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https://www.readbyqxmd.com/read/28073119/in-vitro-inhibition-of-human-cyp450s-1a2-2c9-3a4-5-2d6-and-2e1-by-grandisin
#1
Maísa Daniela Habenschus, Fernanda de Lima Moreira, Norberto Peporine Lopes, Anderson R M de Oliveira
Grandisin, a lignan isolated from many species of plants, such as Virola surinamensis, is a potential drug candidate due to its biological properties, highlighted by its antitumor and trypanocidal activities. In this study, the inhibitory effects of grandisin on the activities of human cytochrome P450 enzymes were investigated by using human liver microsomes. Results showed that grandisin is a competitive inhibitor of CYP2C9 and a competitive and mechanism-based inhibitor of CYP3A4/5. The apparent Ki value for CYP2C9 was 50...
January 10, 2017: Planta Medica
https://www.readbyqxmd.com/read/28058783/characterization-of-phase-i-and-phase-ii-hepatic-metabolism-and-reactive-intermediates-of-larrea-nitida-cav-and-its-lignan-compounds
#2
Hyesoo Jeong, Soolin Kim, Jimin Lee, Jin Young Park, Wenmei Zhou, Xiyuan Liu, So Dam Kim, Yun Seon Song, Chang-Young Jang, Sei-Ryang Oh, Sangho Choi, Minsun Chang
Larrea nitida Cav. (LNC), which belongs to the family Zygophyllaceae, is widely indigenous and used in South America to treat various pathological conditions. It contains the antioxidant and antiinflammatory but toxic nordihydroguaiaretic acid (NDGA) as well as O-methylated metabolite of NDGA (MNDGA) as bioactive compounds. The hepatic metabolism-based toxicological potential of extracts of LNC (LNE), NDGA, and MNDGA has not previously been reported. The present study aimed to characterize the phase I and phase II hepatic metabolism and reactive intermediates of LNE, NDGA, and MNDGA and their effects on the major drug-metabolizing enzymes in vitro and ex vivo...
January 2017: Phytotherapy Research: PTR
https://www.readbyqxmd.com/read/28056947/triptolide-induces-hepatotoxicity-via-inhibition-of-cyp450s-in-rat-liver-microsomes
#3
Yan Lu, Tong Xie, Yajie Zhang, Fuqiong Zhou, Jie Ruan, Weina Zhu, Huaxu Zhu, Zhe Feng, Xueping Zhou
BACKGROUND: Triptolide (TP), an active constituent of Tripterygium wilfordii, possesses numerous pharmacological activities. However, its effects on cytochrome P450 enzymes (CYP450s) in rats remain unexplored. METHODS: In this study, the effects of triptolide on the six main CYP450 isoforms (1A2, 2C9, 2C19, 2D6, 2E1, and 3A) were investigated both in vivo and in vitro. We monitored the body weight, survival proportions, liver index, changes in pathology, and biochemical index upon TP administration, in vivo...
January 5, 2017: BMC Complementary and Alternative Medicine
https://www.readbyqxmd.com/read/27994733/identification-synthesis-and-biological-evaluation-of-the-major-human-metabolite-of-nlrp3-inflammasome-inhibitor-mcc950
#4
Manohar Salla, Mark S Butler, Ruby Pelingon, Geraldine Kaeslin, Daniel E Croker, Janet C Reid, Jong Min Baek, Paul V Bernhardt, Elizabeth M J Gillam, Matthew A Cooper, Avril A B Robertson
MCC950 is an orally bioavailable small molecule inhibitor of the NOD-like receptor pyrin domain-containing protein 3 (NLRP3) inflammasome that exhibits remarkable activity in multiple models of inflammatory disease. Incubation of MCC950 with human liver microsomes, and subsequent analysis by HPLC-MS/MS, revealed a major metabolite, where hydroxylation of MCC950 had occurred on the 1,2,3,5,6,7-hexahydro-s-indacene moiety. Three possible regioisomers were synthesized, and coelution using HPLC-MS/MS confirmed the structure of the metabolite...
