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https://www.readbyqxmd.com/read/29520587/p-glycoprotein-restricts-ocular-penetration-of-loperamide-across-the-blood-ocular-barriers-a-comparative-study-in-mdr1a-knock-out-and-wild-type-sprague-dawley-rats
#1
Akshaya Tatke, Karthik Yadav Janga, Bharathi Avula, XiangDi Wang, Monica M Jablonski, Ikhlas A Khan, Soumyajit Majumdar
The current research was undertaken to determine the existence and magnitude of P-glycoprotein (P-gp) expression on the blood-ocular barriers by studying the ocular penetration of loperamide, a specific P-gp substrate, in P-gp (Mdr1a) knock-out (KO) and wild type (WT) Sprague Dawley rats. A clear, stable, sterile solution of loperamide (1 mg/mL), for intravenous administration, was formulated and evaluated. Ocular distribution was studied in P-gp KO and WT rats following intravenous administration of loperamide (at two doses)...
March 8, 2018: AAPS PharmSciTech
https://www.readbyqxmd.com/read/29454148/-68-ga-galmydar-biodistribution-and-radiation-dosimetry-studies-in-rodents
#2
Jothilingam Sivapackiam, Richard Laforest, Vijay Sharma
INTRODUCTION: 68 Ga-Galmydar is an avid transport substrate of ABCB1 (P-Glycoprotein; 170kDa plasma membrane protein), breast cancer resistance protein (BCRP; ABCG2; 72kDa), penetrates human epidermal carcinoma (KB3-1), breast cancer (MCF7), embryonic kidney (HEK 293) tumor cells and rat cardiomyoblasts, and localizes within the mitochondria of tumor and myocardium cells. 68 Ga-Galmydar excretes from blood pool quickly, and shows stable retention within rat myocardium in vivo for extended periods, therefore, the agent shows potential to enable myocardial perfusion imaging...
December 1, 2017: Nuclear Medicine and Biology
https://www.readbyqxmd.com/read/29437873/brain-distribution-of-a-novel-mek-inhibitor-e6201-implications-in-the-treatment-of-melanoma-brain-metastases
#3
Gautham Gampa, Minjee Kim, Nicholas Cook-Rostie, Janice Laramy, Jann N Sarkaria, Linda Paradiso, Louis DePalatis, William F Elmquist
Clinically meaningful efficacy in the treatment of brain tumors, including melanoma brain metastases (MBM), requires selection of a potent inhibitor against a suitable target, and adequate drug distribution to target sites in the brain. Deregulated constitutive signaling of mitogen-activated protein kinase (MAPK) pathway has been frequently observed in melanoma, and MEK has been identified to be an important target. E6201 is a potent synthetic small molecule MEK inhibitor. The purpose of this study was to evaluate brain distribution of E6201, and examine the impact of active efflux transport at the BBB on the CNS exposure of E6201...
February 2, 2018: Drug Metabolism and Disposition: the Biological Fate of Chemicals
https://www.readbyqxmd.com/read/28971602/daikenchuto-tu-100-alters-murine-hepatic-and-intestinal-drug-metabolizing-enzymes-in-an-in%C3%A2-vivo-dietary-model-effects-of-gender-and-withdrawal
#4
Kentaro Nobutani, Jun Miyoshi, Mark W Musch, Mitsue Nishiyama, Junko Watanabe, Atsushi Kaneko, Masahiro Yamamoto, Masaru Yoshida, Toru Kono, Hyunyoung Jeong, Eugene B Chang
Herbal medicines and natural products used for maintenance of health or treatment of diseases have many biological effects, including altering the pharmacokinetics and metabolism of other medications. Daikenchuto (TU-100), an aqueous extract of ginger, ginseng, and Japanese green pepper fruit, is a commonly prescribed Kampo (Japanese herbal medicine) for postoperative ileus or bloating. The effects of TU-100 on drug metabolism have not been investigated. In this study, we analyzed the effect of TU-100 on expression of key drug-metabolizing enzymes (DMEs) and drug transporters (DTs) in murine liver and gastrointestinal tract using a dietary model...
