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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
#1
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...
July 12, 2017: Pharmaceutical Research
https://www.readbyqxmd.com/read/28686677/mdr1a-deficiency-restrains-tumor-growth-in-murine-colitis-associated-carcinogenesis
#2
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
#3
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
#4
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...
July 10, 2017: ACS Chemical Neuroscience
https://www.readbyqxmd.com/read/28498157/compositional-changes-in-the-gut-mucus-microbiota-precede-the-onset-of-colitis-induced-inflammation
#5
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
#6
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
#7
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...
March 16, 2017: Neurochemical Research
https://www.readbyqxmd.com/read/28242377/p-glycoprotein-in-skin-contributes-to-transdermal-absorption-of-topical-corticosteroids
#8
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...
February 24, 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
#9
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
#10
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
#11
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
#12
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
#13
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
https://www.readbyqxmd.com/read/27276518/quantitative-targeted-absolute-proteomics-of-transporters-and-pharmacoproteomics-based-reconstruction-of-p-glycoprotein-function-in-mouse-small-intestine
#14
Takanori Akazawa, Yasuo Uchida, Masanori Tachikawa, Sumio Ohtsuki, Tetsuya Terasaki
The purpose of this study was to investigate whether a pharmacokinetic model integrating in vitro mdr1a efflux activity (which we previously reported) with in vitro/in vivo differences in protein expression level can reconstruct intestinal mdr1a function. In situ intestinal permeability-surface area product ratio between wild-type and mdr1a/1b (-/-) mice is one of the parameters used to describe intestinal mdr1a function. The reconstructed ratios of six mdr1a substrates (dexamethasone, digoxin, loperamide, quinidine, verapamil, vinblastine) and one nonsubstrate (diazepam) were consistent with the observed values reported by Adachi et al...
July 5, 2016: Molecular Pharmaceutics
https://www.readbyqxmd.com/read/27139220/oral-serum-derived-bovine-immunoglobulin-protein-isolate-has-immunomodulatory-effects-on-the-colon-of-mice-that-spontaneously-develop-colitis
#15
Anna Pérez-Bosque, Lluïsa Miró, Mònica Maijó, Javier Polo, Joy M Campbell, Louis Russell, Joe D Crenshaw, Eric Weaver, Miquel Moretó
Dietary immunoglobulin concentrates prepared from animal plasma can modulate the immune response of gut-associated lymphoid tissue (GALT). Previous studies have revealed that supplementation with serum-derived bovine immunoglobulin/protein isolate (SBI) ameliorates colonic barrier alterations in the mdr1a-/- genetic mouse model of IBD. Here, we examine the effects of SBI on mucosal inflammation in mdr1a-/- mice that spontaneously develop colitis. Wild type (WT) mice and mice lacking the mdr1a gene (KO) were fed diets supplemented with either SBI (2% w/w) or milk proteins (Control diet), from day 21 (weaning) until day 56...
2016: PloS One
https://www.readbyqxmd.com/read/27026287/visualizing-spatial-distribution-of-alectinib-in-murine-brain-using-quantitative-mass-spectrometry-imaging
#16
Hiroaki Aikawa, Mitsuhiro Hayashi, Shoraku Ryu, Makiko Yamashita, Naoto Ohtsuka, Masanobu Nishidate, Yasuhiro Fujiwara, Akinobu Hamada
In the development of anticancer drugs, drug concentration measurements in the target tissue have been thought to be crucial for predicting drug efficacy and safety. Liquid chromatography-tandem mass spectrometry (LC-MS/MS) is commonly used for determination of average drug concentrations; however, complete loss of spatial information in the target tissue occurs. Mass spectrometry imaging (MSI) has been recently applied as an innovative tool for detection of molecular distribution of pharmacological agents in heterogeneous targets...
