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CYP2C8.3

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https://www.readbyqxmd.com/read/27924364/metabolic-characterization-of-1-5-fluoropentyl-1h-indol-3-yl-4-methyl-1-naphthalenyl-methanone-mam-2201-using-human-liver-microsomes-and-cdna-overexpressed-cytochrome-p450-enzymes
#1
Tae Yeon Kong, Ju-Hyun Kim, Won Gu Choi, Joo Young Lee, Hee Seung Kim, Jin Young Kim, Moon Kyo In, Hye Suk Lee
MAM-2201 is a synthetic cannabinoid that is increasingly found in recreational drug abusers and cases of severe intoxication. Thus, characterization of the metabolic pathways of MAM-2201 is necessary to predict individual pharmacokinetics and toxicity differences, and to avoid toxic drug-drug interactions. Collectively, 19 phase 1 metabolites of MAM-2201 were identified using liquid chromatography-Orbitrap mass spectrometry following human liver microsomal incubations in the presence of NADPH: 7 hydroxy-MAM-2201 (M1-M7), 4 dihydroxy-MAM-2201 (M8-M11), dihydrodiol-MAM-2201 (M12), N-(5-hydroxypentyl)-MAM-2201 (M13), hydroxy-M13 (M14), N-dealkyl-MAM-2201 (M15), 2 hydroxy-M15 (M16, M17), MAM-2201 N-pentanoic acid (M18), and hydroxy-M18 (M19)...
December 6, 2016: Analytical and Bioanalytical Chemistry
https://www.readbyqxmd.com/read/27916259/cyp-genetic-variants-cyp-metabolite-levels-and-neurologic-deterioration-in-acute-ischemic-stroke-in-chinese-population
#2
Xingyang Yi, Jing Lin, Chun Wang, Qiang Zhou
BACKGROUND: The mechanisms of neurologic deterioration (ND) are not fully understood. The aim of the present study was to evaluate the relationship between CYP genetic variants and CYP metabolite levels with ND in acute ischemic stroke patients. METHODS: Eleven single nucleotide polymorphisms (SNPs) of seven CYP genes were genotyped in 396 patients with acute ischemic stroke. The CYP plasma metabolite levels (20-hydroxyeicosatetraenoic acid [HETE], total epoxyeicosatrienoic acids [EETs], and dihydroxyeicosatrienoic acids [DiHETEs]) were also assessed...
December 1, 2016: Journal of Stroke and Cerebrovascular Diseases: the Official Journal of National Stroke Association
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
#3
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/27862160/in-vitro-and-pbpk-based-assessment-of-drug-drug-interaction-potential-of-canagliflozin
#4
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
#5
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
#6
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/27803446/genetic-polymorphisms-and-in-vitro-functional-characterization-of-cyp2c8-cyp2c9-and-cyp2c19-allelic-variants
#7
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
#8
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/27736846/genotypes-of-cyp2c8-and-fgd4-and-their-association-with-peripheral-neuropathy-or-early-dose-reduction-in-paclitaxel-treated-breast-cancer-patients
#9
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/27720395/fenofibrate-inhibits-cytochrome-p450-epoxygenase-2c-activity-to-suppress-pathological-ocular-angiogenesis
#10
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
#11
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/27574448/polymorphism-of-cyp3a4-and-abcb1-genes-increase-the-risk-of-neuropathy-in-breast-cancer-patients-treated-with-paclitaxel-and-docetaxel
#12
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
https://www.readbyqxmd.com/read/27548563/role-of-gemfibrozil-as-an-inhibitor-of-cyp2c8-and-membrane-transporters
#13
Aleksi Tornio, Pertti J Neuvonen, Mikko Niemi, Janne T Backman
Cytochrome P450 (CYP) 2C8 is a drug metabolizing enzyme of major importance. The lipid-lowering drug gemfibrozil has been identified as a strong inhibitor of CYP2C8 in vivo. This effect is due to mechanism-based inhibition of CYP2C8 by gemfibrozil 1-O-β-glucuronide. In vivo, gemfibrozil is a fairly selective CYP2C8 inhibitor, which lacks significant inhibitory effect on other CYP enzymes. Gemfibrozil can, however, have a smaller but clinically meaningful inhibitory effect on membrane transporters, such as organic anion transporting polypeptide 1B1 and organic anion transporter 3...