October 2017: Pharmacology Research & Perspectives
https://www.readbyqxmd.com/read/28947502/restricted-delivery-of-talazoparib-across-the-blood-brain-barrier-limits-the-sensitizing-effects-of-parp-inhibition-on-temozolomide-therapy-in-glioblastoma
#5
Sani H Kizilbash, Shiv K Gupta, Kenneth Chang, Ryo Kawashima, Karen E Parrish, Brett L Carlson, Katrina K Bakken, Ann C Mladek, Mark A Schroeder, Paul A Decker, Gaspar J Kitange, Yuqiao Shen, Ying Feng, Andrew A Protter, William F Elmquist, Jann N Sarkaria
Poly ADP-ribose polymerase (PARP) inhibitors, including talazoparib, potentiate temozolomide efficacy in multiple tumor types; however, talazoparib-mediated sensitization has not been evaluated in orthotopic glioblastoma (GBM) models. This study evaluates talazoparib ± temozolomide in clinically relevant GBM models. Talazoparib at 1-3 nmol/L sensitized T98G, U251, and GBM12 cells to temozolomide, and enhanced DNA damage signaling and G2 -M arrest in vitro In vivo cyclical therapy with talazoparib (0.15 mg/kg twice daily) combined with low-dose temozolomide (5 mg/kg daily) was well tolerated...
December 2017: Molecular Cancer Therapeutics
https://www.readbyqxmd.com/read/28893245/age-dependent-redox-status-in-the-brain-stem-of-no-deficient-hypertensive-rats
#6
Miroslava Majzúnová, Zuzana Pakanová, Peter Kvasnička, Peter Bališ, Soňa Čačányiová, Ima Dovinová
BACKGROUND: The brain stem contains important nuclei that control cardiovascular function via the sympathetic nervous system (SNS), which is strongly influenced by nitric oxide. Its biological activity is also largely determined by oxygen free radicals. Despite many experimental studies, the role of AT1R-NAD(P)H oxidase-superoxide pathway in NO-deficiency is not yet sufficiently clarified. We determined changes in free radical signaling and antioxidant and detoxification response in the brain stem of young and adult Wistar rats during chronic administration of exogenous NO inhibitors...
September 11, 2017: Journal of Biomedical Science
https://www.readbyqxmd.com/read/28821731/stability-in-metabolic-phenotypes-and-inferred-metagenome-profiles-before-the-onset-of-colitis-induced-inflammation
#7
M Glymenaki, A Barnes, S O' Hagan, G Warhurst, A J McBain, I D Wilson, D B Kell, K J Else, S M Cruickshank
Inflammatory bowel disease (IBD) is associated with altered microbiota composition and metabolism, but it is unclear whether these changes precede inflammation or are the result of it since current studies have mainly focused on changes after the onset of disease. We previously showed differences in mucus gut microbiota composition preceded colitis-induced inflammation and stool microbial differences only became apparent at colitis onset. In the present study, we aimed to investigate whether microbial dysbiosis was associated with differences in both predicted microbial gene content and endogenous metabolite profiles...
August 18, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28702798/the-differential-absorption-of-a-series-of-p-glycoprotein-substrates-in-isolated-perfused-lungs-from-mdr1a-1b-genetic-knockout-mice-can-be-attributed-to-distinct-physico-chemical-properties-an-insight-into-predicting-transporter-mediated-pulmonary-specific
#8
Daniel F Price, Chris N Luscombe, Peter J Eddershaw, Chris D Edwards, Mark Gumbleton
PURPOSE: To examine if pulmonary P-glycoprotein (P-gp) is functional in an intact lung; impeding the pulmonary absorption and increasing lung retention of P-gp substrates administered into the airways. Using calculated physico-chemical properties alone build a predictive Quantitative Structure-Activity Relationship (QSAR) model distinguishing whether a substrate's pulmonary absorption would be limited by P-gp or not. METHODS: A panel of 18 P-gp substrates were administered into the airways of an isolated perfused mouse lung (IPML) model derived from Mdr1a/Mdr1b knockout mice...
