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https://www.readbyqxmd.com/read/28642710/tacrolimus-updated-guidelines-through-poppk-modeling-how-to-benefit-more-from-cyp3a-pre-emptive-genotyping-prior-to-kidney-transplantation
#1
Jean-Baptiste Woillard, Michel Mourad, Michael Neely, Arnaud Capron, Ron H van Schaik, Teun van Gelder, Nuria Lloberas, Dennis A Hesselink, Pierre Marquet, Vincent Haufroid, Laure Elens
Tacrolimus (Tac) is a profoundly effective immunosuppressant that reduces the risk of rejection after solid organ transplantation. However, its use is hampered by its narrow therapeutic window along with its highly variable pharmacological (pharmacokinetic [PK] and pharmacodynamic [PD]) profile. Part of this variability is explained by genetic polymorphisms affecting the metabolic pathway. The integration of CYP3A4 and CY3A5 genotype in tacrolimus population-based PK (PopPK) modeling approaches has been proven to accurately predict the dose requirement to reach the therapeutic window...
2017: Frontiers in Pharmacology
https://www.readbyqxmd.com/read/28642094/investigation-of-the-component-in-artemisia-annua-l-leading-to-enhanced-antiplasmodial-potency-of-artemisinin-via-regulation-of-its-metabolism
#2
Tian-Yu Cai, Yun-Rui Zhang, Jian-Bo Ji, Jie Xing
ETHNOPHARMACOLOGICAL RELEVANCE: The chemical matrix of the herb Artemisia annua L. (A. annua), from which artemisinin (QHS) is isolated, can enhance both the bioavailability and efficacy of QHS. However, the exact mechanism of this synergism remains unknown. The biotransformation of QHS and potential "enzyme inhibitors" in plant matrix could be of great importance in understanding the improved efficacy of QHS in A. annua, which has been limited to the synergism with flavonoid components...
June 19, 2017: Journal of Ethnopharmacology
https://www.readbyqxmd.com/read/28640225/herb-drug-interaction-between-the-traditional-hepatoprotective-formulation-and-sorafenib-on-hepatotoxicity-histopathology-and-pharmacokinetics-in-rats
#3
Chin-Tsung Ting, Yung-Yi Cheng, Tung-Hu Tsai
Sorafenib has been used as a standard therapy for advanced hepatocellular carcinoma (HCC). In Asia, patients with HCC are potentially treated with the combination of sorafenib and Chinese herbal medicines to improve the efficiency and reduce the side effects of sorafenib. However, limited information about the herb-drug interactions is available. We hypothesize that the Chinese herbal medicine may exert hepatoprotective effects on the sorafenib-treated group. The aim of this study is to investigate the pharmacokinetic mechanism of drug-drug interactions of sorafenib including interacting with hepatoprotective formulation, Long-Dan-Xie-Gan-Tang formulation (LDXGT) and with two cytochrome P450 3A4 (CYP3A4) inhibitors, grapefruit juice and ketoconazole...
June 22, 2017: Molecules: a Journal of Synthetic Chemistry and Natural Product Chemistry
https://www.readbyqxmd.com/read/28639119/a-pharmacokinetic-drug-drug-interaction-study-between-selexipag-and-midazolam-a-cyp3a4-substrate-in-healthy-male-subjects
#4
Pierre-Eric Juif, Margaux Boehler, Yves Donazzolo, Shirin Bruderer, Jasper Dingemanse
PURPOSE: In vitro data showed that selexipag and its active metabolite (ACT-333679) have an inductive effect on CYP3A4, CYP2B6, and CYP2C9 at concentrations approximately 100-fold higher than the maximum plasma concentration (C max) measured under steady-state conditions. In order to confirm in vivo the lack of induction at the enterocyte level, we assessed the effect of selexipag on midazolam, a substrate of hepatic and intestinal CYP3A4. METHODS: This study was conducted according to an open-label, randomized, two-way crossover design...
