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Canine digoxin

Burak Ozgür, Lasse Saaby, Kristine Langthaler, Birger Brodin
Recently, we transfected the porcine intestinal cell line IPEC-J2, with human P-glycoprotein (P-gp, ABCB1). The resulting cell line, iP-gp, has a high expression of functional human P-gp in the apical membrane, and a low expression of nonhuman ATP-binding cassette (ABC) transporters. The aim of the present work was to investigate the usability of iP-gp cell line for determining transepithelial transport kinetics of the prototypical P-gp substrates digoxin and rhodamine 123. The cell line generated tight monolayers after 16days of culture, reflected by high transepithelial electrical resistance values (TEER>15,000Ω·cm2 ), immunocytochemistry and low fluxes of the paracellular flux marker [14 C]-mannitol...
January 15, 2018: European Journal of Pharmaceutical Sciences
Ivailo Simoff, Maria Karlgren, Maria Backlund, Anne-Christine Lindström, Fabienne Z Gaugaz, Pär Matsson, Per Artursson
Madin-Darby canine kidney II cells transfected with one or several transport proteins are commonly used models to study drug transport. In these cells, however, endogenous transporters such as canine Mdr1/P-glycoprotein (Abcb1) complicate the interpretation of transport studies. The aim of this investigation was to establish a Madin-Darby canine kidney II cell line using CRISPR-Cas9 gene-editing technology to knock out endogenous canine Mdr1 (cMdr1) expression. CRISPR-Cas9-mediated Abcb1 homozygous disruption occurred at frequencies of around 20% and resulted in several genotypes...
February 2016: Journal of Pharmaceutical Sciences
Kishore Cholkar, Hoang M Trinh, Aswani Dutt Vadlapudi, Zhiying Wang, Dhananjay Pal, Ashim K Mitra
PURPOSE: Screening interactions of a resolvin E1 analog (RX-10045) with efflux transporters (P-glycoprotein [P-gp], multidrug resistance-associated protein [MRP2], and breast cancer-resistant protein [BCRP]). METHODS: Madin-Darby canine kidney cells transfected with P-gp, MRP2, and BCRP genes were selected for this study. [3H]-Digoxin, [3H]-vinblastine and [3H]-abacavir were selected as model substrates for P-gp, MRP2, and BCRP. Uptake and permeability studies across cell monolayer in both apical to basal (AP-BL) and BL-AP of these substrates were conducted in the presence of specific efflux pump inhibitors and RX-10045...
May 2015: Journal of Ocular Pharmacology and Therapeutics
Min Zhu, Yi Ming, Heidi Swaim, Marla D Swain, Michael J Myers, Christine Deaver, Xiaolin Wu, Yolanda L Jones, Haile F Yancy
OBJECTIVE: To identify biomarkers of P-glycoprotein (P-gp) substrate neurotoxicity in transgenic mice expressing the mutant canine ABCB1 gene (ABCB1-1Δ). ANIMALS: 8 ABCB1 knock-in and knock-out transgenic mice expressing the ABCB1-1Δ gene and 8 control mice expressing the wild-type canine ABCB1 gene (ABCB1-WT). PROCEDURES: Groups including 2 ABCB1-1Δ mutant mice and 2 ABCB1-WT mice were administered the P-gp substrates ivermectin (10 mg/kg, SC), doramectin (10 mg/kg, SC), moxidectin (10 mg/kg, PO), or digoxin (1...
December 2014: American Journal of Veterinary Research
Pengyuan Sun, Changyuan Wang, Qi Liu, Qiang Meng, Aijie Zhang, Xiaokui Huo, Huijun Sun, Kexin Liu
BACKGROUND: Eprosartan is an angiotensin II receptor antagonist, used in the treatment of hypertension and heart failure in clinical patients. The objective of this study was to clarify the mechanism underlying hepatic uptake and biliary excretion of eprosartan in rats and humans. METHODS: Perfused rat liver in situ, rat liver slices, isolated rat hepatocytes and human organic anion-transporting polypeptide (OATP)-transfected cells in vitro were used in this study...