December 2017: Pharmaceutical Research
https://www.readbyqxmd.com/read/28686677/mdr1a-deficiency-restrains-tumor-growth-in-murine-colitis-associated-carcinogenesis
#9
Eva Maria Hennenberg, Annette Eyking, Henning Reis, Elke Cario
Patients with Ulcerative Colitis (UC) have an increased risk to develop colitis-associated colorectal cancer (CAC). Here, we found that protein expression of ABCB1 (ATP Binding Cassette Subfamily B Member 1) / MDR1 (multidrug resistance 1) was diminished in the intestinal mucosa of patients with active UC with or without CAC, but not in non-UC patients with sporadic colon cancer. We investigated the consequences of ABCB1/MDR1 loss-of-function in a common murine model for CAC (AOM/DSS). Mice deficient in MDR1A (MDR1A KO) showed enhanced intratumoral inflammation and cellular damage, which were associated with reduced colonic tumor size and decreased degree of dysplasia, when compared to wild-type (WT)...
2017: PloS One
https://www.readbyqxmd.com/read/28661152/profiles-and-gender-specifics-of-udp-glucuronosyltransferases-and-sulfotransferases-expressions-in-the-major-metabolic-organs-of-wild-type-and-efflux-transporter-knockout-fvb-mice
#10
Jiamei Chen, Haihui Zheng, Sijing Zeng, Cong Xie, Xiaoyan Li, Tongmeng Yan, Xia Gong, Linlin Lu, Xiaoxiao Qi, Ying Wang, Ming Hu, Lijun Zhu, Zhongqiu Liu
Hepatic and extrahepatic tissues participate in xenobiotic detoxication, carcinogen activation, prodrug processing, and estrogen regulation through UDP-glucuronosyltransferases (UGTs/Ugts) and sulfotransferases (SULTs/Sults). Wild-type (WT) and efflux transporter knockout (KO) FVB mice have been commonly used to perform the studies of pharmacokinetics, metabolism, and toxicity. We employed the developed UHPLC-MS/MS approach to gain systematic insight on gender-specific of Ugts and Sults in major metabolic organs...
July 17, 2017: Molecular Pharmaceutics
https://www.readbyqxmd.com/read/28650628/synthesis-and-evaluation-of-new-fluorine-18-labeled-verapamil-analogs-to-investigate-the-function-of-p-glycoprotein-in-the-blood-brain-barrier
#11
Renske M Raaphorst, Gert Luurtsema, Robert C Schuit, Esther J M Kooijman, Philip H Elsinga, Adriaan A Lammertsma, Albert D Windhorst
P-glycoprotein is an efflux transporter located in the blood-brain barrier. (R)-[(11)C]Verapamil is widely used as a PET tracer to investigate its function in patients with epilepsy, Alzheimer's disease, and other neurodegenerative diseases. Currently it is not possible to use this successful tracer in clinics without a cyclotron, because of the short half-life of carbon-11. We developed two new fluorine-18 labeled (R)-verapamil analogs, with the benefit of a longer half-life. The synthesis of (R)-N-[(18)F]fluoroethylverapamil ([(18)F]1) and (R)-O-[(18)F]fluoroethylnorverapamil ([(18)F]2) has been described...
September 20, 2017: ACS Chemical Neuroscience
https://www.readbyqxmd.com/read/28498157/compositional-changes-in-the-gut-mucus-microbiota-precede-the-onset-of-colitis-induced-inflammation
#12
Maria Glymenaki, Gurdeep Singh, Andrew Brass, Geoffrey Warhurst, Andrew J McBain, Kathryn J Else, Sheena M Cruickshank
BACKGROUND: Inflammatory bowel disease (IBD) is associated with an inappropriate immune response to the gut microbiota. Notably, patients with IBD reportedly have alterations in fecal microbiota. However, the colonic microbiota occupies both the gut lumen and the mucus covering the epithelium. Thus, information about mucus-resident microbiota fails to be conveyed in the routine microbiota analyses of stool samples. Further, studies analyzing microbiota in IBD have mainly focused on stool samples taken after onset of inflammation...
