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drug metabolism, preclinical

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https://www.readbyqxmd.com/read/28088572/bcs-class-iv-drugs-highly-notorious-candidates-for-formulation-development
#1
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/28088042/strategies-for-metabolite-profiling-based-on-liquid-chromatography
#2
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
https://www.readbyqxmd.com/read/28079010/discovery-of-natural-product-proteasome-inhibitors-as-novel-anticancer-therapeutics-current-status-and-perspectives
#3
Hui Wang, Qingzhu Yang, Ping Dou, Huanjie Yang
Natural products serve as a main resource for drug discovery. The ubiquitin-proteasome system (UPS) is one of the primary intracellular protein degradation systems, which is responsible for the degradation of most short-lived, mis-folded and aged proteins. The proteasome is a validated target for cancer treatment, since cancer cells are more reliant on high levels of proteasome activity to maintain the dynamic protein homeostasis required for enhanced metabolism and unrestricted proliferation inherent in cancer cells...
January 11, 2017: Current Protein & Peptide Science
https://www.readbyqxmd.com/read/28077438/fibroblast-drug-scavenging-increases-intratumoural-gemcitabine-accumulation-in-murine-pancreas-cancer
#4
E Hessmann, M S Patzak, L Klein, N Chen, V Kari, I Ramu, T E Bapiro, K K Frese, A Gopinathan, F M Richards, D I Jodrell, C Verbeke, X Li, R Heuchel, J M Löhr, S A Johnsen, T M Gress, V Ellenrieder, A Neesse
OBJECTIVE: Desmoplasia and hypovascularity are thought to impede drug delivery in pancreatic ductal adenocarcinoma (PDAC). However, stromal depletion approaches have failed to show clinical responses in patients. Here, we aimed to revisit the role of the tumour microenvironment as a physical barrier for gemcitabine delivery. DESIGN: Gemcitabine metabolites were analysed in LSL-Kras(G12D/+); LSL-Trp53(R172H/+); Pdx-1-Cre (KPC) murine tumours and matched liver metastases, primary tumour cell lines, cancer-associated fibroblasts (CAFs) and pancreatic stellate cells (PSCs) by liquid chromatography-mass spectrometry/mass spectrometry...
January 10, 2017: Gut
https://www.readbyqxmd.com/read/28076702/lasmiditan-for-the-treatment-of-migraine
#5
Matilde Capi, Fernando de Andrés, Luana Lionetto, Giovanna Gentile, Fabiola Cipolla, Marina Borro, Paolo Martelletti, Martina Curto
Migraine is one of the most common diseases in the world, with high economical and subjective burden. Migraine acute therapy is nowadays based on specific and non-specific drugs but up to 40% of episodic migraineurs still have unmet treatment needs and over 35% do not benefit from triptans administration. Serotonin-1F receptors have been identified in trigeminal system and became an ideal target for anti-migraine drug development as potential trigeminal neural inhibitors. Lasmiditan, a novel serotonin1F receptor agonist, showed specific affinity in vitro for the receptor with any vasoconstrictive action and inhibited markers associated with electrical stimulation of trigeminal ganglion in migraine animal models...
January 11, 2017: Expert Opinion on Investigational Drugs
https://www.readbyqxmd.com/read/28073907/metformin-prevents-metabolic-side-effects-during-systemic-glucocorticod-treatment
#6
Eleonora Seelig, Stefanie Meyer, Katharina Timper, Nicole Nigro, Martina Bally, Ida Pernicova, Philipp Schuetz, Beat Muller, Marta Korbonits, Mirjam Christ-Crain
Objectives Patients receiving glucocorticoid treatment are prone to develop metabolic complications. In preclinical studies metformin prevented the development of the metabolic syndrome during glucocorticoid excess. We herein investigated the metabolic effect of metformin during glucocorticoid treatment in non-diabetic patients. Methods In a double-blind, placebo-controlled trial, patients starting glucocorticoid treatment (prednisone, prednisolone or methylprednisolone) for four weeks were randomized to concomitantly receive metformin (850mg once daily for one week followed by 850mg twice daily for three weeks) or placebo...
