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Xenobiotica; the Fate of Foreign Compounds in Biological Systems

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https://www.readbyqxmd.com/read/28925806/population-pharmacokinetics-of-arginine-glutamate-in-healthy-chinese-volunteers
#1
Jing Wang, Heng Zheng, Kun Wang, Zheng Wang, Yufeng Ding
1. The present study developed population pharmacokinetic models of arginine and glutamate in healthy Chinese volunteers. Two nonlinear mixed-effect models were developed using NONMEM® software (ICON Development Solutions, Ellicott City, MD) to describe the pharmacokinetic properties and to assess the relevant parameters as well as the inter-individual variability. The potential covariates were screened using stepwise approach and the stability and predictive capability of the models were performed using bootstrap and visual predictive check...
September 19, 2017: Xenobiotica; the Fate of Foreign Compounds in Biological Systems
https://www.readbyqxmd.com/read/28906164/comparative-pharmacokinetics-study-of-anastrozole-after-single-administration-and-combination-with-celecoxib
#2
Xiaoyang Sun, Mingming Lv, Binjie Wang, Simin Zhao, Ping Guo, Shixiao Wang, Liqiang Gu, Xiaohui Chen
1. There are numerous investigations demonstrating that the cyclooxygenase-2 (COX-2) inhibitors might enhance the efficiency of anastrozole in breast cancer. Hence, this study was conducted to investigate the comparative pharmacokinetics of anastrozole after single administration and combination with celecoxib. 2. A simple protein precipitation procedure was adopted for the sample preparation with satisfactory extraction recovery for both anastrozole and the internal standard, and then anastrozole was separated and analysed on an ACQUITY BEH UPLC C18 column (50 × 2...
September 14, 2017: Xenobiotica; the Fate of Foreign Compounds in Biological Systems
https://www.readbyqxmd.com/read/28891397/pharmacokinetic-evaluation-of-%C3%AE-caryophyllene-alcohol-in-rats-and-beagle-dogs
#3
Jiake He, Sufeng Zhou, Xiaonan Li, Chunfeng Wang, Yang Yu, Xijing Chen, Yang Lu
1. β-caryophyllene alcohol (BCPA) has shown therapeutic promise in the treatment of asthma and inflammation with low toxicity. The aim of the current study was to report the pharmacokinetic profiles of BCPA in rats and dogs. 2. Following intravenous administration, BCPA exhibited moderate volumes of distribution (Vz) ranging from 5.63 to 8.97 L/kg in rats and low Vz (2.89 ± 1.12 L/kg) in dogs. Systemic plasma clearance was high in both species, resulting in a short elimination half-life ranging from 29...
September 11, 2017: Xenobiotica; the Fate of Foreign Compounds in Biological Systems
https://www.readbyqxmd.com/read/28891378/in-vitro-inhibition-of-human-ugt-isoforms-by-ritonavir-and-cobicistat
#4
Sara Algeelani, Novera Alam, Md Amin Hossain, Gerd Mikus, David J Greenblatt
1. Ritonavir and cobicistat are pharmacokinetic boosting agents used to increase systemic exposure to other antiretroviral therapies. The manufacturer's data suggests that cobicistat is a more selective CYP3A4 inhibitor than ritonavir. However, the inhibitory effect of ritonavir and cobicistat on human UDP glucuronosyltransferase (UGT) enzymes in Phase II metabolism is not established. This study evaluated the inhibition of human UGT isoforms by ritonavir versus cobicistat. 2. Acetaminophen and ibuprofen were used as substrates to evaluate the metabolic activity of the principal human UGTs...
September 11, 2017: Xenobiotica; the Fate of Foreign Compounds in Biological Systems
https://www.readbyqxmd.com/read/28882082/changes-in-hepatic-phase-i-and-phase-ii-biotransformation-enzyme-expression-and-glutathione-levels-following-atrazine-exposure-in-female-rats
#5
Arthur D Zimmerman, Charles B Breckenridge, Kun D Yi, Pragati Sawhney Coder, Desiree Wanders, Robert L Judd, Chad D Foradori
1. To determine the effects of repeated atrazine (ATR) treatment on hepatic phase I and II enzymes, adult female rats were treated with vehicle or 100mg/kg of ATR for 1, 2, 3 or 4 days. Glutathione-s-transferases (GST) mRNA expression, protein levels (mu, pi, alpha, omega), and activity (cytosolic and microsomal), along with bioavailable glutathione (GSH) were assayed. 2. GST expression, concentrations, and activity were increased, along with GSH levels, in animals treated with ATR for 3 and 4 days. 3. A subsequent study was performed with animals treated with vehicle, 6...
