scholarly journals Tetrahydrofurofuranoid Lignans, Eudesmin, Fargesin, Epimagnolin A, Magnolin, and Yangambin Inhibit UDP-Glucuronosyltransferase 1A1 and 1A3 Activities in Human Liver Microsomes

Pharmaceutics ◽  
2021 ◽  
Vol 13 (2) ◽  
pp. 187
Author(s):  
Ria Park ◽  
Eun Jeong Park ◽  
Yong-Yeon Cho ◽  
Joo Young Lee ◽  
Han Chang Kang ◽  
...  
Keyword(s):  
Human Liver ◽  
Liver Microsomes ◽  
Human Liver Microsomes ◽  
Tandem Mass ◽  
Pharmacological Activities ◽  
Chromatography Tandem Mass Spectrometry ◽  
Liquid Chromatography Tandem Mass ◽  
Inhibition Potencies

Eudesmin, fargesin, epimagnolin A, magnolin, and yangambin are tetrahydrofurofuranoid lignans with various pharmacological activities found in Magnoliae Flos. The inhibition potencies of eudesmin, fargesin, epimagnolin A, magnolin, and yangambin on six major human uridine 5′-diphospho-glucuronosyltransferase (UGT) activities in human liver microsomes were evaluated using liquid chromatography–tandem mass spectrometry and cocktail substrates. Eudesmin, fargesin, epimagnolin A, magnolin, and yangambin inhibited UGT1A1 and UGT1A3 activities, but showed negligible inhibition of UGT1A4, UGT16, UGT1A9, and UGT2B7 activities at 200 μM in pooled human liver microsomes. Moreover, eudesmin, fargesin, epimagnolin A, magnolin, and yangambin noncompetitively inhibited UGT1A1-catalyzed SN38 glucuronidation with Ki values of 25.7, 25.3, 3.6, 26.0, and 17.1 μM, respectively, based on kinetic analysis of UGT1A1 inhibition in pooled human liver microsomes. Conversely, the aforementioned tetrahydrofurofuranoid lignans competitively inhibited UGT1A3-catalyzed chenodeoxycholic acid 24-acyl-glucuronidation with 39.8, 24.3, 15.1, 37.6, and 66.8 μM, respectively in pooled human liver microsomes. These in vitro results suggest the necessity of evaluating whether the five tetrahydrofurofuranoid lignans can cause drug–drug interactions with UGT1A1 and UGT1A3 substrates in vivo.

scholarly journals Reactive intermediates in naquotinib metabolism identified by liquid chromatography-tandem mass spectrometry: phase I metabolic profiling

RSC Advances ◽  
2019 ◽  
Vol 9 (18) ◽  
pp. 10211-10225 ◽  
Author(s):  
Mohamed W. Attwa ◽  
Adnan A. Kadi ◽  
Haitham AlRabiah ◽  
Hany W. Darwish
Keyword(s):  
Mass Spectrometry ◽  
Liquid Chromatography ◽  
Metabolic Profiling ◽  
Human Liver ◽  
Liver Microsomes ◽  
Reactive Intermediates ◽  
Tandem Mass ◽  
Chromatography Tandem Mass Spectrometry ◽  
Liquid Chromatography Tandem Mass

LC-MS/MS was used to screen for in vitro metabolites of NQT formed during incubation with human liver microsomes (HLMs) and then evaluated the generation of reactive electrophiles using capturing agents.

Differences and Similarities in the Metabolism of Erlotinib across various Species: An Analysis by Liquid Chromatography - Tandem Mass Spectrometry

2021 ◽  
pp. 5683-5690
Author(s):  
Laxman D. Khatal ◽  
Harinath N. More
Keyword(s):  
Mass Spectrometry ◽  
Liquid Chromatography ◽  
Phase I ◽  
Human Liver ◽  
Liver Microsomes ◽  
Human Liver Microsomes ◽  
Tandem Mass ◽  
Chromatography Tandem Mass Spectrometry ◽  
Liquid Chromatography Tandem Mass ◽  
S9 Fraction

Erlotinib is an inhibitor of the epidermal growth factor receptor (EGFR), primarily used to treat non-small cell lung cancer (NSCLC) or pancreatic cancer. The main objective of the present study was to identify differences and similarities in the metabolism of erlotinib across various species and to identify new phase I metabolites. Metabolic characteristics of erlotinib were investigated in liver microsomes of human, mice, rat, dog, hamster, and S9-fraction of mice by liquid chromatography-tandem mass spectrometry (LC-MS/MS). A total of 19 phase I metabolites were detected in human liver microsomes; whereas, 12 metabolites in each of mice-, rat- liver microsomes and S9-fraction of mice; 10 in dog liver microsomes and 7 in hamster liver microsomes were detected. Out of these 19 metabolites, 8 metabolites were newly found including 1- novel metabolite (M23) which was identified with its putative structure in human liver microsomes. All phase I metabolites reported in healthy human volunteers were identified in human liver microsomes. Similar metabolic behavior had shown by liver microsomes of mice, rat, and S9-fraction of mice. Metabolites M6, M13, M14, M16, M22, and M25 were found in all tested species. These differences and similarities in the metabolism of erlotinib confirmed the role of CYP 450 enzymes and their distinct activity across various species.

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.

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