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https://www.readbyqxmd.com/read/29044450/antipsychotic-therapy-amongst-cytochrome-p450-2d6-poor-metabolizers-in-the-clinical-practice-a-case-report
#1
Laura Espinosa-Martínez, Adriana Fortea, Giovanni Oriolo, Alexandre González-Rodríguez, Mercè Brunet, Virginia Fortuna, Eduard Parellada
No abstract text is available yet for this article.
September 2017: Actas Españolas de Psiquiatría
https://www.readbyqxmd.com/read/28994497/effects-of-vernonia-cinerea-compounds-on-drug-metabolizing-cytochrome-p450s-in-human-liver-microsomes
#2
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/28990182/effect-of-chronic-kidney-disease-on-nonrenal-elimination-pathways-a-systematic-assessment-of-cyp1a2-cyp2c8-cyp2c9-cyp2c19-and-oatp
#3
Ming-Liang Tan, Kenta Yoshida, Ping Zhao, Lei Zhang, Thomas D Nolin, Micheline Piquette-Miller, Aleksandra Galetin, Shiew-Mei Huang
Our recent studies have shown that chronic kidney disease (CKD) affects the pharmacokinetics (PKs) of cytochrome P450 (CYP)2D6-metabolized drugs, whereas effects were less evident on CYP3A4/5. Therefore, the effect of CKD on the disposition of CYP1A2-metabolized, CYP2C8-metabolized, CYP2C9-metabolized, CYP2C19-metabolized, and organic anion-transporting polypeptide (OATP)-transported drugs was investigated. We identified dedicated CKD studies with 6, 5, 6, 4, and 12 "model" substrates for CYP1A2, CYP2C8, CYP2C9, CYP2C19, and OATP, respectively...
October 9, 2017: Clinical Pharmacology and Therapeutics
https://www.readbyqxmd.com/read/28955222/improved-prediction-of-endoxifen-metabolism-by-cyp2d6-genotype-in-breast-cancer-patients-treated-with-tamoxifen
#4
Werner Schroth, Stefan Winter, Thomas Mürdter, Elke Schaeffeler, Diana Eccles, Bryony Eccles, Balram Chowbay, Chiea C Khor, Arafat Tfayli, Nathalie K Zgheib, Michel Eichelbaum, Matthias Schwab, Hiltrud Brauch
Purpose: Prediction of impaired tamoxifen (TAM) to endoxifen metabolism may be relevant to improve breast cancer treatment, e.g., via TAM dose increase. The polymorphic cytochrome P450 2D6 (CYP2D6) strongly determines an individual's capacity for endoxifen formation, however, CYP2D6 phenotype assignments inferred from genotype widely differ between studies. Thus, we modeled plasma endoxifen predictability depending on variable CYP2D6 genotype groupings. Methods: CYP2D6 diplotype and metabolite plasma concentrations were assessed in 908 pre- and post-menopausal estrogen receptor (ER)-positive, TAM treated early breast cancer patients of Caucasian (N = 678), Middle-Eastern Arab (N = 77), and Asian (N = 153) origin...
2017: Frontiers in 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
#5
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/28920579/point-of-care-companion-diagnostic-tests-for-personalizing-psychiatric-medications-fulfilling-an-unmet-clinical-need
#6
Anil S Modak
Over the last decade stable isotope labeled substrates have been used as probes for rapid, point of care, non invasive and user friendly phenotype breath tests to evaluate activity of drug metabolizing enzymes. These diagnostic breath tests can be potentially used as Companion diagnostics (CDx) by physicians to personalize medications especially psychiatric drugs with narrow therapeutic windows, to monitor the progress of disease severity, medication efficacy and to study in vivo the pharmacokinetics of xenobiotics, Several genotype tests have been approved by the FDA over the last 15 years, however, they have not been cleared for use in personalizing medications since they fall woefully short in identifying all non responders to drugs especially for the CYP450 enzymes...
September 18, 2017: Journal of Breath Research
https://www.readbyqxmd.com/read/28917081/evaluation-of-the-ecstasy-influence-on-tramadol-and-its-main-metabolite-plasma-concentration-in-rats
#7
Bardia Jamali, Behjat Sheikholeslami, Yalda Hosseinzadeh Ardakani, Hoda Lavasani, Mohammad-Reza Rouini
BACKGROUND: Tramadol is prone to be abused alone, or in combination with 3,4-methylenedioxymethamphetamine (MDMA, Ecstasy). It was reported that 95% of people with a history of substance abuse in the United States used tramadol in 2004. According to the WHO report in 2016, there was a growing number of tramadol abusers alone or in combination with psychoactive substances such as MDMA in particular in some Middle East countries. Higher concentrations of tramadol in plasma may lead to adverse drug reactions or lethal intoxication...