December 8, 2016: ACS Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/27978469/highly-sensitive-lc-ms-ms-methods-for-the-determination-of-seven-human-cyp450-activities-using-small-oral-doses-of-probe-drugs-in-human
#5
Alexia Grangeon, Sophie Gravel, Fleur Gaudette, Jacques Turgeon, Veronique Michaud
Cocktails composed of several Cytochrome P450 (CYP450)-selective probe drugs have been shown of value to characterize in vivo drug-metabolism activities. Our objective was to develop and validate highly sensitive and selective LC-MS/MS assays allowing the determination of seven major human CYP450 isoenzyme activities following administration of low oral doses of a modified CYP450 probe-drug cocktail in patients. The seven-drug cocktail was composed of caffeine, bupropion, tolbutamide, omeprazole, dextromethorphan, midazolam (all administered concomitantly) and chlorzoxazone (administered separately) to phenotype for CYP1A2, 2B6, 2C9, 2C19, 2D6, 3A4/5 and 2E1, respectively...
January 1, 2017: Journal of Chromatography. B, Analytical Technologies in the Biomedical and Life Sciences
https://www.readbyqxmd.com/read/27910036/evaluation-of-the-pharmacokinetic-interaction-between-venetoclax-a-selective-bcl-2-inhibitor-and-warfarin-in-healthy-volunteers
#6
Ahmed Hamed Salem, Beibei Hu, Kevin J Freise, Suresh K Agarwal, Dilraj S Sidhu, Shekman L Wong
BACKGROUND AND OBJECTIVE: Venetoclax is a selective, B-cell lymphoma-2 inhibitor that has demonstrated clinical efficacy in a variety of hematological malignancies. In vitro data indicated weak cytochrome P450 (CYP) 2C9 inhibition by venetoclax; however, it is not predicted to cause clinically relevant inhibition due to high plasma protein binding. A Phase 1 study was conducted in healthy volunteers to evaluate the effect of venetoclax on warfarin pharmacokinetics. METHODS: Subjects received a single oral dose of 5 mg warfarin on day 1 of both periods 1 and 2, separated by a 14 days washout...
December 2, 2016: Clinical Drug Investigation
https://www.readbyqxmd.com/read/27879469/frequency-of-common-vkorc1-polymorphisms-and-their-impact-on-warfarin-dose-requirement-in-pakistani-population
#7
Aisha Qayyum, Muzammil Hasan Najmi, Qaisar Mansoor, Muhammad Irfan, Abdul Khaliq Naveed, Andleeb Hanif, Ali Raza Kazmi, Muhammad Ismail
Polymorphisms in vitamin K epoxide reductase complex subunit 1 (VKORC1) gene lead to interindividual variability in warfarin dose requirement. The characterization of genotype frequency distribution is required in different populations for construction of customized dosing algorithms to enhance the efficacy and reduce the toxicity of warfarin therapy. This study was carried out in Pakistani population to evaluate the contribution of common VKORC1 polymorphisms to warfarin therapy. A total of 550 stable patients taking warfarin were enrolled after medical history, physical examination, and laboratory investigations...
November 21, 2016: Clinical and Applied Thrombosis/hemostasis
https://www.readbyqxmd.com/read/27853934/evaluation-of-in-vitro-cytochrome-p450-inhibition-and-in-vitro-fate-of-structurally-diverse-n-oxide-metabolites-case-studies-with-clozapine-levofloxacin-roflumilast-voriconazole-and-zopiclone
#8
Poonam Giri, Sneha Naidu, Nirmal Patel, Harilal Patel, Nuggehally R Srinivas
BACKGROUND AND OBJECTIVES: The role of metabolite(s) to elicit potential clinical drug-drug interaction (DDI) via cytochrome P450 enzymes (CYP) is gaining momentum. In this context, the role of N-oxides for in vitro CYP inhibition has not been evaluated. The objectives of this study were: (a) to examine in vitro CYP inhibition of N-oxides of clozapine, levofloxacin, roflumilast, voriconazole and zopiclone in a tiered approach and (b) evaluate in vitro fate of aforementioned N-oxides examined in recombinant CYPs, human microsomes and hepatocytes...
