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Drug metabolism

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https://www.readbyqxmd.com/read/28092722/synthetic-and-natural-peroxisome-proliferator-activated-receptor-ppar-agonists-as-candidates-for-the-therapy-of-the-metabolic-syndrome
#1
Chek Kun Tan, Yan Zhuang, Walter Wahli
Introduction Peroxisome proliferator-activated receptors (PPARs) are the molecular targets of hypolipidemic and insulin-sensitizing drugs and implicated in a multitude of processes that fine-tune the functions of all organs in vertebrates. As transcription factors they sense endogenous and exogenous lipid signaling molecules and convert these signals into intricate gene responses that impact health and disease. The PPARs act as modulators of cellular, organ, and systemic processes, such as lipid and carbohydrate metabolism, making them valuable for understanding body homeostasis influenced by nutrition and exercise...
January 16, 2017: Expert Opinion on Therapeutic Targets
https://www.readbyqxmd.com/read/28092103/species-differences-in-hepatic-biotransformation-of-the-anthelmintic-drug-flubendazole
#2
M L Maté, T Geary, C Mackenzie, C Lanusse, G Virkel
Flubendazole (FLBZ) is a broad-spectrum benzimidazole anthelmintic used in pigs, poultry, and humans. It has been proposed as a candidate for development for use in elimination programmes for lymphatic filariasis and onchocerciasis in humans. Moreover, FLBZ has shown promise in cancer chemotherapy, particularly for neuroblastoma. This work investigated the hepatic carbonyl-reducing pathway of FLBZ in different species, including humans. Microsomal and cytosolic fractions were obtained from sheep, cattle, pig, hen, rat, and human liver...
January 16, 2017: Journal of Veterinary Pharmacology and Therapeutics
https://www.readbyqxmd.com/read/28091894/mechanisms-of-action-of-surgical-interventions-on-weight-related-diseases-the-potential-role-of-bile-acids
#3
REVIEW
Mohsen Mazidi, Pedro Paulo P de Caravatto, John R Speakman, Ricardo V Cohen
Surgical interventions for weight-related diseases (SWRD) may have substantial and sustainable effect on weight reduction, also leading to a higher remission rate of type 2 diabetes (T2D) mellitus than any other medical treatment or lifestyle intervention. The resolution of T2D after Roux-en-Y gastric bypass (RYGB) typically occurs too quickly to be accounted for by weight loss alone, suggesting that these operations have a direct impact on glucose homeostasis. The mechanisms underlying these beneficial effects however remain unclear...
January 14, 2017: Obesity Surgery
https://www.readbyqxmd.com/read/28091881/identifying-metabolites-of-meclonazepam-by-high-resolution-mass-spectrometry-using-human-liver-microsomes-hepatocytes-a-mouse-model-and-authentic-urine-samples
#4
Svante Vikingsson, Ariane Wohlfarth, Mikael Andersson, Henrik Gréen, Markus Roman, Martin Josefsson, Fredrik C Kugelberg, Robert Kronstrand
Meclonazepam is a benzodiazepine patented in 1977 to treat parasitic worms, which recently appeared as a designer benzodiazepine and drug of abuse. The aim of this study was to identify metabolites suitable as biomarkers of drug intake in urine using high-resolution mass spectrometry, authentic urine samples, and different model systems including human liver microsomes, cryopreserved hepatocytes, and a mice model. The main metabolites of meclonazepam found in human urine were amino-meclonazepam and acetamido-meclonazepam; also, minor peaks for meclonazepam were observed in three of four urine samples...
January 13, 2017: AAPS Journal
https://www.readbyqxmd.com/read/28090779/preparation-and-in-vitro-in-vivo-evaluation-of-metformin-hydrochloride-rectal-dosage-forms-for-treatment-of-patients-with-type-ii-diabetes
#5
Abdel-Azim Zaghloul, Ahmad Lila, Fathy Abd-Allah, Aly Nada
BACKGROUND: Metformin hydrochloride (MtHCL) is an oral antidiabetic drug and has many other therapeutic benefits. It has poor bioavailability, narrow absorption window and extensive liver metabolism. Moreover, children and elders face difficulty to swallow the commercial oral tablets. OBJECTIVES: Preparation, in vitro/in vivo evaluation of MtHCL suppositories for rectal administration to solve some of these problems. METHODS: Suppository fatty bases (Witepsol®, Suppocire® and Massa®; different grades) and PEG bases 1000, 4000 and 6000 (different ratios), were used to prepare rectal suppository formulations each containing 500 mg drug...