September 26, 2017: Drug Metabolism and Personalized Therapy
https://www.readbyqxmd.com/read/28916283/deuterated-d6-dextromethorphan-elicits-antidepressant-like-effects-in-mice
#8
Linda Nguyen, Anna L Scandinaro, Rae R Matsumoto
The over-the-counter antitussive dextromethorphan (DM) may have rapid antidepressant actions based on its overlapping pharmacology with ketamine, which has shown fast antidepressant effects but whose widespread use remains limited by problematic side effects. We have previously shown that DM produces antidepressant-like effects in the forced swim test (FST) and tail suspension test (TST) that are mediated in part through α-amino-3-hydroxy-5-methyl-4-isoxazole propionic (AMPA) and sigma-1 receptors, two protein targets associated with a faster onset of antidepressant efficacy...
October 2017: Pharmacology, Biochemistry, and Behavior
https://www.readbyqxmd.com/read/28871472/cytochrome-p450-2d6-and-parkinson-s-disease-polymorphism-metabolic-role-risk-and-protection
#9
REVIEW
Mohd Sami Ur Rasheed, Abhishek Kumar Mishra, Mahendra Pratap Singh
Cytochrome P450 (CYP) 2D6 is one of the most highly active, oxidative and polymorphic enzymes known to metabolize Parkinsonian toxins and clinically established anti-Parkinson's disease (PD) drugs. Albeit CYP2D6 gene is not present in rodents, its orthologs perform almost the similar function with imprecise substrate and inhibitor specificity. CYP2D6 expression and catalytic activity are found to be regulated at every stage of the central dogma except replication as well as at the epigenetic level. CYP2D6 gene codes for a set of alternate splice variants that give rise to a range of enzymes possessing variable catalytic activity...
September 4, 2017: Neurochemical Research
https://www.readbyqxmd.com/read/28866862/acetylshikonin-is-a-novel-non-selective-cytochrome-p450-inhibitor
#10
Jong Cheol Shon, Nguyen Minh Phuc, Won Cheol Kim, Jae Kyung Heo, Zhexue Wu, Hyunyoung Lee, Kwang-Hyeon Liu
Acetylshikonin is biologically active compound with anti-cancer and anti-inflammatory activity, which is isolated from the root of Lithospermum erythrorhizoma. We have recently discovered a inhibitory effect of acetylshikonin against CYP2J2 activity. Based on this result, we expanded our study to evaluate the inhibitory effects of acetylshikonin against nine different cytochrome P450 (P450) isoforms in human liver microsomes (HLMs) using substrate cocktails incubation assay. Acetylshikonin showed strong inhibitory effect against all P450s tested with IC50 values of 1...
September 3, 2017: Biopharmaceutics & Drug Disposition
https://www.readbyqxmd.com/read/28834279/the-cytochrome-p450-enzyme-responsible-for-the-production-of-z-norendoxifen-in-vitro
#11
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/28808272/a-combinatorial-approach-for-the-discovery-of-cytochrome-p450-2d6-inhibitors-from-nature
#12
Johannes Hochleitner, Muhammad Akram, Martina Ueberall, Rohan A Davis, Birgit Waltenberger, Hermann Stuppner, Sonja Sturm, Florian Ueberall, Johanna M Gostner, Daniela Schuster
The human cytochrome P450 2D6 (CYP2D6) enzyme is part of phase-I metabolism and metabolizes at least 20% of all clinically relevant drugs. Therefore, it is an important target for drug-drug interaction (DDI) studies. High-throughput screening (HTS) assays are commonly used tools to examine DDI, but show certain drawbacks with regard to their applicability to natural products. We propose an in silico - in vitro workflow for the reliable identification of natural products with CYP2D6 inhibitory potential. In order to identify candidates from natural product-based databases that share similar structural features with established inhibitors, a pharmacophore model was applied...
