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CYP2C8

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https://www.readbyqxmd.com/read/27910729/identification-of-cytochrome-p450s-involved-in-the-metabolism-of-6-benzyl-1-benzyloxymethyl-5-iodouracil-w-1-using-human-recombinant-enzymes-and-rat-liver-microsomes-in-vitro
#1
Ying-Yuan Lu, Hai-Xu Cheng, Xin Wang, Xiao-Wei Wang, Jun-Yi Liu, Pu Li, Ya-Qing Lou, Jun Li, Chuang Lu, Guo-Liang Zhang
1. The aim of this study was to identify the hepatic metabolic enzymes, which involved in the biotransformation of 6-benzyl-1-benzyloxymethyl-5-iodouracil (W-1), a novel non-nucleoside reverse transcriptase inhibitor (NNRTIs) in rat and human in vitro. 2. The parent drug of W-1 was incubated with RLMs or recombinant CYPs (CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP2E1, CYP3A4 and CYP3A5, respectively) in the presence or absence of NADPH regenerating system. The metabolites of W-1 were analyzed with liquid chromatography-ion trap-time of flight-mass spectrometry (LC-IT-TOF-MS)...
December 2, 2016: Xenobiotica; the Fate of Foreign Compounds in Biological Systems
https://www.readbyqxmd.com/read/27896399/cytochrome-p450-mediated-metabolism-of-triclosan-attenuates-its-cytotoxicity-in-hepatic-cells
#2
Yuanfeng Wu, Priyanka Chitranshi, Lucie Loukotková, Gonçalo Gamboa da Costa, Frederick A Beland, Jie Zhang, Jia-Long Fang
Triclosan is a widely used broad-spectrum anti-bacterial agent. The objectives of this study were to identify which cytochrome P450 (CYP) isoforms metabolize triclosan and to examine the effects of CYP-mediated metabolism on triclosan-induced cytotoxicity. A panel of HepG2-derived cell lines was established, each of which overexpressed a single CYP isoform, including CYP1A1, CYP1A2, CYP1B1, CYP2A6, CYP2A7, CYP2A13, CYP2B6, CYP2C8, CYP2C9, CYP2C18, CYP2C19, CYP2D6, CYP2E1, CYP3A4, CYP3A5, CYP3A7, CYP4A11, and CYP4B1...
November 28, 2016: Archives of Toxicology
https://www.readbyqxmd.com/read/27891633/direct-inhibition-of-re-du-ning-injection-and-its-active-compounds-on-human-liver-cytochrome-p450-enzymes-by-a-cocktail-method
#3
Danyu Kang, Ting Geng, Yuanpei Lian, Yanjing Li, Gang Ding, Wenzhe Huang, Shiping Ma, Zhenzhong Wang, Zheng Ma, Wei Xiao
The aim of this study was to investigate the direct inhibitory effects of Re Du Ning Injection (RDN) and its active compounds on the major CYP isoforms (CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6 and CYP3A4) of human liver microsomes by "a cocktail method". The activity of each CYP isform was represented as the formation rate of the specific metabolite from relevant substrate. Then a sensitive and specific ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) method was developed and validated to simultaneously analyze the seven metabolites...
November 28, 2016: Biomedical Chromatography: BMC
https://www.readbyqxmd.com/read/27878971/pregnane-x-receptors-regulate-cyp2c8-and-p-glycoprotein-to-impact-on-the-resistance-of-nsclc-cells-to-taxol
#4
Yan Chen, Wandan Huang, Feiyu Chen, Guoping Hu, Fenglei Li, Jianhua Li, Aiguo Xuan
Cytochrome P450 2C8 (CYP2C8) is one of the enzymes that primarily participate in producing metabolisms of medications and P-glycoprotein (P-gp) has been regarded as one of the important molecules in chemotherapeutically induced multidrug resistance (MDR). In addition, the pregnane X receptor (PXR) is involved in regulating both CYP2C8 and P-gp. We aim to research the effect of PXR on Taxol-resistant non-small-cell lung cancer (NSCLC cells) via regulating CYP2C8 and P-gp. NSCLC cells were treated with SR12813, LY335979, or PXR siRNA...