September 8, 2017: Xenobiotica; the Fate of Foreign Compounds in Biological Systems
https://www.readbyqxmd.com/read/28879798/inhalation-exposure-of-nano-diamond-induced-oxidative-stress-in-lung-heart-and-brain
#6
Yahya Khosravi, Ahmad Salimi, Jalal Pourahmad, Parvaneh Naserzadeh, Enayatollah Seydi
1. Today, diamond nanoparticles have several industrial applications. Nano diamond (ND) as a carbon allotrope diffuses in the air easily during producing and processing procedures. 2. In this study, we investigated sub-acute exposed to ND at the exposure chamber in mice. The animals were divided into two groups (control and exposed a group to ND at the concentration of 3 µg/m(3) for 3 h/day, 5 days/week, for 30-days) in a whole-body inhalation chamber. 3. Our result showed that exposure to ND-induced the hematological and biochemical changes...
September 7, 2017: Xenobiotica; the Fate of Foreign Compounds in Biological Systems
https://www.readbyqxmd.com/read/28879796/assessment-of-the-pulmonary-cyp1a1-metabolism-of-mavoglurant-afq056-in-rat
#7
Yildiz Yilmaz, Kenichi Umehara, Gareth Williams, Thomas Faller, Hilmar Schiller, Markus Walles, Stephan Kraehenbuehl, Gian Camenisch, Nenad Manevski
1. AFQ056 phenotyping results indicate that CYP1A1 is responsible for the formation of the oxidative metabolite, M3. In line with the predominant assumption that CYP1A1 is mainly expressed in extrahepatic tissues, only traces of M3 were detected in hepatic systems. The aim of this study was to investigate the pulmonary CYP1A1 mediated metabolism of AFQ056 in rat. 2. Western blot analysis confirmed that CYP1A1 is expressed in rat lung albeit at low levels. M3 formation was clearly observed in recombinant rat CYP1A1, lung microsomes and lung tissue slices and was strongly inhibited by ketoconazole in the incubations...
September 7, 2017: Xenobiotica; the Fate of Foreign Compounds in Biological Systems
https://www.readbyqxmd.com/read/28876959/chirality-and-neuropsychiatric-drugs-an-update-on-stereoselective-disposition-and-clinical-pharmacokinetics-of-bupropion
#8
Ranjeet Prasad Dash, Rana Rais, Nuggehally R Srinivas
Bupropion, an antidepressant drug has been approved as a racemate containing equal amounts of R- and S- enantiomers. Recently, the chirality of bupropion has received significant attention in the delineation of stereoselective pharmacokinetic and disposition data. Although the non-stereoselective metabolism of bupropion was well established, the emerging data suggests that bupropion exhibits complex stereoselective metabolism, leading to the formation of various stereoisomeric metabolites. Along with the chiral pharmacokinetics of bupropion, hydroxybupropion, threohydrobupropion and erythrohydrobupropion, the metabolism data also provided insights into the roles of both CYP2B6 and CYP2C19 enzymes in the stereoselective disposition...
September 6, 2017: Xenobiotica; the Fate of Foreign Compounds in Biological Systems
https://www.readbyqxmd.com/read/28868965/the-effects-of-udp-sugars-udp-and-mg-2-on-uridine-diphosphate-glucuronosyltransferase-activity-in-human-liver-microsomes
#9
Gurinder Walia, Alexander D Smith, Zoe Riches, Abby C Collier, Michael W H Coughtrie
1. The UDP-glucuronosyltransferase (UGT) enzymes are important in the metabolism, elimination and detoxification of many xenobiotics and endogenous compounds. As extrapolation of in vitro kinetics of drug metabolizing enzymes to predict in vivo clearance rates becomes more sophisticated, it is important to ensure proper optimization of enzyme assays. The luminal location of the enzyme active site (i.e. latency), and the complexity of UGT kinetics, results in consistent under-prediction of clearance of drugs metabolized by glucuronidation...