November 16, 2016: European Journal of Drug Metabolism and Pharmacokinetics
https://www.readbyqxmd.com/read/27819189/inhibitory-effects-of-curculigoside-on-human-liver-cytochrome-p450-enzymes
#9
Jixiao Lang, Wei Li, Jingming Zhao, Kaiyou Wang, Dexi Chen
1. Curculigoside possesses numerous pharmacological activities, and however, little data available for the effects of curculigoside on the activity of human liver cytochrome P450 (CYP) enzymes. 2. This study investigates the inhibitory effects of curculigoside on the main human liver CYP isoforms. In this study, the inhibitory effects of curculigoside on the eight human liver CYP isoforms 1A2, 2A6, 2E1, 2D6, 2C9, 2C19, 2C8, and 3A4 were investigated in human liver microsomes. 3. The results indicated that curculigoside could inhibit the activity of CYP1A2, CYP2C8, and CYP3A4, with IC50 values of 15...
November 5, 2016: Xenobiotica; the Fate of Foreign Compounds in Biological Systems
https://www.readbyqxmd.com/read/27783977/targeting-the-entry-region-of-hsp90-s-atp-binding-pocket-with-a-novel-6-7-dihydrothieno-3-2-c-pyridin-5-4h-yl-amide
#10
Ju Hui Jeong, Yong Jin Oh, Yunmee Lho, Sun You Park, Kwang-Hyeon Liu, Eunyoung Ha, Young Ho Seo
The molecular chaperone Hsp90 plays an important role in cancer cell survival and proliferation by regulating the maturation and stabilization of numerous oncogenic proteins. Due to its potential to simultaneously disable multiple signaling pathways, Hsp90 has emerged as an attractive therapeutic target for cancer treatment. In this study, the design, synthesis, and biological evaluation of a series of Hsp90 inhibitors are described. Among the synthetic compounds, 6,7-dihydrothieno [3,2-c]pyridin-5(4H)-yl amide 19 exhibits a remarkable binding affinity to the N-terminus of Hsp90 in a fluorescence polarization (FP) binding assay (IC50 = 50...
November 29, 2016: European Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/27761064/human-cytochrome-p450-enzyme-modulation-by-gymnema-sylvestre-a-predictive-safety-evaluation-by-lc-ms-ms
#11
Bera Rammohan, Karmakar Samit, Das Chinmoy, Saha Arup, Kundu Amit, Sarkar Ratul, Karmakar Sanmoy, Adhikari Dipan, Sen Tuhinadri
BACKGROUND: Traditionally GS is used to treat diabetes mellitus. Drug-herb interaction of GS via cytochrome P450 enzyme system by substrate cocktail method using HLM has not been reported. OBJECTIVE: To evaluate the in-vitro modulatory effects of GS extracts (aqueous, methanol, ethyl acetate, chloroform and n-hexane) and deacylgymnemic acid (DGA) on human CYP1A2, 2C8, 2C9, 2D6 and 3A4 activities in HLM. MATERIAL AND METHODS: Probe substrate-based LCMS/MS method was established for all CYPs...
July 2016: Pharmacognosy Magazine
https://www.readbyqxmd.com/read/27758707/new-psychoactive-substances-3-methoxyphencyclidine-3-meo-pcp-and-3-methoxyrolicyclidine-3-meo-pcpy-metabolic-fate-elucidated-with-rat-urine-and-human-liver-preparations-and-their-detectability-in-urine-by-gc-ms-lc-high-resolution-msn-and-lc-high-resolution
#12
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
https://www.readbyqxmd.com/read/27751854/evaluation-of-the-in%C3%A2-vitro-and-in%C3%A2-vivo-metabolic-pathway-and-cytochrome-p450-inhibition-induction-profile-of-huperzine-a
#13
Ping-Ping Lin, Xue-Ning Li, Fei Yuan, Wei-Li Chen, Meng-Jie Yang, Hong-Rong Xu
Huperzine A (HupA), one of the reversible and selective acetylcholinesterase inhibitors derived from Chinese herb Huperzia Serrata, possesses affirmative action of ameliorating cognitive dysfunction of Alzheimer's disease. Up to now, the effects of HupA on human cytochrome P450s (CYPs) have not been fully elucidated. The purpose of the present study was to clarify the metabolic pathway of HupA in vitro and in vivo, and to evaluate the CYPs inhibition/induction profile of HupA in vitro. The catalytic activity of CYP enzymes (CYP1A2, 2A6, 2C9, 2C19, 2D6, 2E1 and 3A4) was measured by the quantification of specific enzyme substrates using validated liquid chromatography-tandem mass spectrometry (LC/MS/MS) methods...