January 10, 2017: European Journal of Endocrinology
https://www.readbyqxmd.com/read/28069987/transgenic-zebrafish-reporter-lines-as-alternative-in-vivo-organ-toxicity-models
#7
Kar Lai Poon, Xingang Wang, Serene Gp Lee, Ashley S Ng, Wei Huang Goh, Zhonghua Zhao, Muthafar Al-Haddawi, Haishan Wang, Sinnakaruppan Mathavan, Phillip W Ingham, Claudia Mcginnis, Tom J Carney
Organ toxicity, particularly liver toxicity, remains one of the major reasons for termination of drug candidates in the development pipeline as well as withdrawal or restrictions of marketed drugs. A screening-amenable alternative in vivo model such as zebrafish would therefore find immediate application in the early prediction of unacceptable organ toxicity. To identify highly upregulated genes as biomarkers of toxic responses in the zebrafish model, a set of well-characterized reference drugs that cause drug induced liver injury (DILI) in the clinic were applied to zebrafish larvae and adults...
January 9, 2017: Toxicological Sciences: An Official Journal of the Society of Toxicology
https://www.readbyqxmd.com/read/28063511/tiny-molecule-big-power-multi-target-approach-for-curcumin-in-diabetic-cardiomyopathy
#8
REVIEW
Vengadeshprabhu Karuppagounder, Somasundaram Arumugam, Vijayasree V Giridharan, Remya Sreedhar, Rajendran J C Bose, Jyothi Vanama, Suresh S Palaniyandi, Tetsuya Konishi, Kenichi Watanabe, Rajarajan A Thandavarayan
Diabetic cardiomyopathy (DCM) is described as impaired cardiac diastolic and systolic functions. Diabetes mellitus (DM), a related cardiovascular disease, has become one of the major causes of death in DM patients. Mortality in these diseases is 2 to 3 times higher than in non-DM patients with cardiovascular disease. The progression of DCM and the cellular and molecular perturbations associated with the pathogenesis are complex and multifactorial. Although considerable progress has been achieved, the molecular etiologies of DCM remain poorly understood...
February 2017: Nutrition
https://www.readbyqxmd.com/read/28042884/pharmacokinetics-of-the-antimicrobial-drug-sulfanilamide-is-altered-in-a-preclinical-model-of-vascular-calcification
#9
Anabel Brandoni, Adriana Mónica Torres
In vascular smooth muscle, calcium overload is linked to advancing age. The pharmacokinetics of sulfanilamide (SA), a compound with antibacterial properties, was evaluated in a preclinical model of vascular calcification. SA was used since it is useful to study possible modifications in the renal and hepatic management of drugs. Vascular calcification was induced by administration of a single high dose of vitamin D3 to rats (treated group) 10 days before the experiments. A parallel control group was processed...
January 2, 2017: Clinical and Experimental Pharmacology & Physiology
https://www.readbyqxmd.com/read/28039084/halofuginone-enhances-the-chemo-sensitivity-of-cancer-cells-by-suppressing-nrf2-accumulation
#10
Kouhei Tsuchida, Tadayuki Tsujita, Makiko Hayashi, Asaka Ojima, Nadine Keleku-Lukwete, Fumiki Katsuoka, Akihito Otsuki, Haruhisa Kikuchi, Yoshiteru Oshima, Mikiko Suzuki, Masayuki Yamamoto
The KEAP1-NRF2 system regulates the cellular defence against oxidative and xenobiotic stresses. NRF2 is a transcription factor that activates the expression of cytoprotective genes encoding antioxidative, detoxifying and metabolic enzymes as well as transporters. Under normal conditions, KEAP1 represses NRF2 activity by degrading the NRF2 protein. When cells are exposed to stresses, KEAP1 stops promoting NRF2 degradation, and NRF2 rapidly accumulates and activates the transcription of target genes. Constitutive accumulation of NRF2 via a variety of mechanisms that disrupt KEAP1-mediated NRF2 degradation has been observed in various cancer types...
December 28, 2016: Free Radical Biology & Medicine
https://www.readbyqxmd.com/read/28004284/a-phase-i-study-of-tivantinib-in-combination-with-temsirolimus-in-patients-with-advanced-solid-tumors
#11
Christos E Kyriakopoulos, Amy M Braden, Jill M Kolesar, Jens C Eickhoff, Howard H Bailey, Jennifer Heideman, Glenn Liu, Kari B Wisinski
Background A wide variety of human cancers exhibit dysregulated c-Met activity that has implications in oncogenesis. Phosphorylation of c-Met results in activation of the PI3K/AKT/mTOR pathway. Combined blockade of c-Met and mTOR pathways has shown efficacy in preclinical studies. Tivantinib is a c-Met inhibitor and temsirolimus is a selective mTOR inhibitor. We aimed to determine the maximum tolerated dose (MTD) and the recommended phase II dose (RP2D), dose-limiting toxicities (DLT), adverse events (AEs), clinical activity and pharmacokinetic (PK) parameters of the combination...
