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Julian A Michely, Sascha K Manier, Achim T Caspar, Simon D Brandt, Jason Wallach, Hans H Maurer
3-Methoxyphencyclidine (3-MeO-PCP) and 3-methoxyrolicyclidine (3-MeO-PCPy) are two new psychoactive substances (NPS). The aims of the present study were the elucidation of their metabolic fate in rat and pooled human liver microsomes (pHLM), the identification of the cytochrome P450 (CYP) isoenzymes involved, and the detectability using standard urine screening approaches (SUSA) after intake of common users' doses using gas chromatography-mass spectrometry (GC-MS), liquid chromatography-multi-stage mass spectrometry (LC-MSn), and liquid chromatography-high-resolution tandem mass spectrometry (LC-HR-MS/MS)...
October 18, 2016: Current Neuropharmacology
Daisuke Mayumi, Hanako Mochimaru, Hideyuki Tamaki, Kyosuke Yamamoto, Hideyoshi Yoshioka, Yuichiro Suzuki, Yoichi Kamagata, Susumu Sakata
Coal-bed methane is one of the largest unconventional natural gas resources. Although microbial activity may greatly contribute to coal-bed methane formation, it is unclear whether the complex aromatic organic compounds present in coal can be used for methanogenesis. We show that deep subsurface-derived Methermicoccus methanogens can produce methane from more than 30 types of methoxylated aromatic compounds (MACs) as well as from coals containing MACs. In contrast to known methanogenesis pathways involving one- and two-carbon compounds, this "methoxydotrophic" mode of methanogenesis couples O-demethylation, CO2 reduction, and possibly acetyl-coenzyme A metabolism...
October 14, 2016: Science
Stéphanie Romand, Dany Spaggiari, Niloufar Marsousi, Caroline Samer, Jules Desmeules, Youssef Daali, Serge Rudaz
The hepatic metabolism of oxycodone by cytochromes P450 (CYP) and the UDP-glucuronosyltransferases (UGT), the main metabolic enzymes of phase I and phase II, respectively, was assessed in vitro. The N-demethylation by CYP3A4/5 and the O-demethylation by CYP2D6 in human liver microsomes (HLM) followed Michaelis-Menten kinetics, with intrinsic clearances of 1.46μL/min/mg and 0.35μL/min/mg, respectively. Although noroxycodone and oxymorphone mainly contribute to the elimination of oxycodone, the simulated total in vivo clearance using in vitro phase I metabolism was underestimated...
September 26, 2016: Journal of Pharmaceutical and Biomedical Analysis
Lucas M M Marques, Daniel R Callejon, Larissa G Pinto, Michel L de Campos, Anderson R M de Oliveira, Ricardo Vessecchi, Achyut Adhikari, Ram L S Shrestha, Rosangela G Peccinini, Norberto P Lopes
Govaniadine (GOV) is an alkaloid isolated from Corydalis govaniana Wall. It has been reported to show a different number of biological activities including anti-urease, leishmanicidal and antinociceptive. The present study aims to characterize the GOV in vitro metabolism after incubation with rat and human liver microsomes (RLM and HLM, respectively) and to evaluate its pharmacokinetic properties. The identification of GOV metabolites was conducted by different mass analyzers: a micrOTOF II-ESI-ToF Bruker Daltonics(®) and an amaZon-SL ion trap (IT) Bruker Daltonics(®)...
November 30, 2016: Journal of Pharmaceutical and Biomedical Analysis
Gerhard Bringmann, Raina Seupel, Doris Feineis, Guoliang Zhang, Minjuan Xu, Jun Wu, Marcel Kaiser, Reto Brun, Ean-Jeong Seo, Thomas Efferth
From the twigs and stems of the Chinese liana Ancistrocladus tectorius (Ancistrocladaceae), two new 5,8'-coupled naphthylisoquinolines, ancistectorine D (5) and its 6-O-demethyl derivative 6, were isolated, along with two new 7,1'-linked alkaloids, 6-O-methylancistectorine B1 (7) and ancistectorine B2 (8). Two further compounds, ancistroealaine A (4) and 6-O-demethyl-8-O-methyl-7-epi-ancistrobrevine D (10), already known from related Asian and African Ancistrocladus species, were discovered for the first time in A...