November 22, 2016: Cancer Medicine
https://www.readbyqxmd.com/read/27862160/in-vitro-and-pbpk-based-assessment-of-drug-drug-interaction-potential-of-canagliflozin
#5
Rao N V S Mamidi, Shannon Dallas, Carlo Sensenhauser, Heng Keang Lim, Ellen Scheers, Peter Verboven, Filip Cuyckens, Laurent Leclercq, David C Evans, Michael F Kelley, Mark D Johnson, Jan Snoeys
AIMS: Canagliflozin is a recently approved drug for use in the treatment of type 2 diabetes. The potential for canagliflozin to cause clinical drug-drug interactions (DDIs) was assessed. METHODS: DDI potential of canagliflozin was investigated using in vitro test systems containing drug metabolizing enzymes or transporters. Basic predictive approaches were applied to determine potential interaction in vivo. A physiologically-based pharmacokinetic (PBPK) model was developed and clinical DDI simulations were performed to determine the likelihood of CYP inhibition by canagliflozin...
November 11, 2016: British Journal of Clinical Pharmacology
https://www.readbyqxmd.com/read/27845750/inhibitory-interactions-of-aspalathus-linearis-rooibos-extracts-and-compounds-aspalathin-and-z-2-%C3%AE-d-glucopyranosyloxy-3-phenylpropenoic-acid-on-cytochromes-metabolizing-hypoglycemic-and-hypolipidemic-drugs
#6
Oelfah Patel, Christo Muller, Elizabeth Joubert, Johan Louw, Bernd Rosenkranz, Charles Awortwe
Rooibos extract, due to its glucose and lipid lowering effects, has potential as a nutraceutical for improvement of metabolic dysfunction. Potential herb-drug interactions as a result of the use of natural products are of increasing concern. Cytochrome P450 enzymes, CYP2C8, CYP2C9, and CYP3A4, are important in the metabolism of hypoglycemic drugs, such as thiazolidinediones (TZDs) and sulfonylureas, and hypocholesterolemic drugs, such as atorvastatin. This study investigated the effects of rooibos extracts, prepared from "unfermented" and "fermented" rooibos plant material and two of the major bioactive compounds, Z-2-(β-d-glucopyranosyloxy)-3-phenylpropenoic acid (PPAG) and aspalathin (ASP), on Vivid(®) recombinant CYP450 enzymes...
November 12, 2016: Molecules: a Journal of Synthetic Chemistry and Natural Product Chemistry
https://www.readbyqxmd.com/read/27819189/inhibitory-effects-of-curculigoside-on-human-liver-cytochrome-p450-enzymes
#7
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/27816004/diazepam-influences-urinary-bioindicator-of-occupational-toluene-exposure
#8
Alberto Thalison Silveira, Ana Carolina Campos Albuquerque, José Salvador Lepera, Isarita Martins
In the present study, we investigated the influence of diazepam (DZP) on the excretion of TOL by examining their urinary metabolites, hippuric acid (HA) and ortho-cresol (o-C). Male Wistar rats were exposed to TOL (20ppm) in a nose-only exposure chamber (6h/day, 5days/week for 6 weeks) with simultaneous administration of DZP (10mg/kg/day). Urinary o-C levels were determined by GC-MS, while HA, creatinine (CR), DZP and its metabolite, nordiazepam, were analysed by HPLC-DAD. The results of a Mann-Whitney U test showed that DZP influenced the urinary excretion of o-C (p<0...