June 21, 2017: European Journal of Clinical Pharmacology
https://www.readbyqxmd.com/read/28637770/analgesia-and-opioids-a-pharmacogenetics-shortlist-for-implementation-in-clinical-practice
#5
REVIEW
Maja Matic, Saskia N de Wildt, Dick Tibboel, Ron H N van Schaik
BACKGROUND: The use of opioids to alleviate pain is complicated by the risk of severe adverse events and the large variability in dose requirements. Pharmacogenetics (PGx) could possibly be used to tailor pain medication based on an individual's genetic background. Many potential genetic markers have been described, and the importance of genetic predisposition in opioid efficacy and toxicity has been demonstrated in knockout mouse models and human twin studies. Such predictors are especially of value for neonates and young children, in whom the assessment of efficacy or side effects is complicated by the inability of the patient to communicate this properly...
June 21, 2017: Clinical Chemistry
https://www.readbyqxmd.com/read/28636886/sirt1-enzymatically-potentiates-1-25-dihydroxyvitamin-d3-signaling-via-vitamin-d-receptor-deacetylation
#6
Marya S Sabir, Chengcheng Hu, Zainab Khan, Michael A Galligan, Christopher M Dussik, Sanchita Mallick, Angelika Dampf Stone, Shane F Batie, Elizabeth T Jacobs, G Kerr Whitfield, Mark R Haussler, Michael C Heck, Peter W Jurutka
The hormonal metabolite of vitamin D, 1,25-dihydroxyvitamin D3 (1,25D), binds to the vitamin D receptor (VDR) and promotes heterodimerization of VDR with a retinoid-X-receptor (RXR) to genomically regulate diverse cellular processes. Herein, it is revealed for the first time that VDR is post-translationally acetylated, and that VDR immunoprecipitated from human embryonic kidney (HEK293) cells displays a dramatic decrease in acetylated receptor in the presence of 1,25D-ligand, sirtuin-1 (SIRT1) deacetylase, or the resveratrol activator of SIRT1...
June 18, 2017: Journal of Steroid Biochemistry and Molecular Biology
https://www.readbyqxmd.com/read/28633424/three-dimensional-3d-heparg-spheroid-model-with-physiologically-relevant-xenobiotic-metabolism-competence-and-hepatocyte-functionality-for-liver-toxicity-screening
#7
Sreenivasa C Ramaiahgari, Suramya Waidyanatha, Darlene Dixon, Michael J DeVito, Richard S Paules, Stephen S Ferguson
Effective prediction of human responses to chemical and drug exposure is of critical importance in environmental toxicology research and drug development. While significant progress has been made to address this challenge using in vitro liver models, these approaches often fail due to inadequate tissue model functionality. Herein, we describe the development, optimization, and characterization of a novel three-dimensional (3D) spheroid model using differentiated HepaRG cells that achieve and maintain physiologically-relevant levels of xenobiotic metabolism (CYP1A2, CYP2B6, and CYP3A4/5)...
June 15, 2017: Toxicological Sciences: An Official Journal of the Society of Toxicology
https://www.readbyqxmd.com/read/28627229/cobicistat-versus-ritonavir-similar-pharmacokinetic-enhancers-but-some-important-differences
#8
Alice Tseng, Christine A Hughes, Janet Wu, Jason Seet, Elizabeth J Phillips
OBJECTIVE: To describe properties of cobicistat and ritonavir; compare boosting data with atazanavir, darunavir, and elvitegravir; and summarize antiretroviral and comedication interaction studies, with a focus on similarities and differences between ritonavir and cobicistat. Considerations when switching from one booster to another are discussed. DATA SOURCES: A literature search of MEDLINE was performed (1985 to April 2017) using the following search terms: cobicistat, ritonavir, pharmacokinetic, drug interactions, booster, pharmacokinetic enhancer, HIV, antiretrovirals...