September 19, 2016: Fitoterapia
Andrzej T Slominski, Igor Semak, Tobias W Fischer, Tae-Kang Kim, Konrad Kleszczyński, Ruediger Hardeland, Russel J Reiter
Melatonin is produced in almost all living taxa and is probaly 2-3 billion years old. Its pleiotropic activities are related to its local concentration that is secondary to its local synthesis, delivery from distant sites and metabolic or non-enzymatic consumption. This consumption generates metabolites through indolic, kynuric and cytochrome P450 (CYP) mediated hydroxylations and O-demethylation or non-enzymatic processes, with potentially diverse phenotypic effects. While melatonin acts through receptor dependent and independent mechanism, receptors for melatonin metabolites remain to be identified, while their receptor independent activities are well documented...
September 13, 2016: Experimental Dermatology
Hiroaki Kitagishi, Shun Kurosawa, Koji Kano
The intramolecular oxidation of ROCH3 to ROCH2 OH, where the latter compound spontaneously decomposed to ROH and HCHO, was observed during the reaction of the supramolecular complex (met-hemoCD3) with cumene hydroperoxide in aqueous solution. Met-hemoCD3 is composed of meso-tetrakis(4-sulfonatophenyl)porphinatoiron(III) (Fe(III) TPPS) and a per-O-methylated β-cyclodextrin dimer having an -OCH2 PyCH2 O- linker (Py=pyridine-3,5-diyl). The O=Fe(IV) TPPS complex was formed by the reaction of met-hemoCD3 with cumene hydroperoxide, and isolated by gel-filtration chromatography...
September 12, 2016: Chemistry, An Asian Journal
Jenni Viinamäki, Ilkka Ojanperä
There is a constant demand for the quantification of drug metabolites within post-mortem toxicology. Especially electrospray ionization-mass spectrometry techniques necessitate that calibration is carried out using primary reference standards due to the non-uniform ionization efficiency between parent drugs and their metabolites. As reference standards for metabolites are not readily available and their costs are high, alternative methods for immediate quantification are required. In this study, ultra-high performance liquid chromatography coupled with photodiode array detection and corona charged aerosol detection was utilized for the concurrent quantification of 23 drug metabolites using the corresponding parent drug for calibration...
October 2016: Forensic Science International
Carley R Corado, Daniel S McKemie, Heather K Knych
Dextromethorphan is an N-methyl-D-aspartate (NMDA) non-competitive antagonist commonly used in human medicine as an antitussive. Dextromethorphan is metabolized in humans by cytochrome P450 2D6 into dextrorphan, which is reported to be more potent than the parent compound. The goal of this study is to describe the metabolism of and determine the pharmacokinetics of dextromethorphan and its major metabolites following oral administration to horses. A total of 23 horses received a single oral dose of 2 mg/kg...
September 1, 2016: Drug Testing and Analysis
Rong Shi, Jiasheng Wu, Cong Meng, Bingliang Ma, Tianming Wang, Yuanyuan Li, Yueming Ma
The db/db mouse is one of the most popular animal models for type 2 diabetes mellitus, but changes in the activities of important P450s and UGTs are still not completely clear. This study was designed to investigate the alterations of major hepatic cytochrome P450s and UDP-glucuronyltransferase enzymes in db/db mice. Mouse liver microsomes (MLMs) were obtained from male db/db mice and their wild type littermates. After incubation of the substrates separately with MLMs, the samples were pooled and analysed by high-throughput liquid chromatography-tandem mass spectrometry system for the simultaneous study of nine phase I metabolic reactions and three glucuronidation conjugation reactions to determine the activity of the metabolic enzymes...
October 2016: Biopharmaceutics & Drug Disposition
J Zegarska, E Hryniewiecka, D Zochowska, E Samborowska, R Jazwiec, A Borowiec, W Tszyrsznic, A Chmura, S Nazarewski, M Dadlez, L Paczek
BACKGROUND: Tacrolimus (Tac) is one of the most commonly used immunosuppressive drugs after solid organ transplantation. Eight Tac metabolites have been described, but their clinical importance remains unclear. The aim of this study was quantification of the 2 major Tac metabolites, 13-O-demethyl (M-I) and 15-O-demethyl (M-III), in kidney transplant recipients and to link them with parameters of kidney and liver function, peripheral blood cell counts, and infection incidence. METHODS: In 81 kidney transplant recipients, concentrations of Tac, M-I, and M-III were measured with the use of liquid chromatography combined with tandem mass spectrometry (LC-MS-MS)...