December 2016: Environmental Toxicology and Pharmacology
https://www.readbyqxmd.com/read/27803446/genetic-polymorphisms-and-in-vitro-functional-characterization-of-cyp2c8-cyp2c9-and-cyp2c19-allelic-variants
#9
Masahiro Hiratsuka
Genetic variations in CYP 2C (CYP2C) subfamily, CYP2C8, CYP2C9, and CYP2C19 contribute to interindividual variability in the metabolism of clinically used drugs. Changes in the drug metabolizing activity of CYP2C members may cause unexpected and serious adverse drug reactions and inadequate therapeutic effects. Therefore, CYP2C gene polymorphism is used as a genome biomarker for predicting responsiveness to administered drugs. The most direct method for understanding the extent of the effects of CYP2C gene polymorphism on drug pharmacokinetics is by evaluating the blood and urine concentrations of the drug in subjects...
2016: Biological & Pharmaceutical Bulletin
https://www.readbyqxmd.com/read/27785404/the-influence-of-cyp2c8-3-on-carbamazepine-serum-concentration-in-epileptic-pediatric-patients
#10
D D Milovanovic, J R Milovanovic, M Radovanovic, I Radosavljevic, S Obradovic, S Jankovic, D Milovanovic, N Djordjevic
The aim of the present study was to investigate the distribution of CYP2C8 variants *3 and *5, as well as their effect on carbamazepine pharmacokinetic properties, in 40 epileptic pediatric patients on carbamazepine treatment. Genotyping was conducted using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP), and allele-specific (AS)-PCR methods, and steady-state carbamazepine plasma concentrations were determined by high performance liquid chromatography (HPLC). The CYP2C8 *3 and *5 polymorphisms were found at frequencies of 17...
July 1, 2016: Balkan Journal of Medical Genetics: BJMG
https://www.readbyqxmd.com/read/27767381/the-effect-of-snps-in-cyp450-in-chloroquine-primaquine-plasmodium-vivax-malaria-treatment
#11
Vinicius A Sortica, Juliana D Lindenau, Maristela G Cunha, Maria DO Ohnishi, Ana Maria R Ventura, Ândrea Kc Ribeiro-Dos-Santos, Sidney Eb Santos, Luciano Sp Guimarães, Mara H Hutz
BACKGROUND: Chloroquine/primaquine is the current therapy to eliminate Plasmodium vivax infection in the Amazon region. AIMS: This study investigates CYP1A2, CYP2C8, CYP2C9, CYP3A4 and CYP3A5 genetic polymorphisms influence on cloroquine/primaquine treatment. PATIENTS & METHODS: Generalized estimating equations analyses were performed to determine the genetic influence in parasitemia and/or gametocytemia clearance over treatment time in 164 patients...
October 21, 2016: Pharmacogenomics
https://www.readbyqxmd.com/read/27736846/genotypes-of-cyp2c8-and-fgd4-and-their-association-with-peripheral-neuropathy-or-early-dose-reduction-in-paclitaxel-treated-breast-cancer-patients
#12
Siu W Lam, Charlotte N Frederiks, Tahar van der Straaten, Aafke H Honkoop, Henk-Jan Guchelaar, Epie Boven
BACKGROUND: The purpose of this study was to evaluate single-nucleotide polymorphisms (SNPs) in genes encoding key metabolising enzymes or involved in pharmacodynamics for possible associations with paclitaxel-induced peripheral neuropathy. METHODS: The study population consists of 188 women from the multicenter, randomised, phase II ATX trial (BOOG2006-06; EudraCT number 2006-006058-83) that received paclitaxel and bevacizumab without or with capecitabine as first-line palliative therapy of HER2-negative metastatic breast cancer...
November 22, 2016: British Journal of Cancer
https://www.readbyqxmd.com/read/27734142/a-liquid%C3%A2-chromatography-tandem-mass-spectrometry-analysis-of-nine-cytochrome-p450-probe-drugs-and-their-corresponding-metabolites-in-human-serum-and-urine
#13
Elena Puris, Markku Pasanen, Mikko Gynther, Merja R Häkkinen, Jussi Pihlajamäki, Tapani Keränen, Paavo Honkakoski, Hannu Raunio, Aleksanteri Petsalo
Cocktail phenotyping using specific probe drugs for cytochrome P450 (CYP) enzymes provides information on the real-time activity of multiple CYPs. We investigated different sample preparation techniques and validated a liquid chromatography-tandem mass spectrometry (LC-MS/MS) method with simple protein precipitation for the analysis of nine CYP probe drugs and their metabolites in human serum and urine. Specific CYP probe drugs (melatonin, CYP1A2; nicotine, CYP2A6; bupropion, CYP2B6; repaglinide, CYP2C8; losartan, CYP2C9; omeprazole, CYP2C19 and CYP3A4; dextromethorphan, CYP2D6; chlorzoxazone, CYP2E; midazolam, CYP3A4) and their main metabolites, with the exception of 3'-hydroxyrepaglinide, were quantified in human serum and urine using the developed LC-MS/MS method...
