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https://www.readbyqxmd.com/read/28239482/aggressive-clinical-approach-to-obesity-improves-metabolic-and-clinical-outcomes-and-can-prevent-bariatric-surgery-a-single-center-experience
#1
Flavio A Cadegiani, Gustavo C Diniz, Gabriella Alves
BACKGROUND: The number of bariatric procedures has exponentially increased in the past decade, as a result of the lack of successful clinical weight-loss interventions. The main reasons for the failure of clinical obesity management are: (1) anti-obesity medications are administered as monotherapies (or pre-combined drugs); (2) lack of combination between pharmacotherapy and non-pharmacological modalities; (3) short duration of pharmacotherapy for obesity; (4) lack of weight-loss maintenance strategies; (5) misunderstanding of the complex pathophysiology of obesity; and (6) underprescription of anti-obesity medications...
2017: BMC Obesity
https://www.readbyqxmd.com/read/28239160/insights-into-the-molecular-mechanisms-of-polygonum-multiflorum-thunb-induced-liver-injury-a-computational-systems-toxicology-approach
#2
Yin-Yin Wang, Jie Li, Zeng-Rui Wu, Bo Zhang, Hong-Bin Yang, Qin Wang, Ying-Chun Cai, Gui-Xia Liu, Wei-Hua Li, Yun Tang
An increasing number of cases of herb-induced liver injury (HILI) have been reported, presenting new clinical challenges. In this study, taking Polygonum multiflorum Thunb (PmT) as an example, we proposed a computational systems toxicology approach to explore the molecular mechanisms of HILI. First, the chemical components of PmT were extracted from 3 main TCM databases as well as the literature related to natural products. Then, the known targets were collected through data integration, and the potential compound-target interactions (CTIs) were predicted using our substructure-drug-target network-based inference (SDTNBI) method...
February 27, 2017: Acta Pharmacologica Sinica
https://www.readbyqxmd.com/read/28238946/involvement-of-pregnane-x-receptor-in-the-suppression-of-carboxylesterases-by-metformin-in-vivo-and-in-vitro-mediated-by-the-activation-of-ampk-and-jnk-signaling-pathway
#3
Enfang Shan, Zhu Zhu, Shuangcheng He, Dongbao Chu, Dinghao Ge, Yunran Zhan, Wei Liu, Jian Yang, Jing Xiong
Type 2 diabetes mellitus (T2D) is a complex metabolic disorder requiring polypharmacy treatment in clinic, with metformin being widely used antihyperglycemic drug. However, the mechanisms of metformin as a perpetrator inducing potential drug-drug interactions and adverse drug reactions are scarcely known to date. Carboxylesterases (CESs) are major hydrolytic enzymes highly expressed in the liver, including mouse carboxylesterase 1d (Ces1d) and Ces1e. In the present study, experiments are designed to investigate the effects and mechanisms of metformin on Ces1d and Ces1e in vivo and in vitro...
February 23, 2017: European Journal of Pharmaceutical Sciences
https://www.readbyqxmd.com/read/28238899/estimation-of-the-contribution-of-cyp2c8-and-cyp3a4-in-repaglinide-metabolism-by-human-liver-microsomes-under-various-buffer-conditions
#4
Toshiyuki Kudo, Hitomi Goda, Yuki Yokosuka, Ryo Tanaka, Seina Komatsu, Kiyomi Ito
We have previously reported that the microsomal activities of CYP2C8 and CYP3A4 largely depend on the buffer condition used in in vitro metabolic studies, with different patterns observed between the two isozymes. In the present study, therefore, the possibility of buffer condition dependence of the fraction metabolized by CYP2C8 (fm2C8) for repaglinide, a dual substrate of CYP2C8 and CYP3A4, was estimated using human liver microsomes under various buffer conditions. Montelukast and ketoconazole showed a potent and concentration-dependent inhibition of CYP2C8-mediated paclitaxel 6α-hydroxylation and CYP3A4-mediated triazolam α-hydroxylation, respectively, without dependence on the buffer condition...