August 14, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28782945/fame-2-simple-and-effective-machine-learning-model-of-cytochrome-p450-regioselectivity
#13
Martin Šícho, Christina de Bruyn Kops, Conrad Stork, Daniel Svozil, Johannes Kirchmair
We report on the further development of FAst MEtabolizer (FAME; J. Chem. Inf. MODEL: 2013, 53, 2896-2907), a collection of random forest models for the prediction of sites of metabolism (SoMs) of xenobiotics. A broad set of descriptors was explored, from simple 2D descriptors such as those used in FAME, to quantum chemical descriptors employed in some of the most accurate models for SoM prediction currently available. In line with the original FAME approach, our objective was to keep things simple and to come up with accurate and robust models that are based on a small number of 2D descriptors...
August 28, 2017: Journal of Chemical Information and Modeling
https://www.readbyqxmd.com/read/28726718/inhibitory-effects-of-trapping-agents-of-sulfur-drug-reactive-intermediates-against-major-human-cytochrome-p450-isoforms
#14
Jasleen K Sodhi, Erlie Marie Delarosa, Jason S Halladay, James P Driscoll, Teresa Mulder, Patrick M Dansette, S Cyrus Khojasteh
In some cases, the formation of reactive species from the metabolism of xenobiotics has been linked to toxicity and therefore it is imperative to detect potential bioactivation for candidate drugs during drug discovery. Reactive species can covalently bind to trapping agents in in vitro incubations of compound with human liver microsomes (HLM) fortified with β-nicotinamide adenine dinucleotide phosphate (NADPH), resulting in a stable conjugate of trapping agent and reactive species, thereby facilitating analytical detection and providing evidence of short-lived reactive metabolites...
July 20, 2017: International Journal of Molecular Sciences
https://www.readbyqxmd.com/read/28716517/lethal-suicide-attempt-with-a-mixed-drug-intoxication-of-metoprolol-and-propafenone-a-first-pediatric-case-report
#15
Ivana Kacirova, Milan Grundmann, Martin Kolek, Erika Vyskocilova-Hrudikova, Romana Urinovska, Petr Handlos
INTRODUCTION: The β1 adrenergic receptor blocker metoprolol is often prescribed together with the antiarrhythmic drug propafenone. Both are metabolized by cytochrome P450 2D6 and propafenone is also an inhibitor of this enzyme. We present a pediatric case showing metoprolol and propafenone intoxication in combination. CASE: A 14-year-old girl was admitted to a local emergency department after ingestion of metoprolol (probably 1g) and propafenone (probably 1.5-3g) in a suicide attempt...
September 2017: Forensic Science International
https://www.readbyqxmd.com/read/28696416/cytochrome-p450-interactions-are-common-and-consequential-in-massachusetts-hospital-discharges
#16
T H McCoy, V M Castro, A Cagan, L Snapper, A Roberson, R H Perlis
Despite the recognition that drug-drug interactions contribute substantially to preventable health-care costs, the prevalence of such interactions related to the cytochrome P450 system in clinical practice remains poorly characterized. This study drew retrospective hospital discharge cohorts from a large health claims data set and a large health system data set. For every hospital discharge, frequency of co-occurrence of substrates and inducers or inhibitors at cytochrome P450 2D6, 2C19, 3A4 and 1A2 were determined...
July 11, 2017: Pharmacogenomics Journal
https://www.readbyqxmd.com/read/28663285/inhibitory-effects-of-selected-antituberculosis-drugs-on-common-human-hepatic-cytochrome-p450-and-udp-glucuronosyltransferase-enzymes
#17
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
#18
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
#19
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
https://www.readbyqxmd.com/read/28648122/phase-1-study-to-investigate-the-pharmacokinetic-properties-of-dacomitinib-in-healthy-adult-chinese-subjects-genotyped-for-cyp2d6
#20
Xia Chen, Ji Jiang, Nagdeep Giri, Pei Hu
1. This study aimed to characterise the pharmacokinetics of dacomitinib, a pan-human epidermal growth factor receptor tyrosine kinase inhibitor, and its metabolite, PF-05199265, in healthy Chinese subjects. 2. In this open-label, single-centre, nonrandomised study (NCT02097433), 14 subjects received a single dacomitinib 45-mg oral dose. Pharmacokinetic samples for dacomitinib and PF-05199265 were collected pre- and postdose. Subjects were genotyped for cytochrome P450 (CYP)2D6 metaboliser status. Safety was assessed throughout the study...
June 26, 2017: Xenobiotica; the Fate of Foreign Compounds in Biological Systems
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