October 12, 2016: Analytical and Bioanalytical Chemistry
https://www.readbyqxmd.com/read/27720395/fenofibrate-inhibits-cytochrome-p450-epoxygenase-2c-activity-to-suppress-pathological-ocular-angiogenesis
#14
Yan Gong, Zhuo Shao, Zhongjie Fu, Matthew L Edin, Ye Sun, Raffael G Liegl, Zhongxiao Wang, Chi-Hsiu Liu, Samuel B Burnim, Steven S Meng, Fred B Lih, John Paul SanGiovanni, Darryl C Zeldin, Ann Hellström, Lois E H Smith
Neovascular eye diseases including retinopathy of prematurity, diabetic retinopathy and age-related-macular-degeneration are major causes of blindness. Fenofibrate treatment in type 2 diabetes patients reduces progression of diabetic retinopathy independent of its peroxisome proliferator-activated receptor (PPAR)α agonist lipid lowering effect. The mechanism is unknown. Fenofibrate binds to and inhibits cytochrome P450 epoxygenase (CYP)2C with higher affinity than to PPARα. CYP2C metabolizes ω-3 long-chain polyunsaturated fatty acids (LCPUFAs)...
September 30, 2016: EBioMedicine
https://www.readbyqxmd.com/read/27718269/characterization-of-human-cytochrome-p450-mediated-bioactivation-of-amodiaquine-and-its-major-metabolite-n-desethylamodiaquine
#15
Yongjie Zhang, Nico P E Vermeulen, Jan N M Commandeur
AIMS: Oxidative bioactivation of amodiaquine (AQ) by cytochrome P450s to a reactive quinoneimine is considered as an important mechanism underlying its idiosyncratic hepatotoxicity. However, because internal exposure to its major metabolite N-desethylamodiaquine (DEAQ) is up to 240 fold higher than AQ, bioactivation of DEAQ might significant contribute to covalent binding. The aim of the present study was to compare the kinetics of bioactivation of AQ and DEAQ by human liver microsomes and to characterize the CYPs involved in bioactivation of AQ and DEAQ...
October 8, 2016: British Journal of Clinical Pharmacology
https://www.readbyqxmd.com/read/27695271/inhibition-of-human-cytochrome-p450-2c8-catalyzed-amodiaquine-n-desethylation-effect-of-five-traditionally-and-commonly-used-herbs
#16
Yasotha Devi Muthiah, Chin Eng Ong, Siti Amrah Sulaiman, Rusli Ismail
BACKGROUND: In Southeast Asia and many parts of the world, herbal products are increasingly used in parallel with modern medicine. OBJECTIVE: This study aimed to investigate the effects of herbs commonly used in Southeast Asia on activity of cytochrome P450 2C8 (CYP2C8), an important human hepatic enzyme in drug metabolism. MATERIALS AND METHODS: The selected herbs, such as Eurycoma longifolia Jack (ELJ), Labisia pumila (LP), Echinacea purpurea (EP), Andrographis paniculata (AP), and Ginkgo biloba (GB), were subjected to inhibition studies using an in vitro CYP2C8 activity marker, amodiaquine N-desethylase assay...