April 2014: Pharmacological Reports: PR
Dominik Gartzke, Gert Fricker
Madin-Darby canine kidney (MDCK) cells transfected with human MDR1 gene (MDCK-MDR1) encoding for P-glycoprotein (hPgp, ABCB1) are widely used for transport studies to identify drug candidates as substrates of this efflux protein. Therefore, it is necessary to rely on constant and comparable expression levels of Pgp to avoid false negative or positive results. We generated a cell line with homogenously high and stable expression of hPgp through sorting single clones from a MDCK-MDR1 cell pool using fluorescence-activated cell sorting (FACS)...
April 2014: Journal of Pharmaceutical Sciences
Xingrong Liu, Jonathan Cheong, Xiao Ding, Gauri Deshmukh
The study objectives were 1) to test the hypothesis that the lack of P-glycoprotein (P-gp) and the inhibition of breast cancer resistance protein (Bcrp) at the blood-brain barrier after cassette dosing of potent P-gp and Bcrp inhibitors were due to low plasma concentrations of those inhibitors and 2) to examine the effects of P-gp on the unbound brain (C(u,brain)) and cerebrospinal fluid (CSF) concentrations (C(u,CSF)) of P-gp substrates in rats. In vitro inhibition of 11 compounds (amprenavir, citalopram, digoxin, elacridar, imatinib, Ko143 [(3S,6S,12aS)-1,2,3,4,6,7,12,12a-octahydro-9-methoxy-6-(2-methylpropyl)-1,4-dioxopyrazino[1',2':1,6]pyrido[3,4-b]indole-3-propanoic acid 1,1-dimethylethyl ester], loperamide, prazosin, quinidine, sulfasalazine, and verapamil) on P-gp and Bcrp was examined in P-gp- and Bcrp-expressing Madin-Darby canine kidney cells, respectively...
April 2014: Drug Metabolism and Disposition: the Biological Fate of Chemicals
R S Shelton, M Kumar, K Chinda, S Lin, K Murray, P Chen
BACKGROUND: Increased stellate ganglion nerve activity (SGNA) directly precedes the onset of spontaneous atrial tachyarrhythmias (AT) in ambulatory dogs. However, it is difficult to use SGNA for risk stratification and arrhythmia prediction because access to the stellate ganglion requires open chest surgery. Because subcutaneous sympathetic nerve fibers originate from ipsilateral stellate ganglion, we hypothesize that subcutaneous nerve activity (SCNA) can be used as a surrogate of SGNA to predict the immediate onset of AT in ambulatory dogs...
November 2013: Heart Rhythm: the Official Journal of the Heart Rhythm Society
Annie Albin Lumen, Libin Li, Jiben Li, Zeba Ahmed, Zhou Meng, Albert Owen, Harma Ellens, Ismael J Hidalgo, Joe Bentz
We have reported that the P-gp substrate digoxin required basolateral and apical uptake transport in excess of that allowed by digoxin passive permeability (as measured in the presence of GF120918) to achieve the observed efflux kinetics across MDCK-MDR1-NKI (The Netherlands Cancer Institute) confluent cell monolayers. That is, GF120918 inhibitable uptake transport was kinetically required. Therefore, IC50 measurements using digoxin as a probe substrate in this cell line could be due to inhibition of P-gp, of digoxin uptake transport, or both...
2013: PloS One
Victoria Hutter, David Y S Chau, Constanze Hilgendorf, Alan Brown, Anne Cooper, Vanessa Zann, David I Pritchard, Cynthia Bosquillon
The impact of P-glycoprotein (MDR1, ABCB1) on drug disposition in the lungs as well as its presence and activity in in vitro respiratory drug absorption models remain controversial to date. Hence, we characterised MDR1 expression and the bidirectional transport of the common MDR1 probe (3)H-digoxin in air-liquid interfaced (ALI) layers of normal human bronchial epithelial (NHBE) cells and of the Calu-3 bronchial epithelial cell line at different passage numbers. Madin-Darby Canine Kidney (MDCKII) cells transfected with the human MDR1 were used as positive controls...