February 23, 2017: Journal of Pharmaceutical Sciences
https://www.readbyqxmd.com/read/28238896/comparison-of-the-predictability-of-human-hepatic-clearance-for-organic-anion-transporting-polypeptide-oatp-substrate-drugs-between-different-in-vitro-in-vivo-extrapolation-approaches
#5
Saki Izumi, Yoshitane Nozaki, Takafumi Komori, Osamu Takenaka, Maeda Kazuya, Hiroyuki Kusuhara, Yuichi Sugiyama
Prediction of human pharmacokinetic profiles of drug candidates is an essential step towards first-in-human studies. However, it remains difficult to quantitatively predict hepatic clearance, particularly when hepatic uptake is mediated by transporter(s). Using 15 organic anion transporting polypeptide (OATP) substrate drugs, we tested 3 in vitro-in vivo extrapolation (IVIVE) approaches to predict overall hepatic intrinsic clearance in vivo (CLint,all,vivo). IVIVE approaches involved metabolic intrinsic clearance in human liver microsomes (CLint,met) with or without hepatocyte-to-buffer maximum unbound concentration ratio (Kp,uu,max) correction and uptake intrinsic clearance at 37°C (PSinf,37°C) in human hepatocyte suspensions...
February 23, 2017: Journal of Pharmaceutical Sciences
https://www.readbyqxmd.com/read/28238819/alkylphospholipids-an-update-on-molecular-mechanisms-and-clinical-relevance
#6
REVIEW
Pablo Ríos-Marco, Carmen Marco, Xiomara Gálvez, Jose M Jiménez-López, María P Carrasco
Alkylphospholipid (APL) represent a new class of drugs which do not interact directly with DNA but act on the cell membrane where they accumulate and interfere with lipid metabolism and signalling pathways. This review summarizes the mode of action at the molecular level of these compounds. In this sense, a diversity of mechanisms has been suggested to explain the actions of clinically-relevant APLs, in particular, in cancer treatment. One consistently reported finding is that APLs reduce the biosynthesis of phosphatidylcholine (PC) by inhibiting the rate-limiting enzyme CTP:phosphocholine cytidylyltransferase (CT)...
February 23, 2017: Biochimica et Biophysica Acta
https://www.readbyqxmd.com/read/28238727/testosterone-metabolism-of-equine-single-cyps-of-the-3a-subfamily-compared-to-the-human-cyp3a4
#7
S Vimercati, M Büchi, J Zielinski, N Peduto, M Mevissen
Cytochrome P450 enzymes (CYPs) are responsible for the phase I metabolism of drugs, xenobiotics and endogenous substances. Knowledge of single CYPs and their substrates is important for drug metabolism, helps to predict adverse effects and may prevent reduced drug efficacy in polypharmacy. In this study, three equine isoenzymes of the 3A subfamily, the equine flavoprotein NADPH-P450 oxidoreductase (POR), and the cytochrome b5 (CYB5) were cloned, sequenced and heterologously expressed in a baculovirus expression system...
February 23, 2017: Toxicology in Vitro: An International Journal Published in Association with BIBRA
https://www.readbyqxmd.com/read/28238268/aryl-alkyl-lysines-membrane-active-fungicides-that-act-against-biofilms-of-candida-albicans
#8
Chandradhish Ghosh, Vikas Yadav, Waleed Younis, Haroon Mohammad, Youssef A Hegazy, Mohamed N Seleem, Kaustuv Sanyal, Jayanta Haldar
Mortality due to pathogenic fungi has been exacerbated by the rapid development of resistance to frontline antifungal drugs. Fungicidal compounds with novel mechanisms of action are urgently needed. Aryl-alkyl-lysines, which are membrane-active small molecules, were earlier shown to be broad-spectrum antibacterial agents with potency in vitro and in vivo. Herein, we report the antifungal properties of aryl-alkyl-lysines. After identifying the most active compound (NCK-10), we tested its activity against a panel of clinically relevant pathogenic fungi and examined NCK-10's effect against immature and mature biofilms of Candida albicans...
