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https://www.readbyqxmd.com/read/29205871/pharmacogenetic-analysis-of-the-model-based-pharmacokinetics-of-five-anti-hiv-drugs-how-does-this-influence-the-effect-of-aging
#1
Jingxian Chen, Farida S Akhtari, Michael J Wagner, Oscar Suzuki, Tim Wiltshire, Alison A Motsinger-Reif, Julie B Dumond
Analysis of aging and pharmacogenetics (PGx) on antiretroviral pharmacokinetics (PKs) could inform precision dosing for older human HIV-infected patients. Seventy-four participants receiving either atazanavir/ritonavir (ATV/RTV) or efavirenz (EFV) with tenofovir/emtricitabine (TFV/FTC) provided PK and PGx information. Aging-PGx-PK association and interaction analyses were conducted using one-way analysis of variance (ANOVA), multiple linear regression, and Random Forest ensemble methods. Our analyses associated unbound ATV disposition with multidrug resistance protein (MRP)4, RTV with P-glycoprotein (P-gp), and EFV with cytochrome P450 (CYP)2B6 and MRP4 genetic variants...
December 3, 2017: Clinical and Translational Science
https://www.readbyqxmd.com/read/29176019/in-vitro-modulation-of-the-cytochrome-p450-and-abcb1-p-glycoprotein-activities-of-the-aqueous-extract-of-allophylus-cominia-l-sw-leaves
#2
Carlos L Pérez, Maria T Donato, Ivones Hernández, Miriam T Paz Lopes, Evangelina Marrero, Jose A Herrera, Maria J Gómez-Lechón, Idania Rodeiro
BACKGROUND: The aqueous extract of the Allophylus cominia (L) Sw (Sapindaceae) leaves has shown anti-diabetic, anti-obesity and anti-inflammatory properties. In the Caribbean region, it is typically used for the treatment of type-2 diabetes. METHODS: Considering the herb-drug interaction, the aim of this study was to evaluate the potential effects of the A. cominia extract on the cytochrome P450 (CYP) (rat hepatocyte model) and P-glycoprotein (P-gp) (4T1 cell line) systems...
November 25, 2017: Drug Metabolism and Personalized Therapy
https://www.readbyqxmd.com/read/29121650/flavin-containing-monooxygenase-3-fmo3-role-in-busulphan-metabolic-pathway
#3
Ibrahim El-Serafi, Ylva Terelius, Manuchehr Abedi-Valugerdi, Seán Naughton, Maryam Saghafian, Ali Moshfegh, Jonas Mattsson, Zuzana Potácová, Moustapha Hassan
Busulphan (Bu) is an alkylating agent used in the conditioning regimen prior to hematopoietic stem cell transplantation (HSCT). Bu is extensively metabolized in the liver via conjugations with glutathione to form the intermediate metabolite (sulfonium ion) which subsequently is degraded to tetrahydrothiophene (THT). THT was reported to be oxidized forming THT-1-oxide that is further oxidized to sulfolane and finally 3-hydroxysulfolane. However, the underlying mechanisms for the formation of these metabolites remain poorly understood...
2017: PloS One
https://www.readbyqxmd.com/read/29120380/in-vitro-phase-i-metabolism-of-crv431-a-novel-oral-drug-candidate-for-chronic-hepatitis-b
#4
Daniel J Trepanier, Daren R Ure, Robert T Foster
The cytochrome P450-mediated Phase I in vitro metabolism of CRV431 was studied using selective chemical inhibition and recombinant human enzymes. Additionally, the metabolic profile of CRV431 in human, rat, and monkey liver microsomes was investigated. Liver microsomes were incubated for 0-80 min with CRV431, and the metabolite profile was assessed by electrospray ionization liquid chromatography mass spectrometry (ESI-LCMS). CRV431 was extensively metabolized through oxidation to produce various hydroxylated and demethylated species...