March 30, 2016: Scientific Reports
https://www.readbyqxmd.com/read/26995548/methods-of-inducing-inflammatory-bowel-disease-in-mice
#17
Byoungwook Bang, Lenard M Lichtenberger
Animal models of experimentally induced inflammatory bowel disease (IBD) are useful for understanding more about the mechanistic basis of the disease, identifying new targets for therapeutic intervention, and testing novel therapeutics. This unit provides detailed protocols for five widely used mouse models of experimentally induced intestinal inflammation: chemical induction of colitis by dextran sodium sulfate (DSS), hapten-induced colitis via 2,4,6-trinitrobenzene sulfonic acid (TNBS), Helicobacter-induced colitis in mdr1a(-/-) mice, the CD4(+) CD45RB(hi) SCID transfer colitis model, and the IL-10(-/-) colitis model...
March 18, 2016: Current Protocols in Pharmacology
https://www.readbyqxmd.com/read/26971931/a-role-for-p-glycoprotein-in-clearance-of-alzheimer-amyloid-%C3%AE-peptide-from-the-brain
#18
Wei Wang, Angela M Bodles-Brakhop, Steven W Barger
Most data indicates that Alzheimer's disease involves an accumulation of amyloid β - peptide (Aβ) in the CNS and that sporadic cases arise from a deficiency in Aβ clearance. Considerable attention has been given to mechanisms by which Aβ might be transported between the brain and blood, and evidence suggests that p-glycoprotein, also known as the multi-drug resistance (MDR) protein (product of the ABCB1 gene), plays a role in Aβ transport across the blood-brain barrier (BBB). We tested this possibility through two approaches: First, wild-type and MDR1A-knockout mice were compared after intravenous injection of [(125)I]-labeled Aβ; after 60 min, homogenates of brain parenchyma were subjected to γ-counting of TCA-precipitable material, and histological sections of brain were subjected to autoradiography...
2016: Current Alzheimer Research
https://www.readbyqxmd.com/read/26940566/inoculation-with-enterococci-does-not-affect-colon-inflammation-in-the-multi-drug-resistance-1a-deficient-mouse-model-of-ibd
#19
Matthew P G Barnett, Yvonne E M Dommels, Christine A Butts, Shuotun Zhu, Warren C McNabb, Nicole C Roy
BACKGROUND: Intestinal bacteria are thought to play a role in the pathogenesis of human inflammatory bowel disease (IBD). We investigated whether oral inoculation with specific intestinal bacteria increased colon inflammation in the multi-drug resistance 1a-deficient (Mdr1a (-/-) ) mouse model of IBD. METHODS: Five-week-old Mdr1a (-/-) mice (FVB background) and FVB mice were randomly assigned to one of two treatment groups (Control or Inoculation, n = 12 per group)...
March 3, 2016: BMC Gastroenterology
https://www.readbyqxmd.com/read/26924499/-67-68-galmydar-a-metalloprobe-for-monitoring-breast-cancer-resistance-protein-bcrp-mediated-functional-transport-activity
#20
Jothilingam Sivapackiam, Scott E Harpstrite, Julie L Prior, Stephen Mattingly, Vijay Sharma
INTRODUCTION: For stratification of chemotherapeutic choices, radiopharmaceuticals capable of imaging breast cancer resistance protein (BCRP/ABCG2)-mediated functional transport are desired. To accomplish this objective, Galmydar, a fluorescent and moderately hydrophobic Ga(III) cationic complex and its (67/68)Ga-radiolabeled counterparts were interrogated in HEK293 cells stably transfected with BCRP and their WT counterparts transfected with empty vector. Additionally, the sensitivity and specificity of (68)Ga-Galmydar to evaluate functional expression of BCRP at the blood-brain barrier (BBB) was investigated in gene-knockout mdr1a/1b(-/-) (double knockout, dKO) and mdr1a/1b(-/-)ABCG2(-/-) (triple knockout, tKO) mouse models...
March 2016: Nuclear Medicine and Biology
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