May 11, 2017: Inflammatory Bowel Diseases
https://www.readbyqxmd.com/read/28321153/p-glycoprotein-multidrug-transporter-in-inflammatory-bowel-diseases-more-questions-than-answers
#13
EDITORIAL
Elke Cario
The gastrointestinal barrier is constantly exposed to numerous environmental substrates that are foreign and potentially harmful. These xenobiotics can cause shifts in the intestinal microbiota composition, affect mucosal immune responses, disturb tissue integrity and impair regeneration. The multidrug transporter ABCB1/MDR1 p-glycoprotein (p-gp) plays a key role at the front line of host defence by efficiently protecting the gastrointestinal barrier from xenobiotic accumulation. This Editorial discusses how altered expression and function of ABCB1/MDR1 p-gp may contribute to the development and persistence of chronic intestinal inflammation in inflammatory bowel diseases (IBD)...
March 7, 2017: World Journal of Gastroenterology: WJG
https://www.readbyqxmd.com/read/28303499/pregnane-x-receptor-not-nuclear-factor-kappa-b-up-regulates-p-glycoprotein-expression-in-the-brain-of-chronic-epileptic-rats-induced-by-kainic-acid
#14
Nian Yu, Yan-Fang Zhang, Kang Zhang, Yong-Fei Cheng, Hai-Yan Ma, Qing Di
Drug-resistance epilepsy (DRE) is attributed to the brain P-glycoprotein (P-gp) overexpression. We previously reported that nuclear factor-kappa B (NF-κB) played a critical role in regulating P-gp expression at the brain of the acute seizure rats. This study was extended further to investigate the interaction effect of NF-κB and pregnane X receptor (PXR) on P-gp expression at the brain of chronic epileptic rats treated with carbamazepine (CBZ). The chronic epileptic models were induced by the micro-injection of kainic acid (KA) into rats' hippocampus...
August 2017: Neurochemical Research
https://www.readbyqxmd.com/read/28242377/p-glycoprotein-in-skin-contributes-to-transdermal-absorption-of-topical-corticosteroids
#15
Naoto Hashimoto, Noritaka Nakamichi, Erina Yamazaki, Masashi Oikawa, Yusuke Masuo, Alfred H Schinkel, Yukio Kato
ATP binding cassette transporters, P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP), are expressed in skin, but their involvement in transdermal absorption of clinically used drugs remains unknown. Here, we examined their role in transdermal absorption of corticosteroids. Skin and plasma concentrations of dexamethasone after dermal application were reduced in P-gp and BCRP triple-knockout (Mdr1a/1b/Bcrp(-/-)) mice. The skin concentration in Mdr1a/1b/Bcrp(-/-) mice was reduced in the dermis, but not in the epidermis, indicating that functional expression of these transporters in skin is compartmentalized...
April 15, 2017: International Journal of Pharmaceutics
https://www.readbyqxmd.com/read/28216407/multidrug-resistance-transporter-1-and-breast-cancer-resistance-protein-protect-against-ovarian-toxicity-and-are-essential-in-ovarian-physiology
#16
Lynae M Brayboy, Nathalie Oulhen, Sokunvichet Long, Niesha Voigt, Christina Raker, Gary M Wessel
Ovarian protection from chemotoxicity is essential for reproductive health. Our objective is to determine the role of ATP-dependent, Multidrug Resistance Transporters (MDRs) in this protection. Previously we identified MDR-dependent cytoprotection from cyclophosphamide in mouse and human oocytes by use of MDR inhibitors. Here we use genetic deletions in MDR1a/b/BCRP of mice to test MDR function in ovarian somatic cells and find that mdr1a/b/bcrp-/- mice had significantly increased sensitivity to cyclophosphamide...