November 9, 2017: Pharmaceutics
https://www.readbyqxmd.com/read/29081796/hepatocyte-cyp2b6-can-be-expressed-in-cell-culture-systems-by-exerting-physiological-levels-of-shear-implications-for-adme-testing
#5
REVIEW
Timothy G Hammond, Holly H Birdsall
Cytochrome 2B6 (CYP2B6) has substantial clinical effects on morbidity and mortality and its effects on drug metabolism should be part of hepatotoxicity screening. Examples of CYP2B6's impacts include its linkage to mortality during cyclophosphamide therapy and its role in determining hepatotoxicity and CNS toxicity during efavirenz therapy for HIV infection. CYP2B6 is key to metabolism of many common drugs from opioids to antidepressants, anesthetics, and anticonvulsants. But CYP2B6 has been extremely difficult to express in cell culture, and as a result, it has been largely deemphasized in preclinical toxicity studies...
2017: Journal of Toxicology
https://www.readbyqxmd.com/read/29054967/prediction-of-cytochrome-p450-mediated-drug-clearance-in-humans-based-on-the-measured-activities-of-selected-cyps
#6
Jie Gao, Jie Wang, Na Gao, Xin Tian, Jun Zhou, Yan Fang, Hai-Feng Zhang, Qiang Wen, Lin-Jing Jia, Dan Zou, Hai-Ling Qiao
Determining drug-metabolizing enzyme activities on an individual basis is an important component of personalized medicine, and cytochrome P450 enzymes (CYPs) play a principal role in hepatic drug metabolism. Herein, a simple method for predicting the major CYP-mediated drug clearance in vitro and in vivo is presented. Ten CYP-mediated drug metabolic activities in human liver microsomes (HLMs) from 105 normal liver samples were determined. The descriptive models for predicting the activities of these CYPs in HLMs were developed solely on the basis of the measured activities of a smaller number of more readily assayed CYPs...
October 20, 2017: Bioscience Reports
https://www.readbyqxmd.com/read/29018344/xanthates-as-useful-probes-for-testing-the-active-sites-of-cytochromes-p450-4a11-and-2e1
#7
Tsveta Stoyanova, Iglika Lessigiarska, Momir Mikov, Ilza Pajeva, Stanislav Yanev
Xanthates (alkyl or aryl derivatives of dithiocarbonic acid) have been shown to be selective mechanism-based inactivators of cytochromes P450 2B1/2B6 and 2E1 due to covalent binding of a reactive intermediate to apoprotein after double hydrogen abstraction at α-carbon atom, suggesting interaction of the xanthate dithiocarbonic head with the enzyme heme. The structures of xanthates with a long alkyl chain are similar to the fatty acids. Saturated fatty acids (FA) such as lauric acid (LA), are metabolized by different cytochrome P450 isoforms to ω- and (ω-1)-hydroxy products, in humans done by CYP4A11 and CYP2E1, respectively...
2017: Frontiers in Pharmacology
https://www.readbyqxmd.com/read/28994497/effects-of-vernonia-cinerea-compounds-on-drug-metabolizing-cytochrome-p450s-in-human-liver-microsomes
#8
Phisit Pouyfung, Songklod Sarapusit, Pornpimol Rongnoparut
Vernonia cinerea has been widely used in traditional medicines for various diseases and shown to aid in smoking abstinence and has anticancer properties. V. cinerea bioactive compounds, including flavonoids and hirsutinolide-type sesquiterpene lactones, have shown an inhibition effect on the nicotine-metabolizing cytochrome P450 2A6 (CYP2A6) enzyme and hirsutinolides reported suppressing cancer growth. In this study, V. cinerea ethanol extract and its bioactive compounds, including four flavonoids and four hirsutinolides, were investigated for an inhibitory effect on human liver microsomal CYPs 1A2, 2A6, 2B6, 2C8, 2C9, 2C19, 2D6, 2E1, and 3A4 using cocktail inhibition assays combined with LC-MS/MS analysis...