June 1, 2017: Annals of Pharmacotherapy
https://www.readbyqxmd.com/read/28626197/evaluation-of-cyp2d6-protein-expression-and-activity-in-the-small-intestine-to-determine-its-metabolic-capability-in-the-japanese-population
#9
Momoko Kawakami, Sachiko Takenoshita-Nakaya, Yuko Takeba, Yuki Nishimura, Masayuki Oda, Minoru Watanabe, Yuki Ohta, Shinjiro Kobayashi, Takehito Ohtsubo, Shinichi Kobayashi, Naoki Uchida, Naoki Matsumoto
CYP2D6 plays an important role in the metabolism of many drugs such as opioids and antidepressants. Polymorphisms of the CYP2D6 gene are widely observed in the Japanese population, and can affect the first-pass metabolism of orally administered drugs. Several CYP enzymes have been identified in the small intestine of Caucasians, but intestinal CYP enzymes have not been reported in the Japanese population, except for CYP3A4 and CYP2C19. In this study, we evaluated the CYP2D6 metabolic capacity by measurement of CYP2D6 mRNA and protein levels and activity in the small intestine of Japanese individuals...
June 14, 2017: Biological & Pharmaceutical Bulletin
https://www.readbyqxmd.com/read/28622553/toxic-responses-of-cytochrome-p450-sub-enzyme-activities-to-heavy-metals-exposure-in-soil-and-correlation-with-their-bioaccumulation-in-eisenia-fetida
#10
Xiufeng Cao, Ran Bi, Yufang Song
The dose- and time- dependent responses of cytochrome P450 (CYP) sub-enzyme activities to heavy metals in soil, and the relationships between biomarker responses and metal bioaccumulation in Eisenia fetida were evaluated. Earthworms were exposed to soils spiked with increasing doses of Cd, Cu, Pb or Zn for 21 d. Results demonstrated that EROD and CYP3A4 activities responded significantly with increasing dose and exposure duration. EROD activity significantly (P < 0.05) correlated with CYP3A4 activity exposed to Pb and Cu...
June 13, 2017: Ecotoxicology and Environmental Safety
https://www.readbyqxmd.com/read/28621555/slc28a3-rs7853758-as-a-new-biomarker-of-tacrolimus-elimination-and-new-onset-hypertension-in-chinese-liver-transplantation-patients
#11
Yuan Liu, Tao Zhang, Changcan Li, Ling Ye, Haitao Gu, Lin Zhong, Hongcheng Sun, Yahuang Sun, Zhihai Peng, Junwei Fan
AIM: The effect of SLC28A3 on tacrolimus disposition and new-onset hypertension (NOHP) after liver transplantation (LT) remains unclear. Methodology & results: A total of 169 patients in two cohorts from the China Liver Transplant Registry database were included. Rs7853758 in recipients'SLC28A3 could predict tacrolimus pharmacokinetics in two sets. The model of donors' CYP3A5 rs776746 and recipients' CYP3A4 rs2242480 could predict tacrolimus metabolism at week 1 and the model of donors' CYP3A5 rs776746, recipients' CYP3A4 rs2242480, recipients' SLC28A3 rs7853758 and hemoglobin could predict tacrolimus disposition at weeks 2, 3 and 4...
June 16, 2017: Biomarkers in Medicine
https://www.readbyqxmd.com/read/28618157/liver-microsomal-lipid-enhances-the-activity-and-redox-coupling-of-co-localised-cytochrome-p450-reductase-cytochrome-p450-3a4-in-nanodiscs
#12
Kang-Cheng Liu, John M X Hughes, Sam Hay, Nigel S Scrutton
The haem-containing monooxygenase cytochrome P450 3A4 (CYP3A4) and its redox partner NADPH-dependent cytochrome P450 oxidoreductase (CPR) are among the most important enzymes in human liver for metabolising drugs and xenobiotic compounds. They are membrane-bound in the endoplasmic reticulum (ER). How ER co-localisation and the complex ER phospholipid composition influence enzyme activity are not well understood. CPR and CYP3A4 were incorporated into phospholipid bilayer nanodiscs, both singly, and together in a 1:1 ratio, to investigate the significance of membrane insertion and the influence of varying membrane composition on steady-state reaction kinetics...