September 4, 2017: Xenobiotica; the Fate of Foreign Compounds in Biological Systems
https://www.readbyqxmd.com/read/28851254/quantitative-prediction-of-the-extent-of-drug-drug-interaction-using-a-physiologically-based-pharmacokinetic-model-that-includes-inhibition-of-drug-metabolism-determined-in-cryopreserved-hepatocytes
#10
Shinji Iwasaki, Hideki Hirabayashi, Nobuyuki Amano
1. A physiologically based pharmacokinetic (PBPK) model that includes inhibition constant evaluated in cryopreserved hepatocytes was used to predict drug-drug interactions (DDIs) between orally administered nifedipine, a CYP substrate, and fluconazole or ketoconazole, CYP inhibitors, in rats. 2. The Kp,uu, ratio of unbound inhibitor concentration in liver ([I]liver,u) to that in plasma ([I]sys,u), of fluconazole and ketoconazole was 1.0 and 13.0, indicating that ketoconazole accumulates in liver. The ratios of inhibition constants in rat liver microsomes (Ki,mic,u) to that in rat cryopreserved hepatocytes (Ki,hep,u) for fluconazole and ketoconazole were 1...
September 4, 2017: Xenobiotica; the Fate of Foreign Compounds in Biological Systems
https://www.readbyqxmd.com/read/28859520/the-downfall-of-tba-354-a-possible-explanation-for-its-neurotoxicity-via-mass-spectrometric-imaging
#11
Sphamandla Ntshangase, Adeola Shobo, Hendrik G Kruger, Arndt Asperger, Dagmar Niemeyer, Per I Arvidsson, Thavendran Govender, Sooraj Baijnath
TBA-354 was a promising antitubercular compound with activity against both replicating and static Mycobacterium tuberculosis (M.tb), making it the focal point of many clinical trials conducted by the TB Alliance. However, findings from these trials have shown that TBA-354 results in mild signs of reversible neurotoxicity; this left the TB Alliance with no other choice but to stop the research. In this study, mass spectrometric methods were used to evaluate the pharmacokinetics and spatial distribution of TBA-354 in the brain using a validated liquid chromatography tandem-mass spectrometry (LC-MS/MS) and mass spectrometric imaging (MSI), respectively...
September 1, 2017: Xenobiotica; the Fate of Foreign Compounds in Biological Systems
https://www.readbyqxmd.com/read/28845725/characterizing-the-in-vitro-species-differences-in-n-glucuronidation-of-a-potent-pan-pim-inhibitor-gne-924-containing-a-3-5-substituted-6-azaindazole
#12
Molly Lin, Justin Ly, Ryan Takahashi, John Chen, Alan Deese, Sarah J Robinson, Aleksandr Kolesnikov, Susan Wong, Xiaojing Wang, Jae H Chang
Glucuronidation of amines has been shown to exhibit large species differences, where the activity is typically more pronounced in human than in many preclinical species such as rat, mouse, dog and monkey. The purpose of this work was to characterize the in vitro glucuronidation of GNE-924, a potent pan-PIM inhibitor, to form M1 using liver microsomes (LM) and intestinal microsomes (IM). M1 formation kinetics varied highly across species and between liver and intestinal microsomes. In LM incubations, rat exhibited the highest rate of M1 formation (CLint,app) at 140 ± 10 µL/min/mg protein, which was approximately 30-fold higher than human...
August 28, 2017: Xenobiotica; the Fate of Foreign Compounds in Biological Systems
https://www.readbyqxmd.com/read/28840784/indirect-regulation-of-cyp2c19-gene-expression-via-dna-methylation
#13
Kathryn Elisa Burns, Phillip Shepherd, Graeme Finlay, Malcolm Drummond Tingle, Nuala Ann Helsby
Despite speculation that the CYP2C19 gene may contain CpG islands, there has been little direct assessment of the role for epigenetics in the regulation of this pharmacogene. The effect of 5-aza-2'-deoxycytidine (5azaDC), a DNA methyltransferase inhibitor, and trichostatin A (TSA), an inhibitor of histone deacetylases, on the expression of CYP2C19 and five of its known transcription factors (TF) has been assessed in cell lines derived from neoplastic liver and intestine. CYP2C19 mRNA was substantially up-regulated (>18-fold) after treatment with 5azaDC despite the fact that the two intronic CpG islands in this gene remained substantially methylated (>50%)...