October 10, 2017: Phytotherapy Research: PTR
https://www.readbyqxmd.com/read/28962520/editor-s-highlight-complete-attenuation-of-mouse-lung-cell-proliferation-and-tumorigenicity-in-cyp2f2-knockout-and-cyp2f1-humanized-mice-exposed-to-inhaled-styrene-for-up-to-2%C3%A2-years-supports-a-lack-of-human-relevance
#9
George Cruzan, James S Bus, Marcy I Banton, Satinder S Sarang, Robbie Waites, Debra B Layko, James Raymond, Darol Dodd, Melvin E Andersen
Styrene is a mouse-specific lung carcinogen, and short-term mode of action studies have demonstrated that cytotoxicity and/or cell proliferation, and genomic changes are dependent on CYP2F2 metabolism. The current study examined histopathology, cell proliferation, and genomic changes in CD-1, C57BL/6 (WT), CYP2F2(-/-) (KO), and CYP2F2(-/-) (CYP2F1, 2B6, 2A13-transgene) (TG; humanized) mice following exposure for up to 104 weeks to 0- or 120-ppm styrene vapor. Five mice per treatment group were sacrificed at 1, 26, 52, and 78 weeks...
October 1, 2017: Toxicological Sciences: An Official Journal of the Society of Toxicology
https://www.readbyqxmd.com/read/28951217/assessing-molecular-initiating-events-mies-key-events-kes-and-modulating-factors-mfs-for-styrene-responses-in-mouse-lungs-using-whole-genome-gene-expression-profiling-following-1-day-and-multi-week-exposures
#10
Melvin E Andersen, George Cruzan, Michael B Black, Salil N Pendse, Darol Dodd, James S Bus, Satinder S Sarang, Marcy I Banton, Robbie Waites, Patrick D McMullen
Styrene increased lung tumors in mice at chronic inhalation exposures of 20ppm and greater. MIEs, KEs and MFs were examined using gene expression in three strains of male mice (the parental C57BL/6 strain, a CYP2F2(-/-) knock out and a CYP2F2(-/-) transgenic containing human CYP2F1, 2A13 and 2B6). Exposures were for 1-day and 1, 4 and 26weeks. After 1-day exposures at 1, 5, 10, 20, 40 and 120ppm significant increases in differentially expressed genes (DEGs) occurred only in parental strain lungs where there was already an increase in DEGs at 5ppm and then many thousands of DEGs by 120ppm...
November 15, 2017: Toxicology and Applied Pharmacology
https://www.readbyqxmd.com/read/28934153/inhibitory-effect-of-selaginellins-from-selaginella-tamariscina-beauv-spring-against-cytochrome-p450-and-uridine-5-diphosphoglucuronosyltransferase-isoforms-on-human-liver-microsomes
#11
Jae-Kyung Heo, Phi-Hung Nguyen, Won Cheol Kim, Nguyen Minh Phuc, Kwang-Hyeon Liu
Selaginella tamariscina (Beauv.) has been used for traditional herbal medicine for treatment of cancer, hepatitis, and diabetes in the Orient. Numerous bioactive compounds including alkaloids, flavonoids, lignans, and selaginellins have been identified in this medicinal plant. Among them, selaginellins having a quinone methide unit and an alkylphenol moiety have been known to possess anticancer, antidiabetic, and neuroprotective activity. Although there have been studies on the biological activities of selaginellins, their modulatory potential of cytochrome P450 (P450) and uridine 5'-diphosphoglucuronosyltransferase (UGT) activities have not been previously evaluated...
September 21, 2017: Molecules: a Journal of Synthetic Chemistry and Natural Product Chemistry
https://www.readbyqxmd.com/read/28858450/ketamine-for-depression-5-potential-pharmacokinetic-and-pharmacodynamic-drug-interactions
#12
REVIEW
Chittaranjan Andrade
Ketamine, administered in subanesthetic doses, is gaining recognition as an off-label treatment for severe and even treatment-refractory depression. This article explores potential pharmacokinetic and pharmacodynamic drug interactions of relevance to the use of ketamine in depression. Sparse evidence suggests that ketamine will not induce clinically significant drug interactions except to the extent that these are predictable by its clinical actions. A small body of literature indicates that drugs that induce cytochrome P450 (CYP)2B6 and CYP3A4 will reduce exposure to ketamine and that drugs that inhibit these enzymes will increase exposure to ketamine...