June 15, 2017: FEBS Journal
https://www.readbyqxmd.com/read/28616684/influence-of-ethanol-on-darunavir-hepatic-clearance-and-intracellular-pk-pd-in-hiv-infected-monocytes-and-cyp3a4-darunavir-interactions-using-inhibition-and-in-silico-binding-studies
#13
Narasimha M Midde, Yuqing Gong, Theodore J Cory, Junhao Li, Bernd Meibohm, Weihua Li, Santosh Kumar
PURPOSE: Although the prevalence of alcohol consumption is higher in HIV+ people than general public, limited information is available on how alcohol affects the metabolism and bioavailability of darunavir (DRV). METHODS: DRV was quantified by using LC-MS/MS method. All in vitro experiments were performed using human liver microsomes and HIV-infected monocytic cells. CYP3A4 and DRV/Ritonavir (RTV) docking was performed using GOLD suite 5.8. RESULTS: Ethanol (20 mM) significantly decreased apparent half-life and increased degradation rate constant of RTV-boosted DRV but not for DRV alone...
June 14, 2017: Pharmaceutical Research
https://www.readbyqxmd.com/read/28614988/in-vitro-inhibitory-effects-of-dihydromyricetin-on-human-liver-cytochrome-p450-enzymes
#14
Lu Liu, Sen Sun, Hongbing Rui, Xiaohua Li
CONTEXT: Dihydromyricetin (DHM) is the most abundant and active flavonoid component isolated from Ampelopsis grossedentata (Hand-Mazz) W.T. Wang (Vitaceae) and it possesses numerous pharmacological activities. However, whether DHM affects the activity of human liver cytochrome P450 (CYP) enzymes remains unclear. MATERIALS AND METHODS: The inhibitory effects of DHM on eight human liver CYP isoforms (i.e., 1A2, 3A4, 2A6, 2E1, 2D6, 2C9, 2C19 and 2C8) were investigated in vitro using human liver microsomes (HLMs)...
December 2017: Pharmaceutical Biology
https://www.readbyqxmd.com/read/28610444/midostaurin-for-the-treatment-of-acute-myeloid-leukemia
#15
Mrinal M Patnaik
Midostaurin is a multikinase tyrosine kinase inhibitor acting against targets known to be expressed in hematologic malignancies, especially acute myeloid leukemia. Midostaurin combined with chemotherapy followed by single-agent maintenance therapy elicited statistically significant and clinically meaningful improvement in overall survival versus placebo in patients with newly diagnosed FLT3-mutant acute myeloid leukemia. Although gastrointestinal events were more common with midostaurin, overall the drug was relatively well tolerated...
June 14, 2017: Future Oncology
https://www.readbyqxmd.com/read/28606603/identification-of-enzymes-responsible-for-nitrazepam-metabolism-and-toxicity-in-human
#16
Keigo Konishi, Tatsuki Fukami, Saki Gotoh, Miki Nakajima
Nitrazepam (NZP) is a hypnotic agent that rarely causes liver injuries in humans and teratogenicity in rodents. In humans, NZP is primarily metabolized to 7-aminonitrazepam (ANZP) by reduction and subsequently to 7-acetylamino nitrazepam (AANZP) by acetylation. ANZP can be regenerated from AANZP by hydrolysis in rodents, but it is still unclear whether this reaction occurs in humans. In rodents, AANZP may be associated with teratogenicity, while in humans, it is known that drug-induced liver injuries may be caused by NZP reactive metabolite(s)...