February 27, 2017: ACS Infectious Diseases
https://www.readbyqxmd.com/read/28237809/pregnenolone-16%C3%AE-carbonitrile-ameliorates-concanavalin-a-induced-liver-injury-in-mice-independent-of-the-nuclear-receptor-pxr-activation
#9
Susumu Kodama, Takuto Shimura, Hideaki Kuribayashi, Taiki Abe, Kouichi Yoshinari
The pregnane X receptor (PXR) is well-known as a key regulator of drug/xenobiotic clearance. Upon activation by ligand, PXR transcriptionally upregulates the expression of drug-metabolizing enzymes and drug transporters. Recent studies have revealed that PXR also plays a role in regulating immune/inflammatory responses. Specific PXR activators, including synthetic ligands and phytochemicals, have been shown to ameliorate chemically induced colitis in mice. In this study, we investigated an anti-inflammatory effect of pregnenolone 16α-carbonitrile (PCN), a prototypical activator for rodent PXR, in concanavalin A (Con A)-induced liver injury, a model of immune-mediated liver injury, using wild-type and Pxr(-/-) mice...
February 22, 2017: Toxicology Letters
https://www.readbyqxmd.com/read/28237619/glutamate-affects-the-production-of-epoxyeicosanoids-within-the-brain-the-up-regulation-of-brain-cyp2j-through-the-mapk-creb-signaling-pathway
#10
Mingzhou Liu, Quanfei Zhu, Jinhua Wu, Xuming Yu, Mingbai Hu, Xianfei Xie, Zheqiong Yang, Jing Yang, Yu-Qi Feng, Jiang Yue
Glutamate is the major excitatory neurotransmitter in the brain, and chronic glutamate excitotoxicity has been thought to be involved in numerous neurodegenerative diseases. We investigated the effects of glutamate at concentrations lower than the usual extrasynaptic concentrations on the production of epoxyeicosanoids mediated by brain CYP2J. Glutamate increased CYP2J2 mRNA levels in astrocytes in a dose-dependent manner, while an antagonist of the metabotropic glutamate receptor subtype 5 (mGlu5 receptor) attenuated the glutamate-induced increases in CYP2J2 levels by glutamate...
February 22, 2017: Toxicology
https://www.readbyqxmd.com/read/28237556/in-vivo-instability-of-platensimycin-and-platencin-synthesis-and-biological-evaluation-of-urea-and-carbamate-platensimycin
#11
Liao-Bin Dong, Jeffrey D Rudolf, Li Lin, Claudia Ruiz, Michael D Cameron, Ben Shen
Platensimycin (PTM) and platencin (PTN), two natural products and promising drug leads that target bacterial and mammalian fatty acid synthases, are known to have unfavorable pharmacokinetic properties. It is not clear, however, what the metabolic fates of PTM and PTN are and no efforts have been reported to address this key roadblock in the development of these compounds as viable drug options. Here we describe the pharmacokinetics of PTM and PTN, and reveal rapid renal clearance as the primary metabolic liability with three additional sites of chemical liability: (i) amide hydrolysis, (ii) glucuronidation, and (iii) oxidation...
February 16, 2017: Bioorganic & Medicinal Chemistry
https://www.readbyqxmd.com/read/28237404/pharmacogenetics-in-cardiovascular-diseases-state-of-the-art-and-implementation-recommendations-of-the-french-national-network-of-pharmacogenetics-rnpgx
#12
Fabien Lamoureux, Thomas Duflot
The use of genomic markers to predict drug response and effectiveness has the potential to improve healthcare by increasing drug efficacy and minimizing adverse effects. Polymorphisms associated with inter-individual variability in drug metabolism, transport, or pharmacodynamics of major cardiovascular drugs have been identified. These include single nucleotide polymorphisms (SNP) affecting clinical outcomes in patients receiving antiplatelet agents, oral anticoagulants and statins. Based on clinical evidence supporting genetic testing in the management of cardiovascular diseases using these drug classes, this short review presents clinical guidance regarding current pharmacogenetics implementation in routine medical practice...