November 11, 2016: Biochemical and Biophysical Research Communications
https://www.readbyqxmd.com/read/27735849/construction-of-metabolism-prediction-models-for-cyp450-3a4-2d6-and-2c9-based-on-microsomal-metabolic-reaction-system
#14
Shuai-Bing He, Man-Man Li, Bai-Xia Zhang, Xiao-Tong Ye, Ran-Feng Du, Yun Wang, Yan-Jiang Qiao
During the past decades, there have been continuous attempts in the prediction of metabolism mediated by cytochrome P450s (CYP450s) 3A4, 2D6, and 2C9. However, it has indeed remained a huge challenge to accurately predict the metabolism of xenobiotics mediated by these enzymes. To address this issue, microsomal metabolic reaction system (MMRS)-a novel concept, which integrates information about site of metabolism (SOM) and enzyme-was introduced. By incorporating the use of multiple feature selection (FS) techniques (ChiSquared (CHI), InfoGain (IG), GainRatio (GR), Relief) and hybrid classification procedures (Kstar, Bayes (BN), K-nearest neighbours (IBK), C4...
October 9, 2016: International Journal of Molecular Sciences
https://www.readbyqxmd.com/read/27725449/evaluation-of-the-effects-of-s-allyl-l-cysteine-s-methyl-l-cysteine-trans-s-1-propenyl-l-cysteine-and-their-n-acetylated-and-s-oxidized-metabolites-on-human-cyp-activities
#15
Hirotaka Amano, Daichi Kazamori, Kenji Itoh
Three major organosulfur compounds of aged garlic extract, S-allyl-L-cysteine (SAC), S-methyl-L-cysteine (SMC), and trans-S-1-propenyl-L-cysteine (S1PC), were examined for their effects on the activities of five major isoforms of human CYP enzymes: CYP1A2, 2C9, 2C19, 2D6, and 3A4. The metabolite formation from probe substrates for the CYP isoforms was examined in human liver microsomes in the presence of organosulfur compounds at 0.01-1 mM by using liquid chromatography-tandem mass spectrometry (LC-MS/MS) analysis...
2016: Biological & Pharmaceutical Bulletin
https://www.readbyqxmd.com/read/27721546/metabolism-mediated-interaction-potential-of-standardized-extract-of-tinospora-cordifolia-through-rat-and-human-liver-microsomes
#16
Shiv Bahadur, Pulok K Mukherjee, S K Milan Ahmmed, Amit Kar, Ranjit K Harwansh, Subrata Pandit
OBJECTIVE: Tinospora cordifolia is used for treatment of several diseases in Indian system of medicine. In the present study, the inhibition potential of T. cordifolia extracts and its constituent tinosporaside to cause herb-drug interactions through rat and human liver cytochrome enzymes was evaluated. MATERIALS AND METHODS: Bioactive compound was quantified through reverse phase high-performance liquid chromatography, to standardize the plant extracts and interaction potential of standardized extract...
September 2016: Indian Journal of Pharmacology
https://www.readbyqxmd.com/read/27665573/evaluation-of-concomitant-antiretrovirals-and-cyp2c9-cyp2c19-polymorphisms-on-the-pharmacokinetics-of-etravirine
#17
Bruce Green, Herta Crauwels, Thomas N Kakuda, Simon Vanveggel, Anne Brochot
BACKGROUND: Etravirine is a non-nucleoside reverse transcriptase inhibitor indicated in combination with other antiretrovirals for treatment-experienced HIV patients ≥6 years of age. Etravirine is primarily metabolized by cytochrome P450 (CYP) 2C9, CYP2C19, and CYP3A. This analysis determined the impact of concomitant antiretrovirals and CYP2C9/CYP2C19 phenotype on the pharmacokinetics of etravirine. METHODS: We used 4728 plasma concentrations from 817 adult subjects collected from four clinical studies to develop the population pharmacokinetic model...