January 2017: Expert Opinion on Drug Metabolism & Toxicology
https://www.readbyqxmd.com/read/27541143/pharmacokinetics-and-pharmacogenetics-of-13-cis-retinoic-acid-in-indian-high-risk-neuroblastoma-patients
#14
Vikram Gota, Girish Chinnaswamy, Tushar Vora, Sanhita Rath, Akanksha Yadav, Murari Gurjar, Gareth Veal, Purna Kurkure
PURPOSE: To compare the pharmacokinetics of 13-cis retinoic acid (13-cisRA) between Indian and UK neuroblastoma patients receiving comparable treatment, alongside measures of toxicity and response. METHODS: 13-cisRA (160 mg/m(2)/day) was administered to 36 patients ≤16 years in two divided doses. Plasma 13-cisRA concentrations were determined on days 1 and 14 of cycles 1 and 4 of treatment. Area under the plasma concentration-time curve (AUC0-6h) was estimated using non-compartment modelling...
October 2016: Cancer Chemotherapy and Pharmacology
https://www.readbyqxmd.com/read/27516201/cytochrome-p450-drug-metabolizing-enzymes-in-roma-population-samples-systematic-review-of-the-literature
#15
REVIEW
Renata Szalai, Kinga Hadzsiev, Bela Melegh
The cytochrome P450 drug metabolizing enzymes are highly polymorphic and show inter-individual differences in variability in drug response, which varies widely also with ethnicity. This study aims to summarize the available data on genetic polymorphisms associated with cytochrome enzymes conducted on Roma populations. Our goal was to compare the frequency of the variant alleles, genotypes and predicted phenotypes with corresponding rates from other populations. We carried out a systematic review including the papers published on the pharmacogenetically relevant variants of cytochrome P450 genes related to Roma population...
2016: Current Medicinal Chemistry
https://www.readbyqxmd.com/read/27504016/in-vitro-and-in-vivo-drug-drug-interaction-studies-to-assess-the-effect-of-abiraterone-acetate-abiraterone-and-metabolites-of-abiraterone-on-cyp2c8-activity
#16
Johan Monbaliu, Martha Gonzalez, Apexa Bernard, James Jiao, Carlo Sensenhauser, Jan Snoeys, Hans Stieltjes, Inneke Wynant, Johan W Smit, Caly Chien
Abiraterone acetate, the prodrug of the cytochrome P450 C17 inhibitor abiraterone, plus prednisone is approved for treatment of metastatic castration-resistant prostate cancer. We explored whether abiraterone interacts with drugs metabolized by CYP2C8, an enzyme responsible for the metabolism of many drugs. Abiraterone acetate and abiraterone and its major metabolites, abiraterone sulfate and abiraterone sulfate N-oxide, inhibited CYP2C8 in human liver microsomes, with IC50 values near or below the peak total concentrations observed in patients with metastatic castration-resistant prostate cancer (IC50 values: 1...