June 9, 2017: Biochemical Pharmacology
https://www.readbyqxmd.com/read/28606510/in-vitro-inhibitory-mechanisms-and-molecular-docking-of-1-s-1-acetoxychavicol-acetate-on-human-cytochrome-p450-enzymes
#17
A K M Mahmudul Haque, Kok Hoong Leong, Yoke Lin Lo, Khalijah Awang, Noor Hasima Nagoor
BACKGROUND: The compound, 1'-S-1'-acetoxychavicol acetate (ACA), isolated from the rhizomes of a Malaysian ethno-medicinal plant, Alpinia conchigera Griff. (Zingiberaceae), was previously shown to have potential in vivo antitumour activities. In the development of a new drug entity, potential interactions of the compound with the cytochrome P450 superfamily metabolizing enzymes need to be ascertain. PURPOSE: The concomitant use of therapeutic drugs may cause potential drug-drug interactions by decreasing or increasing plasma levels of the administered drugs, leading to a suboptimal clinical efficacy or a higher risk of toxicity...
July 15, 2017: Phytomedicine: International Journal of Phytotherapy and Phytopharmacology
https://www.readbyqxmd.com/read/28603840/pretransplant-4%C3%AE-hydroxycholesterol-does-not-predict-tacrolimus-exposure-or-dose-requirements-during-the-first-days-after-kidney-transplantation
#18
Thomas Vanhove, Mahmoud Hasan, Pieter Annaert, Stefan Oswald, Dirk R J Kuypers
AIMS: The CYP3A metric 4β-hydroxycholesterol (4βOHC) has been shown to correlate with tacrolimus steady-state apparent oral clearance (CL/F). Recently, pretransplant 4βOHC was shown not to predict tacrolimus CL/F after transplantation in a cohort of renal recipients (n=79). The goal of the current study was determine whether these findings could be validated in a substantially larger cohort. METHODS: In a retrospective analysis of 279 renal recipients, tacrolimus trough concentrations (C0), daily dose, haematocrit and other relevant covariates were registered every day for the first 14 days after transplantation...
June 11, 2017: British Journal of Clinical Pharmacology
https://www.readbyqxmd.com/read/28601507/synthesis-and-pharmacological-evaluation-of-glycine-amide-derivatives-as-novel-vascular-adhesion-protein-1-inhibitors-without-cyp3a4-and-cyp2c19-inhibition
#19
Susumu Yamaki, Yuji Koga, Akira Nagashima, Mitsuhiro Kondo, Yoshiaki Shimada, Keitaro Kadono, Ayako Moritomo, Kosei Yoshihara
Vascular adhesion protein-1 (VAP-1) is a promising therapeutic target for the treatment of diabetic nephropathy. Here, we conducted optimization studies of our lead compound 1, which we previously reported as a novel VAP-1 inhibitor, to enhance the inhibition of human VAP-1 and to reduce CYP3A4 and CYP2C19 inhibition. As a result, we identified 3-chloro-4-{4-[5-(3-{[glycyl(methyl)amino]methyl}phenyl)pyrimidin-2-yl]piperazin-1-yl}benzoic acid (17h) as a novel orally active VAP-1 inhibitor, with 14-fold increased human VAP-1 inhibitory activity compared to 1, without CYP3A4 and CYP2C19 inhibition...
May 31, 2017: Bioorganic & Medicinal Chemistry
https://www.readbyqxmd.com/read/28594339/cardiac-dysrhythmias-associated-with-substitutive-use-of-loperamide-a-systematic-review
#20
Irbaz Bin Riaz, Muhammad Shahzeb Khan, Muhammad Umar Kamal, Qurat-Ul-Ain Riaz Sipra, Anum Riaz, Umar Zahid, Sandipan Bhattacharjee
BACKGROUND: Recently, several deaths secondary to cardiac arrhythmias have been reported in association with substitutive use of loperamide. Therefore, we conducted a systematic review of all reported cases to overview the epidemiologic patterns and clinical outcomes to better elucidate loperamide-induced cardiac complications. AREAS OF UNCERTAINTY: Association between substitutive use of loperamide and cardiac arrhythmias. DATA SOURCES: A comprehensive literature search was conducted across 6 databases using variety of keywords to identify all reports of cardiac side effects associated with loperamide abuse...
April 27, 2017: American Journal of Therapeutics
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