December 21, 2016: Investigational New Drugs
https://www.readbyqxmd.com/read/27993930/absorption-metabolism-and-excretion-of-a-novel-bcl-2-inhibitor-venetoclax-in-humans
#12
Hong Liu, Melissa J Michmerhuizen, Yanbin Lao, Katty Wan, Ahmed Hamed Salem, James Sawicki, Michael Serby, Srirajan Vaidyanathan, Shekman L Wong, Suresh Agarwal, Martin Dunbar, Jens Sydor, Sonia Maria de Morais, Anthony J Lee
Venetoclax (also known as ABT-199) is a B-cell lymphoma-2 (Bcl-2) family protein inhibitor and is currently in clinical development for the treatment of chronic lymphocytic leukaemia (CLL) and other hematological malignancies. The objective of this study was to characterize the absorption, metabolism, and excretion of venetoclax in humans. Following a single oral dose of 200 mg (100 μ - Ci) of [(14)C]venetoclax to four healthy volunteers, recovery of total radioactive dose was 100% (± 5%), with feces being the major route of elimination of the administered dose, whereas urinary excretion was minimal (<0...
December 19, 2016: Drug Metabolism and Disposition: the Biological Fate of Chemicals
https://www.readbyqxmd.com/read/27986627/a-novel-and-selective-melanin-concentrating-hormone-receptor-1-antagonist-ameliorates-obesity-and-hepatic-steatosis-in-diet-induced-obese-rodent-models
#13
Yayoi Kawata, Shoki Okuda, Natsu Hotta, Hideyuki Igawa, Masashi Takahashi, Minoru Ikoma, Shizuo Kasai, Ayumi Ando, Yoshinori Satomi, Mayumi Nishida, Masaharu Nakayama, Syunsuke Yamamoto, Yasutaka Nagisa, Shiro Takekawa
Melanin-concentrating hormone (MCH), a cyclic neuropeptide expressed predominantly in the lateral hypothalamus, plays an important role in the control of feeding behavior and energy homeostasis. Mice lacking MCH or MCH1 receptor are resistant to diet-induced obesity (DIO) and MCH1 receptor antagonists show potent anti-obesity effects in preclinical studies, indicating that MCH1 receptor is a promising target for anti-obesity drugs. Moreover, recent studies have suggested the potential of MCH1 receptor antagonists for treatment of non-alcoholic fatty liver disease (NAFLD)...
December 13, 2016: European Journal of Pharmacology
https://www.readbyqxmd.com/read/27986598/optimizing-oral-bioavailability-in-drug-discovery-an-overview-of-design-and-testing-strategies-and-formulation-options
#14
REVIEW
Bruce J Aungst
For discovery teams working toward new, orally administered therapeutic agents, one requirement is to attain adequate systemic exposure after oral dosing, which is best accomplished when oral bioavailability is optimized. This report summarizes the bioavailability challenges currently faced in drug discovery, and the design and testing methods and strategies currently utilized to address the challenges. Profiling of discovery compounds usually includes separate assessments of solubility, permeability, and susceptibility to first-pass metabolism, which are the three most likely contributors to incomplete oral bioavailability...
December 13, 2016: Journal of Pharmaceutical Sciences
https://www.readbyqxmd.com/read/27984527/agomelatine-a-new-opportunity-to-reduce-neuropathic-pain-preclinical-evidence
#15
Chouki Chenaf, Eric Chapuy, Frédéric Libert, Fabien Marchand, Christine Courteix, Marianne Bertrand, Cecilia Gabriel, Elisabeth Mocaër, Alain Eschalier, Nicolas Authier
Antidepressants are first-line treatments of neuropathic pain but not all these drugs are really effective. Agomelatine is an antidepressant with a novel mode of action, acting as an MT1/MT2 melatonergic receptor agonist and a 5-HT2C receptor antagonist that involves indirect norepinephrine release. Melatonin, serotonin, and norepinephrine have been involved in the pathophysiology of neuropathic pain. Yet, no study has been conducted to determine agomelatine effects on neuropathic pain in animal models. Using 3 rat models of neuropathic pain of toxic (oxaliplatin/OXA), metabolic (streptozocin/STZ), and traumatic (sciatic nerve ligation/CCI [chronic constriction nerve injury]) etiologies, we investigated the antihypersensitivity effect of acute and repeated agomelatine administration...