January 2014: European Journal of Pharmaceutics and Biopharmaceutics
Eric L Reyner, Samantha Sevidal, Mark A West, Andrea Clouser-Roche, Sascha Freiwald, Katherine Fenner, Mohammed Ullah, Caroline A Lee, Bill J Smith
Axitinib is an inhibitor of tyrosine kinase vascular endothelin growth factor receptors 1, 2, and 3. The ATP-binding cassette (ABC) and solute carrier (SLC) transport properties of axitinib were determined in selected cellular systems. Axitinib exhibited high passive permeability in all cell lines evaluated (Papp ≥ 6 × 10(-6) cm/s). Active efflux was observed in Caco-2 cells, and further evaluation in multidrug resistance gene 1 (MDR1) or breast cancer resistance protein (BCRP) transfected Madin-Darby canine kidney cells type 2 (MDCK) cells indicated that axitinib is at most only a weak substrate for P-glycoprotein (P-gp) but not BCRP...
August 2013: Drug Metabolism and Disposition: the Biological Fate of Chemicals
Ghaith Al-Jayyoussi, Daniel F Price, Danielle Francombe, Glyn Taylor, Mathew W Smith, Chris Morris, Chris D Edwards, Peter Eddershaw, Mark Gumbleton
P-glycoprotein (P-gp) mediated efflux is recognised to alter the absorption and disposition of a diverse range of substrates. Despite evidence showing the presence of P-gp within the lung, relatively little is known about the transporter's effect upon the absorption and distribution of drugs delivered via the pulmonary route. Here, we present data from an intact isolated rat lung model, alongside two isolated mouse lung models using either chemical or genetic inhibition of P-gp. Data from all three models show inhibition of P-gp increases the extent of absorption of a subset of P-gp substrates (e...
September 2013: Journal of Pharmaceutical Sciences
Joe Bentz, Michael P O'Connor, Dallas Bednarczyk, Joann Coleman, Caroline Lee, Johan Palm, Y Anne Pak, Elke S Perloff, Eric Reyner, Praveen Balimane, Marie Brännström, Xiaoyan Chu, Christoph Funk, Ailan Guo, Imad Hanna, Krisztina Herédi-Szabó, Kate Hillgren, Libin Li, Evelyn Hollnack-Pusch, Masoud Jamei, Xuena Lin, Andrew K Mason, Sibylle Neuhoff, Aarti Patel, Lalitha Podila, Emile Plise, Ganesh Rajaraman, Laurent Salphati, Eric Sands, Mitchell E Taub, Jan-Shiang Taur, Dietmar Weitz, Heleen M Wortelboer, Cindy Q Xia, Guangqing Xiao, Jocelyn Yabut, Tetsuo Yamagata, Lei Zhang, Harma Ellens
A P-glycoprotein (P-gp) IC₅₀ working group was established with 23 participating pharmaceutical and contract research laboratories and one academic institution to assess interlaboratory variability in P-gp IC₅₀ determinations. Each laboratory followed its in-house protocol to determine in vitro IC₅₀ values for 16 inhibitors using four different test systems: human colon adenocarcinoma cells (Caco-2; eleven laboratories), Madin-Darby canine kidney cells transfected with MDR1 cDNA (MDCKII-MDR1; six laboratories), and Lilly Laboratories Cells--Porcine Kidney Nr...
July 2013: Drug Metabolism and Disposition: the Biological Fate of Chemicals
Vu Tran, Xiaodong Zhang, Lin Cao, Hanqing Li, Benjamin Lee, Michelle So, Yaohui Sun, Wei Chen, Min Zhao
Transepithelial potential (TEP) is the voltage across a polarized epithelium. In epithelia that have active transport functions, the force for transmembrane flux of an ion is dictated by the electrochemical gradient in which TEP plays an essential role. In epithelial injury, disruption of the epithelial barrier collapses the TEP at the wound edge, resulting in the establishment of an endogenous wound electric field (∼100 mV/mm) that is directed towards the center of the wound. This endogenous electric field is implicated to enhance wound healing by guiding cell migration...
2013: PloS One
Aijie Zhang, Changyuan Wang, Qi Liu, Qiang Meng, Jinyong Peng, Huijun Sun, Xiaochi Ma, Xiaokui Huo, Kexin Liu
The objective of this study was to clarify the mechanism underlying hepatic uptake of dioscin (diosgenyl 2,4-di-O-a-L-rhamnopyranosyl-p-D-glucopyranoside), an herbal ingredient with antihepatitis activity, in rats and humans. The liver uptake index (LUI) in vivo, perfused rat liver in situ, rat liver slices, isolated rat hepatocytes, and human organic anion-transporting polypeptide (OATP)-transfected cells in vitro were used to evaluate hepatic uptake of dioscin. Values of 11.9% ± 1.6% and 15.0% ± 0.9% of dose for uptake of dioscin were observed by LUI in vivo and perfused rat livers in situ, respectively...