October 2016: Pharmacognosy Research
https://www.readbyqxmd.com/read/27648490/transporter-mediated-hepatic-uptake-plays-an-important-role-in-the-pharmacokinetics-and-drug-drug-interactions-of-montelukast
#17
M V Varma, E Kimoto, R Scialis, Y Bi, J Lin, H Eng, A S Kalgutkar, A F El-Kattan, A D Rodrigues, L M Tremaine
Montelukast, a leukotriene receptor antagonist commonly prescribed for treatment of asthma, is primarily metabolized by Cytochrome P450 (CYP)2C8, and has been suggested as a probe substrate for investigating CYP2C8 activity in vivo. We evaluated the quantitative role of hepatic uptake transport in its pharmacokinetics and drug-drug interactions (DDIs). Montelukast was characterized with significant active uptake in human hepatocytes, and showed affinity towards organic anion transporting polypeptides (OATPs) in transfected cell systems...
September 20, 2016: Clinical Pharmacology and Therapeutics
https://www.readbyqxmd.com/read/27602771/single-cell-analyses-of-transcriptional-heterogeneity-in-squamous-cell-carcinoma-of-urinary-bladder
#18
Xiaolong Zhang, Meng Zhang, Yong Hou, Liqin Xu, Weidong Li, Zhihui Zou, Chunxiao Liu, Abai Xu, Song Wu
Cell-to-cell expression heterogeneity within a single tumor is a common phenotype among various cancer types including squamous cell carcinoma. To further study the fundamentals and importance of heterogeneity of cell functions and its potential mechanisms, we performed single-cell RNA-seq (scRNA-seq) on human squamous cell carcinoma of the bladder (SCCB) and its corresponding physiologically normal epithelia. Extensive differentially expressed genes were uncovered by comparing cancer and normal single cells, which were preferentially enriched in cancer-correlated pathways, such as p53 signaling and bladder cancer pathway...
September 1, 2016: Oncotarget
https://www.readbyqxmd.com/read/27599706/physiologically-based-pharmacokinetic-modeling-to-predict-drug-drug-interactions-with-efavirenz-involving-simultaneous-inducing-and-inhibitory-effects-on-cytochromes
#19
Catia Marzolini, Rajith Rajoli, Manuel Battegay, Luigia Elzi, David Back, Marco Siccardi
BACKGROUND: Antiretroviral drugs are among the therapeutic agents with the highest potential for drug-drug interactions (DDIs). In the absence of clinical data, DDIs are mainly predicted based on preclinical data and knowledge of the disposition of individual drugs. Predictions can be challenging, especially when antiretroviral drugs induce and inhibit multiple cytochrome P450 (CYP) isoenzymes simultaneously. METHODS: This study predicted the magnitude of the DDI between efavirenz, an inducer of CYP3A4 and inhibitor of CYP2C8, and dual CYP3A4/CYP2C8 substrates (repaglinide, montelukast, pioglitazone, paclitaxel) using a physiologically based pharmacokinetic (PBPK) modeling approach integrating concurrent effects on CYPs...
September 7, 2016: Clinical Pharmacokinetics
https://www.readbyqxmd.com/read/27574448/polymorphism-of-cyp3a4-and-abcb1-genes-increase-the-risk-of-neuropathy-in-breast-cancer-patients-treated-with-paclitaxel-and-docetaxel
#20
Tulay Kus, Gokmen Aktas, Mehmet Emin Kalender, Abdullah Tuncay Demiryurek, Mustafa Ulasli, Serdar Oztuzcu, Alper Sevinc, Seval Kul, Celaletdin Camci
BACKGROUND: Interindividual variability of pharmacogenetics may account for unpredictable neurotoxicities of taxanes. METHODS: From March 2011 to June 2015, female patients with operable breast cancer who had received docetaxel- or paclitaxel-containing adjuvant chemotherapy were included in this study. All patients were treated with single-agent paclitaxel intravenously (IV) 175 mg/m(2) every 3 weeks for four cycles, or IV 80 mg/m(2) weekly for 12 cycles, and IV 100 mg/m(2) docetaxel for four cycles as adjuvant treatment...
2016: OncoTargets and Therapy
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