June 2016: Transplantation Proceedings
Ariane Wohlfarth, Markus Roman, Mikael Andersson, Fredrik C Kugelberg, Xingxing Diao, Jeremy Carlier, Caroline Eriksson, Xiongyu Wu, Peter Konradsson, Martin Josefsson, Marilyn A Huestis, Robert Kronstrand
25C-NBOMe and 25I-NBOMe are potent hallucinogenic drugs that recently emerged as new psychoactive substances. To date, a few metabolism studies were conducted for 25I-NBOMe, whereas 25C-NBOMe metabolism data are scarce. Therefore, we investigated the metabolic profile of these compounds in human hepatocytes, an in vivo mouse model and authentic human urine samples from forensic cases. Cryopreserved human hepatocytes were incubated for 3 h with 10 μM 25C-NBOMe and 25I-NBOMe; samples were analyzed by liquid chromatography high-resolution mass spectrometry (LC-HRMS) on an Accucore C18 column with a Thermo QExactive; data analysis was performed with Compound Discoverer software (Thermo Scientific)...
July 23, 2016: Drug Testing and Analysis
Line Marie Nielsen, Niels Bjerre Holm, Sebastian Leth-Petersen, Jesper Langgaard Kristensen, Lars Olsen, Kristian Linnet
The dimethoxyphenyl-N-((2-methoxyphenyl)methyl)ethanamine (NBOMe) compounds are potent serotonin 5-HT2A receptor agonists and have recently been subject to recreational use due to their hallucinogenic effects. Use of NBOMe compounds has been known since 2011, and several non-fatal and fatal intoxication cases have been reported in the scientific literature. The aim of this study was to determine the importance of the different cytochrome P450 enzymes (CYP) involved in the metabolism of 2-(4-iodo-2,5-dimethoxyphenyl)-N-(2methoxybenzyl)ethanamine (25I-NBOMe) and 2-[[2-(4-iodo-2,5dimethoxyphenyl)ethylamino]methyl]phenol (25I-NBOH) and to characterize the metabolites...
July 12, 2016: Drug Testing and Analysis
Nadine Schaefer, Andreas G Helfer, Mattias Kettner, Matthias W Laschke, Julia Schlote, Andreas H Ewald, Markus R Meyer, Michael D Menger, Hans H Maurer, Peter H Schmidt
The knowledge of pharmacokinetic (PK) properties of synthetic cannabinoids (SCs) is important for interpretation of analytical results found for example in intoxicated individuals. In the absence of human data from controlled studies, animal models elucidating SC PK have to be established. Pigs providing large biofluid sample volumes were tested for prediction of human PK data. In this context, the metabolic fate of two model SCs, namely 4-ethylnaphthalen-1-yl-(1-pentylindol-3-yl)methanone (JWH-210) and 2-(4-methoxyphenyl)-1-(1-pentyl-indol-3-yl)methanone (RCS-4), was elucidated in addition to Δ(9) -tetrahydrocannabinol (THC)...
June 22, 2016: Drug Testing and Analysis
Ya-Jun Huang, Sa Xiao, Zhi-Liang Sun, Jian-Guo Zeng, Yi-Song Liu, Zhao-Ying Liu
RATIONALE: Allocryptopine (AL) and protopine (PR) have been extensively studied because of their anti-parasitic, anti-arrhythmic, anti-thrombotic, anti-inflammatory and anti-bacterial activity. However, limited information on the pharmacokinetics and metabolism of AL and PR has been reported. Therefore, the purpose of the present study was to investigate the in vitro metabolism of AL and PR in rat liver S9 using a rapid and accurate high-performance liquid chromatography/quadrupole-time-of-flight mass spectrometry (HPLC/QqTOFMS) method...
July 15, 2016: Rapid Communications in Mass Spectrometry: RCM
Xiange Tang, Xinyu Di, Zeyu Zhong, Qiushi Xie, Yang Chen, Fan Wang, Zhaoli Ling, Ping Xu, Kaijing Zhao, Zhongjian Wang, Li Liu, Xiaodong Liu
l-Corydalmine (l-CDL) was under development as an oral analgesic agent, exhibiting potent analgesic activity in preclinical models. The objective of this study was to compare metabolic profiles of l-CDL in liver microsomes from mouse, rat, monkey, dog and human. Six metabolites (M1-M6) were identified using LC-Q/TOF in liver microsomes from the five species. The metabolism of l-CDL included O-demethylation (M1-3) and hydroxylation (M4-6). The desmethyl metabolites were the major ones among the five species, which accounted for more than 84%...
