee ◽  
Paul Siedlik ◽  
Robert Chapman
Keyword(s):  
Human Liver ◽  
Liver Microsomes ◽  
Human Liver Microsomes

scholarly journals CYP-Dependent Metabolism of PF9601N, A New Monoamine Oxidase-B Inhibitor, by C57BL / 6 Mouse and Human Liver Microsomes

2007 ◽  
Vol 10 (4) ◽  
pp. 473 ◽  
Author(s):  
Stefania Dragoni ◽  
Giada Materozzi ◽  
Federica Pessina ◽  
Maria Frosini ◽  
José Luis Marco ◽  
...  
Keyword(s):  
Monoamine Oxidase ◽  
Human Liver ◽  
Formation Rate ◽  
Antioxidant Properties ◽  
Liver Microsomes ◽  
Intrinsic Clearance ◽  
Human Liver Microsomes ◽  
Monoamine Oxidase B ◽  
Mao B

Purpose. The selective monoamine oxidase-B (MAO-B) inhibitor, l-deprenyl, is still used for treating Parkinson's patients, however, a disadvantage of its use lies in the formation of l-amphetamine and l-methamphetamine. Subsequently, this has promoted the design of a novel, more potent, MAO-B inhibitor PF9601N, which also has neuroprotective and antioxidant properties. The aim of this work was to investigate the effect of treatment with PF9601N on its own phase I hepatic metabolism. Kinetic parameters of PF9601N CYP-dependent N-dealkylation reaction was also studied and compared with those of l-deprenyl. Methods. C57BL/6 mice were treated with PF9601N for 4 days. After CYP content and related monooxygenase activities were assayed in liver microsomes of control and treated animals. Results. CYP activities, cytochrome b5 content, NADPH-cytochrome P450 reductase and various monooxygenase activities were unaffected by in vivo PF9601N treatment. With microsomes from both control and treated mice, the PF9601N-dealkylation product, FA72, was the only detected metabolite with its formation rate following an hyperbolic, Michaelis-Menten curve. Among various inhibitors, only ketoconazole inhibited the FA72 formation rate, indicating a major involvement for CYP3A. Apparent Km and Vmax values generated by human liver microsomes were similar to those found with mouse microsomes. Ketoconazole inhibition indicates that CYP3A is one of the major enzymes involved in PF9601N metabolism also by human liver microsomes. In mouse liver microsomes, the intrinsic clearance of PF9601N was significantly lower than that of l-deprenyl suggestive of an improved bioavailability for the former. Conclusion. The observed favourable metabolic profile may suggest suitability of PF9601N for clinical use.

Major Phase I Biotransformation Pathways of Trichostatin A in Rat Hepatocytes and in Rat and Human Liver Microsomes

2002 ◽  
Vol 30 (12) ◽  
pp. 1320-1328 ◽  
Author(s):  
G. Elaut ◽  
G. Török ◽  
M. Vinken ◽  
G. Laus ◽  
P. Papeleu ◽  
...  
Keyword(s):  
Phase I ◽  
Human Liver ◽  
Trichostatin A ◽  
Liver Microsomes ◽  
Rat Hepatocytes ◽  
Human Liver Microsomes ◽  
Major Phase

Rapid identification of MDMB-CHMINACA metabolites using Zebrafish and Human Liver microsomes as the Biotransformation system by LC-QE-HF-MS

2020 ◽  
Author(s):  
Duo-qi Xu ◽  
Yong Dai ◽  
Wen-fang Zhang ◽  
Ji-fen Wang ◽  
Yan-yan Wang ◽  
...  
Keyword(s):  
Animal Model ◽  
Human Liver ◽  
Mass Measurement ◽  
Liver Microsomes ◽  
Rapid Identification ◽  
Human Liver Microsomes ◽  
Designer Drugs ◽  
Published Data

Abstract MDMB-CHMINACA is a newly synthetic cannabinoid which scoped in NMS Lab, USA. Since there are currently no published data on MDMB-CHMINACA metabolism, we aimed to identify its biotransformation pathways and major metabolites. Liquid chromatography Q-Extractive HF Hybrid Quadrupole-Orbitrap mass spectrometry (LC-QE-HF-MS) using full scan positive ion mode and targeted MS/MS (ddms2) techniques with accurate mass measurement were employed to analyze the metabolic sites and pathways. An in vivo metabolic animal model of zebrafish was established to verify the metabolic pathways of MDMB-CHMINACA obtained from human liver microsomal experiment in vitro. The results showed that 29 metabolites were generated in the zebrafish animal model and human liver microsomes model. Biotransformations mainly occurred at the cyclohexylmethyl tail of the compound, minor reactions also occurred at the tert-butyl chain, and no reaction was analysised at the indazole ring. We recommend M1 group (MDMB-CHMINACA ester hydroxylation), and M2 group (MDMB-CHMINACA monohydroxylation) as the potential poisoning markers to document MDMB-CHMINACA intake in clinical and forensic cases. Additionally, this study provides preliminary information regarding the metabolism of MDMB-CHMINACA that will guide analytical standard manufacturers to better provide suitable references for further studies on newly encountered designer drugs.

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