January 16, 2017: Journal of Drug Targeting
https://www.readbyqxmd.com/read/28090668/studies-of-anticancer-drug-cytotoxicity-based-on-long-term-hepg2-spheroid-culture-in-a-microfluidic-system
#6
Agnieszka Zuchowska, Karina Kwapiszewska, Michal Chudy, Artur Dybko, Zbigniew Brzozka
Cell-on-a-chip systems have become promising devices to study the effectiveness of new anticancer drugs recently. Several microdevices for liver cancer culture and evaluation of the drug cytotoxicity have been reported. However, there are still no proven reports about high-throughput and simple methods for the evaluation of drug cytotoxicity on liver cancer cells. The paper presents the results of the effects of the anticancer drug (5-fluorouracil, 5-FU) on the HepG2 spheroids as a model of liver cancer. The experiments were based on the long-term 3D spheroid culture in the microfluidic system and monitoring of the effect of 5-FU at two selected concentrations (0...
January 16, 2017: Electrophoresis
https://www.readbyqxmd.com/read/28089915/dendrimers-as-nanocarriers-for-nucleoside-analogues
#7
REVIEW
Michał Gorzkiewicz, Barbara Klajnert-Maculewicz
Dendrimers constitute a class of hyperbranched macromolecules with several potential applications due to their unique properties such as a well-defined structure, multivalency and biocompatibility. These polymers became one of the most promising drug nanocarriers, providing improved solubility of therapeutics, high loading capacity and controllable biodistribution pattern. In addition, the use of dendrimers as drug delivery devices in cancer therapies may help to overcome the resistance mechanisms by transporting activated drug molecules directly to cancer cells...
January 12, 2017: European Journal of Pharmaceutics and Biopharmaceutics
https://www.readbyqxmd.com/read/28089783/characterization-of-rat-or-human-hepatocytes-cultured-in-microphysiological-systems-mps-to-identify-hepatotoxicity
#8
Shih-Yu Chang, Jenna L Voellinger, Kirk P Van Ness, Brian Chapron, Rachel M Shaffer, Thomas Neumann, Collin C White, Terrance J Kavanagh, Edward J Kelly, David L Eaton
The liver is the main site for drug and xenobiotics metabolism, including inactivation or bioactivation. In order to improve the predictability of drug safety and efficacy in clinical development, and to facilitate the evaluation of the potential human health effects from exposure to environmental contaminants, there is a critical need to accurately model human organ systems such as the liver in vitro. We are developing a microphysiological system (MPS) based on a new commercial microfluidic platform (Nortis, Inc...
January 12, 2017: Toxicology in Vitro: An International Journal Published in Association with BIBRA
https://www.readbyqxmd.com/read/28089749/pyroglutamate-5-oxoproline-measured-with-hydrophilic-interaction-chromatography-hilic-tandem-mass-spectrometry-in-acutely-ill-patients
#9
Carel J Pretorius, Michael C Reade, Chris Warnholtz, Brett McWhinney, Meng Mei Phua, Jeffrey Lipman, Jacobus P J Ungerer
BACKGROUND: Pyroglutamic acid (PGA) is challenging to quantify in plasma and is a rare cause of metabolic acidosis that is associated with inherited disorders or acquired after exposure to drugs. METHOD: We developed a hydrophilic interaction liquid chromatography tandem mass spectrometry method with a short analysis time. We established a reference interval and then measured PGA in acutely ill patients to investigate associations with clinical, pharmaceutical and laboratory parameters...
January 12, 2017: Clinica Chimica Acta; International Journal of Clinical Chemistry
https://www.readbyqxmd.com/read/28089686/simulations-of-cytochrome-p450-3a4-mediated-drug-drug-interactions-by-simple-two-compartment-model-assisted-static-method
#10
Katsumi Iga, Akiko Kiriyama
In order to predict cytochrome P450 3A4 (CYP3A4)-mediated drug-drug interactions (DDIs), a simple two-compartment model assisted, overall inhibition-activity (Ai, overall) method was derived based upon two concepts. One concept was that the increase in blood victim-level and fold increase in the area under the blood victim-level curve (AUCR) produced by DDI are determined entirely by Ai, overall, the hepatic availability of the victim and fraction of urinary excreted unchanged victim, where Ai, overall is determined by the perpetrator-specific CYP isoform inhibition activities (Ai,CYPs, DDI predictor-1) and victim-specific fractional CYP isoform contributions (fm,CYPs, predictor-2)...