January 2017: Pain
https://www.readbyqxmd.com/read/27956139/characterization-of-stem-cell-derived-liver-and-intestinal-organoids-as-a-model-system-to-study-nuclear-receptor-biology
#16
Ingrid T G W Bijsmans, Alexandra Milona, Noortje Ijssennagger, Ellen C L Willemsen, José M Ramos Pittol, Johan W Jonker, Katja Lange, Guido J E J Hooiveld, Saskia W C van Mil
Nuclear receptors (NRs) are ligand-activated transcription factors regulating a large variety of processes involved in reproduction, development, and metabolism. NRs are ideal drug targets because they are activated by lipophilic ligands that easily pass cell membranes. Immortalized cell lines recapitulate NR biology poorly and generating primary cultures is laborious and requires a constant need for donor material. There is a clear need for development of novel preclinical model systems that better resemble human physiology...
December 10, 2016: Biochimica et Biophysica Acta
https://www.readbyqxmd.com/read/27942596/development-of-an-in-vitro-human-liver-system-for-interrogating-nonalcoholic-steatohepatitis
#17
Ryan E Feaver, Banumathi K Cole, Mark J Lawson, Stephen A Hoang, Svetlana Marukian, Brett R Blackman, Robert A Figler, Arun J Sanyal, Brian R Wamhoff, Ajit Dash
A barrier to drug development for nonalcoholic steatohepatitis (NASH) is the absence of translational preclinical human-relevant systems. An in vitro liver model was engineered to incorporate hepatic sinusoidal flow, transport, and lipotoxic stress risk factors (glucose, insulin, free fatty acids) with cocultured primary human hepatocytes, hepatic stellate cells (HSCs), and macrophages. Transcriptomic, lipidomic, and functional endpoints were evaluated and compared with clinical data from NASH patient biopsies...
December 8, 2016: JCI Insight
https://www.readbyqxmd.com/read/27934635/metabolism-of-the-mek1-2-inhibitor-pimasertib-involves-a-novel-conjugation-with-phospho-ethanolamine-in-patients-with-solid-tumors
#18
Holger Scheible, Friedrich Kraetzer, Andreas Marx, Andreas Johne, Elmar Wimmer
Pimasertib (AS703026 or MSC1936369B) is a selective inhibitor of MEK1/2, the mitogen-activated protein kinase (MAPK) signaling pathway, which is often dysregulated in cancer cells. Pimasertib has shown potent preclinical anti tumor activity and its clinical activity is being investigated in various tumor types. In this phase I study, the disposition and biotransformation of (14)C-radiolabeled pimasertib was investigated in six patients with locally advanced or metastatic solid tumors (NCT 01713036). Ultra-performance liquid chromatography-mass spectrometry (UPLC-MS) and radiodetection techniques were used to investigate the profiles and structures of metabolites in plasma, urine and feces after a single oral dose of (14)C-pimasertib...
December 1, 2016: Drug Metabolism and Disposition: the Biological Fate of Chemicals
https://www.readbyqxmd.com/read/27932582/translational-safety-genetics-leveraging-genetic-variation-for-enhanced-safety-assessment
#19
Priyasma Bhoumik, Alberto Del Rio-Espinola, Florian Hahne, Jonathan Moggs, Olivier Grenet
The emerging field of translational safety genetics is providing new opportunities to enhance drug discovery and development. Genetic variation in therapeutic drug targets, off-target interactors and relevant drug metabolism/disposition pathways can contribute to diverse drug pharmacologic and toxicologic responses between different animal species, strains and geographic origins. Recent advances in the sequencing of rodent, canine, nonhuman primate, and minipig genomes have dramatically improved the ability to select the most appropriate animal species for preclinical drug toxicity studies based on genotypic characterization of drug targets/pathways and drug metabolism and/or disposition, thus avoiding inconclusive or misleading animal studies, consistent with the principles of the 3Rs (replacement, reduction and refinement)...
December 8, 2016: Toxicologic Pathology
https://www.readbyqxmd.com/read/27909650/pbpk-modeling-and-simulation-in-drug-research-and-development
#20
REVIEW
Xiaomei Zhuang, Chuang Lu
Physiologically based pharmacokinetic (PBPK) modeling and simulation can be used to predict the pharmacokinetic behavior of drugs in humans using preclinical data. It can also explore the effects of various physiologic parameters such as age, ethnicity, or disease status on human pharmacokinetics, as well as guide dose and dose regiment selection and aid drug-drug interaction risk assessment. PBPK modeling has developed rapidly in the last decade within both the field of academia and the pharmaceutical industry, and has become an integral tool in drug discovery and development...
September 2016: Acta Pharmaceutica Sinica. B
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