January 30, 2017: Thérapie
https://www.readbyqxmd.com/read/28237373/african-genetic-diversity-implications-for-cytochrome-p450-mediated-drug-metabolism-and-drug-development
#13
Iris Rajman, Laura Knapp, Thomas Morgan, Collen Masimirembwa
Genetic diversity is greater in Africa than in other continental populations. Genetic variability in genes encoding drug metabolizing enzymes may contribute to the high numbers of adverse drug reactions reported in Africa. We reviewed publications (1995-April 2016) reporting frequencies of known cytochrome P450 (CYP) variants in African populations. Using principal components analysis (PCA) we identified CYP alleles of potential clinical relevance with a marked difference in distribution in Africa, compared with Asian and Caucasian populations...
February 20, 2017: EBioMedicine
https://www.readbyqxmd.com/read/28237032/sclerotiorin-inhibits-protein-kinase-g-from-mycobacterium-tuberculosis-and-impairs-mycobacterial-growth-in-macrophages
#14
Dongni Chen, Shuangshuang Ma, Lei He, Peibo Yuan, Zhigang She, Yongjun Lu
As a eukaryotic-like Ser/Thr protein kinase, Mycobacterium tuberculosis virulent effector protein kinase G (PknG) mediates mycobacterial survival by regulating bacterial cell metabolic processes and preventing phagosome-lysosome fusion in host macrophages. Targeting PknG is an effective strategy for development of anti-tuberculosis (TB) drugs. In the study, we found that sclerotiorin, derived from marine fungi from the South China Sea, exhibited moderately strong inhibitory effects on recombinant PknG, with an IC50 value of 76...
March 2017: Tuberculosis
https://www.readbyqxmd.com/read/28237031/single-nucleotide-polymorphisms-may-explain-the-contrasting-phenotypes-of-two-variants-of-a-multidrug-resistant-mycobacterium-tuberculosis-strain
#15
María Mercedes Bigi, Beatriz Lopez, Federico Carlos Blanco, María Del Carmen Sasiain, Silvia De la Barrera, Marcelo A Marti, Ezequiel Jorge Sosa, Darío Augusto Fernández Do Porto, Viviana Ritacco, Fabiana Bigi, Marcelo Abel Soria
Globally, about 4.5% of new tuberculosis (TB) cases are multi-drug-resistant (MDR), i.e. resistant to the two most powerful first-line anti-TB drugs. Indeed, 480,000 people developed MDR-TB in 2015 and 190,000 people died because of MDR-TB. The MDR Mycobacterium tuberculosis M family, which belongs to the Haarlem lineage, is highly prosperous in Argentina and capable of building up further drug resistance without impairing its ability to spread. In this study, we sequenced the whole genomes of a highly prosperous M-family strain (Mp) and its contemporary variant, strain 410, which produced only one recorded tuberculosis case in the last two decades...
March 2017: Tuberculosis
https://www.readbyqxmd.com/read/28236852/the-promising-anticancer-drug-3-bromopyruvate-is-metabolized-through-glutathione-conjugation-which-affects-chemoresistance-and-clinical-practice-an-evidence-based-view
#16
Salah Mohamed El Sayed, Hussam Baghdadi, Mohammed Zolaly, Hamdi H Almaramhy, Mongi Ayat, Jagadish G Donki
3-Bromopyruvate (3BP) is a promising effective anticancer drug against many different tumors in children and adults. 3BP exhibited strong anticancer effects in both preclinical and human studies e.g. energy depletion, oxidative stress, anti-angiogenesis, anti-metastatic effects, targeting cancer stem cells and antagonizing the Warburg effect. There is no report about 3BP metabolism to guide researchers and oncologists to improve clinical practice and prevent drug resistance. In this article, we provide evidences that 3BP is metabolized through glutathione (GSH) conjugation as a novel report where 3BP was confirmed to be attached to GSH followed by permanent loss of pharmacological effects in a picture similar to cisplatin...