January 12, 2017: Journal of Pharmaceutical Sciences
https://www.readbyqxmd.com/read/28089660/characterization-pharmacokinetics-and-tissue-distribution-of-chlorogenic-acid-loaded-self-microemulsifying-drug-delivery-system
#11
Li Chen, Chang-Shun Liu, Qing-Zhen Chen, Sen Wang, Yong-Ai Xiong, Jing Jing, Jia-Jia Lv
The purpose of this study was to develop a self-microemulsifying drug delivery system (SMEDDS) to improve the oral bioavailability of Chlorogenic acid (CA), an important bioactive compound from Lonicerae Japonicae Flos with poor permeability. SMEDDS was prepared and characterized by self-emulsifying rate, morphological observation, droplet size determination, stability, in vitro release, in vivo bioavailability and tissue distribution experiments. Results shown that the SMEDDS of CA has a high self-emulsifying rate (>98%) in the dissolution media, and its microemulsion exhibits small droplet size (16...
January 12, 2017: European Journal of Pharmaceutical Sciences
https://www.readbyqxmd.com/read/28089566/metformin-inhibits-hepatic-mtorc1-signaling-via-dose-dependent-mechanisms-involving-ampk-and-the-tsc-complex
#12
Jessica J Howell, Kristina Hellberg, Marc Turner, George Talbott, Matthew J Kolar, Debbie S Ross, Gerta Hoxhaj, Alan Saghatelian, Reuben J Shaw, Brendan D Manning
Metformin is the most widely prescribed drug for the treatment of type 2 diabetes. However, knowledge of the full effects of metformin on biochemical pathways and processes in its primary target tissue, the liver, is limited. One established effect of metformin is to decrease cellular energy levels. The AMP-activated protein kinase (AMPK) and mechanistic target of rapamycin (mTOR) complex 1 (mTORC1) are key regulators of metabolism that are respectively activated and inhibited in acute response to cellular energy depletion...
December 30, 2016: Cell Metabolism
https://www.readbyqxmd.com/read/28089347/virtual-screening-and-experimental-validation-identify-novel-modulators-of-nuclear-receptor-rxr%C3%AE-from-drugbank-database
#13
Dan Xu, Lijun Cai, Shangjie Guo, Lei Xie, Meimei Yin, Ziwen Chen, Hu Zhou, Ying Su, Zhiping Zeng, Xiaokun Zhang
Retinoid X receptor alpha (RXRα), an important ligand-dependent transcription factor, plays a critical role in the development of various cancers and metabolic and neurodegenerative diseases. Therefore, RXRα represents one of the most important targets in modern drug discovery. In this study, Drugbank 2.0 with 1280 old drugs were virtually screened by Glide according to the crystal structure of ligand-binding domain (LBP) of RXRα. 15 compounds selected were tested for their binding and transcriptional activity toward RXRα by Biacore and reporter gene assay, respectively...
December 26, 2016: Bioorganic & Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/28088910/sodium-glucose-cotransporter-2-inhibitors-sglt2i-their-role-in-cardiometabolic-risk-management
#14
Niki Katsiki, Dimitri P Mikhailidis, Michael J Theodorakis
BACKGROUND: Sodium-glucose cotransporter 2 inhibitors (SGLT2i) are a novel category of oral antidiabetic drugs that inhibit renal glucose reabsorption and increase renal glucose excretion, thus lowering plasma glucose levels. This unique mechanism of SGLT2i action is insulin independent, thus improving glycemic control without promoting hypoglycemia in the absence of exogenously administered insulin. METHODS: The present narrative review addresses the putative associations between SGLT2i and several cardiovascular (CV) and microvascular risk factors, as well as their effects on cardiac and renal function...