July 2017: Journal of Clinical Psychiatry
https://www.readbyqxmd.com/read/28834279/the-cytochrome-p450-enzyme-responsible-for-the-production-of-z-norendoxifen-in-vitro
#13
Dabei Tang, Zhong Chu, Jessica Bo Li Lu, Jinzhong Liu, Qingyuan Zhang
BACKGROUND: Norendoxifen, an active metabolite of tamoxifen, is a potent aromatase inhibitor. Little information is available regarding production of norendoxifen in vitro. Here, we conducted a series of kinetic and inhibition studies in human liver microsomes (HLMs) and expressed P450s to study the metabolic disposition of norendoxifen. METHODS: To validate that norendoxifen was the metabolite of endoxifen, metabolites in HLMs incubates of endoxifen were measured using a HPLC/MS/MS method...
August 17, 2017: Chemistry & Biodiversity
https://www.readbyqxmd.com/read/28791666/clinical-pharmacokinetics-and-pharmacodynamics-of-micafungin
#14
REVIEW
Roeland E Wasmann, Eline W Muilwijk, David M Burger, Paul E Verweij, Catherijne A Knibbe, Roger J Brüggemann
Micafungin is a selective inhibitor of the synthesis of fungal 1,3-β-D-glucan, an essential component of the fungal cell wall. It is available as a powder for infusion only and is registered for the treatment of invasive and esophageal candidiasis in addition to prophylaxis of Candida infections in both adults and children. Average exposure after a single intravenous 100 mg dose in healthy adults is 133 mg h/L. Both exposure and maximum plasma concentration show linear dose proportional pharmacokinetics (PK) over a 0...
August 8, 2017: Clinical Pharmacokinetics
https://www.readbyqxmd.com/read/28699698/reduced-dosing-and-liability-in-methadone-maintenance-treatment-by-targeting-oestrogen-signal-for-morphine-addiction
#15
Yao-Chang Chiang, Ruey-Yun Wang, Chieh-Liang Huang, Shue-Hwa Chen, Wen-Jing Ho, Hsien-Yuan Lane, Ing-Kang Ho, Hwei-Ting Yang, Wen-Lung Ma
Methadone maintenance treatment (MMT) is the major tapering therapy for morphine addictive patients. There have gender differences reported in response to MMT. This study discovered that the estrogen-response element single nucleotide polymorphism (ERE-SNP; rs16974799, C/T) of cytochrome 2B6 gene (cyp2b6; methadone catabolic enzyme) responded differently to MMT dosing. Oestradiol was associated with high MMT dosing, high enantiomer (R- or S-) of 2-ethylidene-1,5-dimethyl-3,3-dipheny-pyrrolidine (EDDP; methadone metabolite) to methadone ratio and increased drug-seeking behaviour, implicating oestradiol-CYP-EDDP/methadone axis decreasing MMT efficacy...
July 12, 2017: Journal of Cellular and Molecular Medicine
https://www.readbyqxmd.com/read/28692529/cyp2b6-genotypes-and-early-efavirenz-based-hiv-treatment-outcomes-in-botswana
#16
Robert Gross, Scarlett L Bellamy, Bakgaki Ratshaa, Xiaoyan Han, Marijana Vujkovic, Richard Aplenc, Andrew P Steenhoff, Mosepele Mosepele, Ganesh Moorthy, Athena F Zuppa, Brian L Strom, Gregory P Bisson
OBJECTIVES: To determine the association between cytochrome p450 2B6 genotypes and efavirenz-based HIV treatment outcomes. DESIGN: Observational cohort study of HIV-infected adults initiating efavirenz-based regimens in Botswana. METHODS: The primary endpoint was a composite of death or loss to care or HIV RNA more than 25 copies/ml at 6 months. CYP2B6 516G>T and 983T>C genotyping was done with Taqman Open Array platform. Adverse experiences were measured by using the Subject Experience Questionnaire...