March 2017: Medical Hypotheses
https://www.readbyqxmd.com/read/28236849/should-metformin-be-included-in-fertility-treatment-of-pcos-patients
#17
Jigal Haas, Yaakov Bentov
Metformin, a drug developed for the treatment of patients with type II diabetes, has become commonly prescribed medication for PCOS patients. Initially, metformin was prescribed for patients with impaired glucose tolerance at the pre conception period, however more recently its use was expanded to many of the PCOS patients and for the whole duration of pregnancy. Several studies examining the effects of Metformin during pregnancy reported a lower pregnancy loss, reduced gestational diabetes and no increased risk for birth defects, however, several more recent studies also raised concerns about its safe use...
March 2017: Medical Hypotheses
https://www.readbyqxmd.com/read/28236585/the-importance-of-genetic-counseling-and-genetic-screening-a-case-report-of-a-16-year-old-boy-with-resistant-hypertension-and-severe-hypokalemia
#18
Ze-Min Kuang, Ying Wang, Jia-Jie Wang, Jing-Hua Liu, Rong Zeng, Qi Zhou, Zhen-Qiu Yu, Long Jiang
Liddle's syndrome, an autosomal dominant form of monogenic hypertension, is characterized by salt-sensitive hypertension with early penetrance, hypokalemia, metabolic alkalosis, suppression of plasma rennin activity and aldosterone secretion, and a clear-cut response to epithelial sodium channel blockers but not spironolactone therapy. Here, we describe the case of a 16-year-old boy patient with resistant hypertension (maintain 170-180/100-110 mm Hg after administration four kinds of antiypertensive drugs) and severe hypokalemia...
February 3, 2017: Journal of the American Society of Hypertension: JASH
https://www.readbyqxmd.com/read/28236525/role-of-serum-adiponectin-and-vitamin-d-in-prediabetes-and-diabetes-mellitus
#19
Anindita Banerjee, Vineet Kumar Khemka, Debashree Roy, Jit Poddar, Tapan Kumar Sinha Roy, Srikanth Arliganur Karnam
OBJECTIVES: The roles of deficient or deranged insulin, adiponectin and 25 hydroxy vitamin D (25[OH]D) levels regulating food intake, energy metabolism, glucose and lipid metabolism and body weight have been reported in the pathogenesis of prediabetes and type 2 diabetes mellitus. However, their congruity in the etiology of diabetes mellitus is unknown. Thus, the aim of the study was to investigate the roles of these parameters together and to establish their interrelationship in patients with prediabetes and diabetes...
February 21, 2017: Canadian Journal of Diabetes
https://www.readbyqxmd.com/read/28236252/clinical-pharmacokinetics-of-paritaprevir
#20
REVIEW
Rajeev M Menon, Akshanth R Polepally, Amit Khatri, Walid M Awni, Sandeep Dutta
Paritaprevir is a potent hepatitis C virus (HCV) nonstructural (NS) protein 3/4A protease inhibitor that is used in combination with other direct-acting antivirals (DAAs) for the treatment of chronic HCV infection. Paritaprevir is primarily metabolized by cytochrome P450 (CYP) 3A4 and is administered with a low dose of ritonavir to achieve drug concentrations suitable for once-daily dosing. Coadministration of paritaprevir with ritonavir increases the half-life of single-dose paritaprevir from approximately 3 h to 5-8 h, doubles the time to maximum plasma concentration (T max) from 2...
February 25, 2017: Clinical Pharmacokinetics
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