January 13, 2017: Current Pharmaceutical Design
https://www.readbyqxmd.com/read/28088883/candesartan-cilexetil-loaded-nanodelivery-systems-for-improved-oral-bioavailability
#15
Narendar Dudhipala, Kishan Veerabrahma
Candesartan cilexetil (CC), an antihypertensive drug, has low oral bioavailability due to poor solubility and hepatic first-pass metabolism. These are major limitations in oral delivery of CC. Several approaches are known to reduce the problems of solubility and improve the bioavailability of CC. Among various approaches, nanotechnology-based delivery of CC has potential to overcome the challenges associated with the oral administration. This review focuses on various nano-based delivery systems available and tried for improving the aqueous solubility, dissolution and consequently bioavailability of CC upon oral administration...
February 2017: Therapeutic Delivery
https://www.readbyqxmd.com/read/28088879/the-biopharmaceutical-classification-system-of-excipients
#16
Teófilo Vasconcelos, Sara Marques, Bruno Sarmento
The increasing number of new chemical entities is bringing new challenges to the field of drug delivery. These drugs present bioavailability issues that are frequently associated with intestinal metabolism or efflux mechanisms. Some excipients, particularly surfactants, have demonstrated a capacity to interfere with these mechanisms, improving drug bioavailability. Consequently, these excipients can no longer be considered as inert and should be subject to special considerations from a regulatory perspective...
February 2017: Therapeutic Delivery
https://www.readbyqxmd.com/read/28088622/reactive-oxygen-species-and-cancer-paradox-to-promote-or-to-suppress
#17
REVIEW
Sehamuddin Galadari, Anees Rahman, Siraj Pallichankandy, Faisal Thayyullathil
Reactive oxygen species (ROS), a group of highly reactive ions and molecules, are increasingly being appreciated as powerful signaling molecules involved in the regulation of a variety of biological processes. Indeed, their role is continuously being delineated in a variety of pathophysiological conditions. For instance, cancer cells are shown to have increased ROS levels in comparison to their normal counterparts. This is partly due to an enhanced metabolism and mitochondrial dysfunction in cancer cells. The escalated ROS generation in cancer cells contributes to the biochemical and molecular changes necessary for the tumor initiation, promotion and progression, as well as, tumor resistance to chemotherapy...
January 11, 2017: Free Radical Biology & Medicine
https://www.readbyqxmd.com/read/28088572/bcs-class-iv-drugs-highly-notorious-candidates-for-formulation-development
#18
REVIEW
Rohan Ghadi, Neha Dand
BCS class IV drugs (e.g., amphotericin B, furosemide, acetazolamide, ritonavir, paclitaxel) exhibit many characteristics that are problematic for effective oral and per oral delivery. Some of the problems associated include low aqueous solubility, poor permeability, erratic and poor absorption, inter and intra subject variability and significant positive food effect which leads to low and variable bioavailability. Also, most of the class IV drugs are substrate for P-glycoprotein (low permeability) and substrate for CYP3A4 (extensive pre systemic metabolism) which further potentiates the problem of poor therapeutic potential of these drugs...
January 11, 2017: Journal of Controlled Release: Official Journal of the Controlled Release Society
https://www.readbyqxmd.com/read/28088388/activation-of-gr-but-not-pxr-by-dexamethasone-attenuated-acetaminophen-hepatotoxicities-via-fgf21-induction
#19
Saurabh G Vispute, Pengli Bu, Yuan Le, Xingguo Cheng
Glucocorticoid receptor (GR) signaling is indispensable for cell growth and development, and plays important roles in drug metabolism. Fibroblast growth factor (Fgf) 21, an important regulator of glucose, lipid, and energy metabolism, plays a cytoprotective role by attenuating toxicities induced by chemicals such as dioxins, acetaminophen (APAP), and alcohols. The present study investigates the impact of dexamethasone (DEX)-activated GR on Fgf21 expression and how it affects the progression of APAP-induced hepatotoxicity...
January 11, 2017: Toxicology
https://www.readbyqxmd.com/read/28088042/strategies-for-metabolite-profiling-based-on-liquid-chromatography
#20
REVIEW
Javier Saurina, Sonia Sentellas
This paper aims at covering the principal strategies based on liquid chromatography (LC) for metabolite profiling in the field of drug discovery and development. The identification of metabolites generated in the organism is an important task during the early stages of preclinical research to define the most proper strategy for optimizing, adjusting metabolic clearance and minimizing bioactivation. An early assessment of the metabolite profile may be critical since metabolites can contribute to pharmacological and/or toxicological effects...
January 9, 2017: Journal of Chromatography. B, Analytical Technologies in the Biomedical and Life Sciences
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