September 24, 2016: Clinical Pharmacokinetics
https://www.readbyqxmd.com/read/27661060/cytochrome-p450-2c9-gene-polymorphism-and-warfarin-maintenance-dosage-in-pediatric-patients-a-systematic-review-and-meta-analysis
#18
Jinhua Zhang, Lihong Tian, Jinlong Huang, Sihan Huang, Tingting Chai, Jianzhen Shen
AIM: To assess the effect of Cytochrome P450 2C9 (CYP2C9) gene polymorphism on pediatric warfarin maintenance dosage requirement. METHODS: A previously developed search strategy was conducted in PubMed, EMBASE, and the Cochrane Library. Eligible studies published prior to January 27, 2016, were identified and compared against strict inclusion/exclusion criteria. Required data were extracted, and researchers were consulted for additional data if needed. Review Manager version 5...
February 2017: Cardiovascular Therapeutics
https://www.readbyqxmd.com/read/27625140/roles-of-human-cyp2a6-and-monkey-cyp2a24-and-2a26-cytochrome-p450-enzymes-in-the-oxidation-of-2-5-2-5-tetrachlorobiphenyl
#19
Tsutomu Shimada, Kensaku Kakimoto, Shigeo Takenaka, Nobuyuki Koga, Shotaro Uehara, Norie Murayama, Hiroshi Yamazaki, Donghak Kim, Frederick Peter Guengerich, Masayuki Komori
2,5,2',5'-Tetrachlorobiphenyl (TCB) induced Type I binding spectra with cytochrome P450 (P450 or CYP) 2A6 and 2A13, having Ks values of 9.4 and 0.51 μM, respectively. However, CYP2A6 oxidized 2,5,2',5'-TCB to form 4-hydroxylated products at a much higher rate (~1.0 min-1) than CYP2A13 (~0.02 min-1), based on analysis by LC-MS/MS. Formation of 4-hydroxy-2,5,2',5'-TCB by CYP2A6 was greater than that of 3-hydroxy-2,5,2',5'-TCB and three other hydroxylated products. Several human P450 enzymes, including CYP1A1, 1A2, 1B1, 2B6, 2D6, 2E1, 2C9, and 3A4, did not show any detectable activities in oxidizing 2,5,2',5'-TCB...
September 13, 2016: Drug Metabolism and Disposition: the Biological Fate of Chemicals
https://www.readbyqxmd.com/read/27539372/cyp2c9-genotype-dependent-warfarin-pharmacokinetics-impact-of-cyp2c9-genotype-on-r-and-s-warfarin-and-their-oxidative-metabolites
#20
Darcy R Flora, Allan E Rettie, Richard C Brundage, Timothy S Tracy
Multiple factors can impact warfarin therapy, including genetic variations in the drug-metabolizing enzyme cytochrome P450 2C9 (CYP2C9). Compared with individuals with the wild-type allele, CYP2C9*1, carriers of the common *3 variant have significantly impaired CYP2C9 metabolism. Genetic variations in CYP2C9, the primary enzyme governing the metabolic clearance of the more potent S-enantiomer of the racemic anticoagulant warfarin, may impact warfarin-drug interactions. To establish a baseline for such studies, plasma and urine concentrations of R- and S-warfarin and 10 warfarin metabolites were monitored for up to 360 hours following a 10-mg warfarin dose in healthy subjects with 4 different CYP2C9 genotypes: CYP2C9*1/*1 (n = 8), CYP2C9*1/*3 (n = 9), CYP2C9*2/*3 (n = 3), and CYP2C9*3/*3 (n = 4)...
August 19, 2016: Journal of Clinical Pharmacology
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