September 24, 2017: AIDS
https://www.readbyqxmd.com/read/28674261/preliminary-evaluation-of-three-dimensional-primary-human-hepatocyte-culture-system-for-assay-of-drug-metabolizing-enzyme-inducing-potential
#17
Hiroshi Arakawa, Hiroki Kamioka, Tomoko Jomura, Satoshi Koyama, Yoko Idota, Kentaro Yano, Hajime Kojima, Takuo Ogihara
Drug-induced liver injury (DILI) is a common reason for withdrawal of candidate drugs from clinical trials, or of approved drugs from the market. DILI may be induced not only by intact parental drugs, but also by metabolites or intermediates, and therefore should be evaluated in the enzyme-induced state. Here, we present a protocol for assay of drug-metabolizing enzyme-inducing potential using three-dimensional (3D) primary cultures of human hepatocytes (hepatocyte spheroids). Hepatocyte spheroids could be used up to 21 d after seeding (pre-culture for 7 d and exposure to inducer for up to 14 d), based on preliminary evaluation of basal activities of CYP subtypes and mRNA expression of the corresponding transcription factor and xenobiotic receptors (aryl hydrocarbon receptor (AhR), constitutive androstane receptor (CAR) and pregnane X receptor (PXR))...
2017: Biological & Pharmaceutical Bulletin
https://www.readbyqxmd.com/read/28663285/inhibitory-effects-of-selected-antituberculosis-drugs-on-common-human-hepatic-cytochrome-p450-and-udp-glucuronosyltransferase-enzymes
#18
Lei Cao, David J Greenblatt, Awewura Kwara
The comorbidities of tuberculosis and diseases such as HIV require long-term treatment with multiple medications. Despite substantial in vitro and in vivo information on effects of rifampicin and isoniazid on human CYPs, there is limited published data regarding the inhibitory effects of other anti-TB drugs on human CYPs and UGTs. The inhibitory effects of five first-line anti-TB drugs (isoniazid, rifampicin, pyrazinamide, ethambutol, and rifabutin), and the newly approved bedaquiline, were evaluated for six common human hepatic UGT enzymes (UGT1A1, 1A4, 1A6, 1A9, 2B7 and 2B15) in vitro using HLMs...
September 2017: Drug Metabolism and Disposition: the Biological Fate of Chemicals
https://www.readbyqxmd.com/read/28653752/the-potential-of-epimedium-koreanum-nakai-for-herb-drug-interaction
#19
Qingxiang Zhong, Ziqi Shi, Li Zhang, Rongling Zhong, Zhi Xia, Jing Wang, Hao Wu, Yutong Jiang, E Sun, Yingjie Wei, Liang Feng, Zhenhai Zhang, Dan Liu, Jie Song, Xiaobin Jia
OBJECTIVES: This study aims to investigate potential herb-drug interactions (HDI) of Epimedium koreanum Nakai. METHODS: Human liver microsomes (HLMs) were used to determine the enzyme kinetics of the major human cytochrome P450s (CYPs). Inducible potential of E. koreanum on CYP1A2, 2B6, 2C19 and 3A4 activities of human primary hepatocytes was also examined. KEY FINDINGS: Ethanol extract of E. koreanum showed direct inhibitory potency for CYP1A2 (IC50  = 121...
June 27, 2017: Journal of Pharmacy and Pharmacology
https://www.readbyqxmd.com/read/28648140/oxidation-of-1-chloropyrene-by-human-cyp1-family-and-cyp2a-subfamily-cytochrome-p450-enzymes-catalytic-roles-of-two-cyp1b1-and-five-cyp2a13-allelic-variants
#20
Tsutomu Shimada, Norie Murayama, Kensaku Kakimoto, Shigeo Takenaka, Young-Ran Lim, Sora Yeom, Donghak Kim, Hiroshi Yamazaki, F Peter Guengerich, Masayuki Komori
1. 1-Chloropyrene, one of the major chlorinated polycyclic aromatic hydrocarbon contaminants, was incubated with human cytochrome P450 (P450 or CYP) enzymes including CYP1A1, 1A2, 1B1, 2A6, 2A13, 2B6, 2C9, 2D6, 2E1, 3A4 and 3A5. Catalytic differences in 1-chloropyrene oxidation by polymorphic two CYP1B1 and five CYP2A13 allelic variants were also examined. 2. CYP1A1 oxidized 1-chloropyrene at the 6- and 8-positions more actively than at the 3-position, while both CYP1B1.1 and 1B1.3 preferentially catalyzed 6-hydroxylation...
July 21, 2017: Xenobiotica; the Fate of Foreign Compounds in Biological Systems
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