October 2016: Drug Metabolism and Disposition: the Biological Fate of Chemicals
https://www.readbyqxmd.com/read/27457785/clarification-of-the-mechanism-of-clopidogrel-mediated-drug-drug-interaction-in-a-clinical-cassette-small-dose-study-and-its-prediction-based-on-in-vitro-information
#17
Soo-Jin Kim, Takashi Yoshikado, Ichiro Ieiri, Kazuya Maeda, Miyuki Kimura, Shin Irie, Hiroyuki Kusuhara, Yuichi Sugiyama
Clopidogrel is reported to be associated with cerivastatin-induced rhabdomyolysis, and clopidogrel and its metabolites are capable of inhibiting CYP2C8 and OATP 1B1 in vitro. The objective of the present study was to identify the mechanism of clopidogrel-mediated drug-drug interactions (DDIs) on the pharmacokinetics of OATP1B1 and/or CYP2C8 substrates in vivo. A clinical cassette small-dose study using OATPs, CYP2C8, and OATP1B1/CYP2C8 probe drugs (pitavastatin, pioglitazone, and repaglinide, respectively) with or without the coadministration of either 600 mg rifampicin (an inhibitor for OATPs), 200 mg trimethoprim (an inhibitor for CYP2C8), or 300 mg clopidogrel was performed, and the area under the concentration-time curve (AUC) ratios (AUCRs) for probe substrates were predicted using a static model...
October 2016: Drug Metabolism and Disposition: the Biological Fate of Chemicals
https://www.readbyqxmd.com/read/27417579/cytochrome-p450-oxidase-2c-inhibition-adds-to-%C3%AF-3-long-chain-polyunsaturated-fatty-acids-protection-against-retinal-and-choroidal-neovascularization
#18
Yan Gong, Zhongjie Fu, Matthew L Edin, Chi-Hsiu Liu, Zhongxiao Wang, Zhuo Shao, Thomas W Fredrick, Nicholas J Saba, Peyton C Morss, Samuel B Burnim, Steven S Meng, Fred B Lih, Kin Sing Stephen Lee, Elizabeth P Moran, John Paul SanGiovanni, Ann Hellström, Bruce D Hammock, Darryl C Zeldin, Lois E H Smith
OBJECTIVE: Pathological ocular neovascularization is a major cause of blindness. Increased dietary intake of ω-3 long-chain polyunsaturated fatty acids (LCPUFA) reduces retinal neovascularization and choroidal neovascularization (CNV), but ω-3 LCPUFA metabolites of a major metabolizing pathway, cytochrome P450 oxidase (CYP) 2C, promote ocular pathological angiogenesis. We hypothesized that inhibition of CYP2C activity will add to the protective effects of ω-3 LCPUFA on neovascular eye diseases...
September 2016: Arteriosclerosis, Thrombosis, and Vascular Biology
https://www.readbyqxmd.com/read/27399255/drug-interaction-between-dabrafenib-and-immunosuppressive-drugs-about-one-case
#19
Matthieu Levavasseur, Sophie Darras, Laurent Mortier, Céline Goeminne, Marine Auffret, Marie Bertrand
Melanoma is a major public health problem. In recent years, it has been shown that melanoma can be characterized by specific oncogenes mutations such as the BRAF mutation, leading to the development of new therapeutic drugs. Dabrafenib is an inhibitor of BRAF, approved as a first-line treatment of metastatic or unresectable stage 3 or 4 melanoma with the BRAF mutation. Few studies have evaluated the drug interaction potential of dabrafenib. This molecule is an enzyme inducer that increases the synthesis of drug-metabolizing enzymes, including CYP3A4, CYP2B6, CYP2C8, CYP2C9, CYP2C19, and UGT enzymes...
October 2016: Melanoma Research
https://www.readbyqxmd.com/read/27347418/potential-drug-interaction-between-paclitaxel-and-clopidogrel
#20
Yasutaka Shinoda, Michio Kimura, Eiseki Usami, Hiroki Asano, Tomoaki Yoshimura
Paclitaxel is mainly inactivated in vivo by cytochrome P5402C8 (CYP2C8). In recent years, the clopidogrel metabolite has been reported to potently inhibit CYP2C8. However, clinical information regarding the interaction between these two drugs is limited. To the best of our knowledge, this is the first retrospective study investigating the potential for the drug interaction between paclitaxel and clopidogrel. A total of 8 cases in which clopidogrel and paclitaxel were used in combination were examined. The incidence of adverse events and discontinuation rate in these cases were assessed...
July 2016: Biomedical Reports
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