May 2013: Drug Metabolism and Disposition: the Biological Fate of Chemicals
Weibin Zha, Guangji Wang, Weiren Xu, Xuyuan Liu, Yun Wang, Beth S Zha, Jian Shi, Qijin Zhao, Phillip M Gerk, Elaine Studer, Phillip B Hylemon, William M Pandak, Huiping Zhou
BACKGROUND: HIV protease inhibitor (PI)-induced inflammatory response in macrophages is a major risk factor for cardiovascular diseases. We have previously reported that berberine (BBR), a traditional herbal medicine, prevents HIV PI-induced inflammatory response through inhibiting endoplasmic reticulum (ER) stress in macrophages. We also found that HIV PIs significantly increased the intracellular concentrations of BBR in macrophages. However, the underlying mechanisms of HIV PI-induced BBR accumulation are unknown...
2013: PloS One
M D Swain, K L Orzechowski, H L Swaim, Y L Jones, M G Robl, C A Tinaza, M J Myers, M V Jhingory, L E Buckely, V A Lancaster, H F Yancy
Certain dog breeds, especially Collies, are observed to exhibit neurotoxicity to avermectin drugs, which are P-glycoprotein (P-gp) substrates. This neurotoxicity is due to an ABCB1 gene mutation (ABCB1-1Δ) that results in non-functional P-gp expression. A developed Abcb1a knock-in/Abcb1b knock-out mouse model expressing the ABCB1-1Δ canine gene was previously reported and mice exhibited sensitivity upon ivermectin administration. Here, model and wild-type mice were administered P-gp substrates doramectin, moxidectin, and digoxin...
June 2013: Research in Veterinary Science
Yasuhisa Nagasaka, Kazuo Oda, Takafumi Iwatsubo, Akio Kawamura, Takashi Usui
The inhibition potencies of aripiprazole and its active metabolite, dehydroaripiprazole, on the activities of human multidrug resistance protein 1 (MDR1/ABCB1; P-glycoprotein), breast cancer resistance protein (BCRP/ABCG2) and multidrug resistance-associated protein 4 (MRP4/ABCC4), that are drug efflux transporters expressed both in the intestine and at the blood-brain barrier (BBB), were investigated. Aripiprazole and dehydroapripiprazole showed relatively strong inhibitory effects on human MDR1 with IC(50) values of 1...
September 2012: Biopharmaceutics & Drug Disposition
Szu-Yu Yeh, Huei-Ju Pan, Chung-Cheng Lin, Yu-Han Kao, Yen-Hui Chen, Chun-Jung Lin
The purpose of this study is to investigate the regulation of P-glycoprotein expression in the kidney under diabetic condition. Renal P-glycoprotein expression was examined in inbred mice with type 1 or type 2 diabetes by Western blotting. The underlying mechanisms of P-glycoprotein regulation were examined in Madin-Darby canine kidney type II (MDCK-II) cells by Western blotting or qRT-PCR. (3)H-digoxin uptake was measured for P-glycoprotein activity in cells under various treatments. The results showed that P-glycoprotein expression was lower in kidneys of diabetic mice than in controls...
September 5, 2012: European Journal of Pharmacology
Pallabi Mitra, Kenneth Audus, Gervan Williams, Mehran Yazdanian, Deborah Galinis
The purpose of this study was to investigate whether changes in the pH of the gastrointestinal tract can directly affect P-glycoprotein (P-gp) function. The effect of changes in extracellular pH on P-gp functionality was examined by testing colchicine (a nonionizable P-gp substrate) in bidirectional Caco-2 and MDR1-Madine Darby canine kidney (MDCK) cell permeability assays, in which the pH of the apical and basolateral chambers was varied. Reduction of the pH from 7.4 to 5.0 and 4.5 markedly increased the apical-to-basolateral flux of colchicine and reduced the basolateral-to-apical flux...
October 2011: Journal of Pharmaceutical Sciences
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