April 2017: Reproductive Toxicology
https://www.readbyqxmd.com/read/28193520/mdr1a-plays-a-crucial-role-in-regulating-the-analgesic-effect-and-toxicity-of-aconitine-by-altering-its-pharmacokinetic-characteristics
#17
Lijun Zhu, Jinjun Wu, Min Zhao, Wenjie Song, Xiaoxiao Qi, Ying Wang, Linlin Lu, Zhongqiu Liu
Aconitine (AC) is the primary bioactive/toxic alkaloid in plants of the Aconitum species. Our previous study demonstrated that Mdr1 was involved in efflux of AC. However, the mechanism by which Mdr1 regulates the efficacy/toxicity of AC in vivo remains unclear. The present study aimed to determine the effects of Mdr1a on the efficacy/toxicity and pharmacokinetics of AC in wild-type and Mdr1a-/- FVB mice. After oral administration of AC, significantly higher analgesic effect was observed in Mdr1a-/- mice (49% to 105%) compared to wild-type mice (P<0...
April 1, 2017: Toxicology and Applied Pharmacology
https://www.readbyqxmd.com/read/27836711/effect-of-cigarette-smoke-extract-on-p-glycoprotein-function-in-primary-cultured-and-newly-developed-alveolar-epithelial-cells
#18
Mikihisa Takano, Ryosuke Naka, Yoshihiro Sasaki, Saori Nishimoto, Ryoko Yumoto
The effect of cigarette smoke extract (CSE) on P-glycoprotein (P-gp) function in the distal lung is unclear. In this study, we first examined the expression and function of P-gp and the effect of CSE in rat primary cultured alveolar epithelial cells. The expression of P-gp protein was observed in type I-like cells, but not in type II cells. In type I-like cells, rhodamine 123 (Rho123) accumulation was enhanced by various P-gp inhibitors such as verapamil and cyclosporine A. In addition, the expression of P-gp mRNAs, mdr1a and mdr1b, as well as P-gp activity increased along with the transdifferentiation...
December 2016: Drug Metabolism and Pharmacokinetics
https://www.readbyqxmd.com/read/27601334/polysorbate-20-increases-oral-absorption-of-digoxin-in-wild-type-sprague-dawley-rats-but-not-in-mdr1a-sprague-dawley-rats
#19
Carsten Uhd Nielsen, Ahmed A Abdulhussein, Dilan Colak, René Holm
The aim was to investigate the ability of polysorbate 20 to alter oral digoxin absorption in vitro and drug exposure in vivo via modulation of transporter mediated efflux. Transport studies were performed in MDCKII-MDR1 and Caco-2 cells using (3)H-digoxin. Pharmacokinetic studies were performed in wild type and mdr1a deficient Sprague Dawley rats. (3)H-digoxin was quantified using liquid scintillation counting. The results showed an increased absorptive transport and a reduced secretory transport in MDCKII-MDR and Caco-2 cells as a function of polysorbate 20 concentrations...
November 20, 2016: International Journal of Pharmaceutics
https://www.readbyqxmd.com/read/27555820/inhibition-of-p-glycoprotein-and-multidrug-resistance-associated-protein-2-regulates-the-hepatobiliary-excretion-and-plasma-exposure-of-thienorphine-and-its-glucuronide-conjugate
#20
Ling-Lei Kong, Guo-Lin Shen, Zhi-Yuan Wang, Xiao-Mei Zhuang, Wei-Bin Xiao, Mei Yuan, Ze-Hui Gong, Hua Li
Thienorphine (TNP) is a novel partial opioid agonist that has completed phase II clinical evaluation as a promising drug candidate for the treatment of opioid dependence. Previous studies have shown that TNP and its glucuronide conjugate (TNP-G) undergo significant bile excretion. The purpose of this study was to investigate the roles of efflux transporters in regulating biliary excretion and plasma exposure of TNP and TNP-G. An ATPase assay suggested that TNP and TNP-G were substrates of P-gp and MRP2, respectively...
2016: Frontiers in Pharmacology
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