September 5, 2016: Journal of Pharmaceutical and Biomedical Analysis
Hong-Xia Fan, Zheng-Qun Zhou, Jun Peng, Bao-Jian Wu, He-Ru Chen, Xue-Feng Bao, Zhen-Qiang Mu, Wei-Hua Jiao, Xin-Sheng Yao, Hao Gao
1. A filamentous fungus, Cunninghamella blakesleeana CGMCC 3.970, was applied as a microbial system to mimic mammalian metabolism of 4,5-dimethoxyl-canthin-6-one (1). Compound 1 belongs to canthin-6-one type alkaloids, which is a major bioactive constituent of a traditional Chinese medicine (the stems of Picrasma quassioides). 2. After 72 h of incubation in potato dextrose broth, 1 was metabolized to seven metabolites as follows: 4-methoxyl-5-hydroxyl-canthin-6-one (M1), 4-hydroxyl-5-methoxyl-canthin-6-one (M2), canthin-6-one (M3), canthin-6-one N-oxide (M4), 10-hydroxyl-4,5-dimethoxyl-canthin-6-one (M5), 1-methoxycarbonl-β-carboline (M6), and 4-methoxyl-5-O-β-D-glucopyranosyl-canthin-6-one (M7)...
May 30, 2016: Xenobiotica; the Fate of Foreign Compounds in Biological Systems
Shou-Peng Zhang, Rong Huang, Fang-Fang Li, Hong-Xia Wei, Xiao-Wei Fang, Xiao-Song Xie, Dong-Guo Lin, Shao-Hua Wu, Jian He
A new hydroanthraquinone derivative, 6-O-demethyl-4-dehydroxyaltersolanol A (1), and two new azaphilones, 8,11-didehydrochermesinone B (6) and (7S)-7-hydroxy-3,7-dimethyl-isochromene-6,8-dione (8), along with five known analogues (2-5 and 7), were isolated from the culture broth of Nigrospora sp. YE3033, an endophytic fungus obtained from Aconitum carmichaeli. Their structures were elucidated on the basis of spectroscopic analyses. Biological activity test indicated that compounds 1-3, and 7 exhibited the inhibitory effects on influenza viral strain of A/Puerto Rico/8/34 (H1N1) with the IC50 values of 2...
July 2016: Fitoterapia
Rasmus J N Frandsen, Silas A Rasmussen, Peter B Knudsen, Silvio Uhlig, Dirk Petersen, Erik Lysøe, Charlotte H Gotfredsen, Henriette Giese, Thomas O Larsen
Biosynthesis of the black perithecial pigment in the filamentous fungus Fusarium graminearum is dependent on the polyketide synthase PGL1 (oPKS3). A seven-membered PGL1 gene cluster was identified by over-expression of the cluster specific transcription factor pglR. Targeted gene replacement showed that PGL1, pglJ, pglM and pglV were essential for the production of the perithecial pigment. Over-expression of PGL1 resulted in the production of 6-O-demethyl-5-deoxybostrycoidin (1), 5-deoxybostrycoidin (2), and three novel compounds 5-deoxybostrycoidin anthrone (3), 6-O-demethyl-5-deoxybostrycoidin anthrone (4) and purpurfusarin (5)...
2016: Scientific Reports
Bünyamin Özgeriş, Süleyman Göksu, Leyla Polat Köse, İlhami Gülçin, Ramin Ekhteiari Salmas, Serdar Durdagi, Ferhan Tümer, Claudiu T Supuran
In the present study a series of urea and sulfamide compounds incorporating the tetralin scaffolds were synthesized and evaluated for their acetylcholinesterase (AChE), human carbonic anhydrase (CA, EC isoenzyme I, and II (hCA I and hCA II) inhibitory properties. The urea and their sulfamide analogs were synthesized from the reactions of 2-aminotetralins with N,N-dimethylcarbamoyl chloride and N,N-dimethylsulfamoyl chloride, followed by conversion to the corresponding phenols via O-demethylation with BBr3...
May 15, 2016: Bioorganic & Medicinal Chemistry
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