August 25, 2017: Xenobiotica; the Fate of Foreign Compounds in Biological Systems
https://www.readbyqxmd.com/read/28745105/honey-flavonoids-inhibit-hoatp2b1-and-hoatp1a2-transporters-and-hoatp-mediated-rosuvastatin-cell-uptake-in-vitro
#14
Lucie Navrátilová, Jana Ramos Mandíková, Petr Pávek, Přemysl Mladěnka, František Trejtnar
1. Some flavonoids contained in the common diet have been shown to interact with important membrane uptake transporters, including organic anion transporting polypeptides (OATPs). OATP2B1 and OATP1A2 expressed in the apical membrane of human enterocytes may significantly contribute to the intestinal absorption of drugs, e.g. statins. This study is aimed at an evaluation of the inhibitory potency of selected food honey flavonoids (namely galangin, myricetin, pinocembrin, pinobanksin, chrysin and fisetin) toward hOATP2B1 and hOATP1A2 as well as at examining their effect on the cellular uptake of the known OATP substrate rosuvastatin...
August 18, 2017: Xenobiotica; the Fate of Foreign Compounds in Biological Systems
https://www.readbyqxmd.com/read/28812950/expression-of-cytochrome-p450-regulators-in-cynomolgus-macaque
#15
Yasuhiro Uno, Hiroshi Yamazaki
1. Cytochrome P450 (P450) regulators including nuclear receptors and transcription factors have not been fully investigated in cynomolgus macaques, an important species used in drug metabolism studies. In this study, we analyzed seventeen P450 regulators by sequence and phylogenetic analysis, and tissue expression. 2. Gene and genome structures of seventeen P450 regulators were similar to the human orthologs, and the deduced amino acid sequences showed high sequence identities (92-95%) and more closely clustered, with the human orthologs...
August 16, 2017: Xenobiotica; the Fate of Foreign Compounds in Biological Systems
https://www.readbyqxmd.com/read/28803538/pharmacokinetics-of-tafamidis-a-transthyretin-amyloidosis-drug-in-rats
#16
Kyeong-Ryoon Lee, Jong-Woo Jeong, Hun-Chan Hyun, Jang Eunseo, Sunjoo Ahn Ahn, Sungwook Choi, Sang Hoon Joo, Sung-Sub Kim, Tae-Sung Koo
1. We characterized the pharmacokinetics of tafamidis, a novel drug to treat transthyretin-related amyloidosis, in rats after intravenous and oral administration at doses of 0.3-3 mg/kg. In vitro Caco-2 cell permeability and liver microsomal stability, as well as in vivo tissue distribution and plasma protein binding were also examined. 2. After intravenous injection, systemic clearance (CL), volumes of distribution at steady state (Vss), and half-life (T½) remained unaltered as a function of dose, with values in the ranges of 6...
August 14, 2017: Xenobiotica; the Fate of Foreign Compounds in Biological Systems
https://www.readbyqxmd.com/read/28795912/effects-of-verapamil-on-the-pharmacokinetics-of-dihydromyricetin-in-rats-and-its-potential-mechanism
#17
Yixiang Huang, Junyong Zhao, Wei Jian, Gang Wang
1. This study investigates the effects of verapamil on the pharmacokinetics of dihydromyricetin in rats and clarifies its main mechanism. 2. The pharmacokinetic profiles of oral or intravenous administration of dihydromyricetin in Sprague-Dawley rats with or without pretreatment with verapamil were investigated. In addition, the effects of verapamil on the transport and metabolic stability of dihydromyricetin were investigated using Caco-2 cell transwell model and rat liver microsomes. 3. In oral group, verapamil could significantly increase Cmax, and decrease oral clearance of dihydromyricetin (P < 0...
August 10, 2017: Xenobiotica; the Fate of Foreign Compounds in Biological Systems
https://www.readbyqxmd.com/read/28786731/comparative-pharmacokinetics-of-s-mp3950-a-novel-5-ht4-receptor-agonist-in-normal-and-atropine-induced-gastrointestinal-motility-disorders-rats
#18
Binjie Wang, Xiaoyang Sun, Shixiao Wang, Ping Guo, Shujuan Li, Meiyu Zhang, Longshan Zhao, Xiaohui Chen
1. (S)-MP3950 is the (S)-enantiomer of active metabolite of mosapride, which exhibits higher 5-HT4 receptor agonistic effect than mosapride. It shows promise to become a novel drug candidate for the treatment of gastrointestinal motility disorders. However, the pharmacokinetic behavior of (S)-MP3950 in the pathological state of gastrointestinal motility disorders remains unclear. Herein, we investigated the comparative pharmacokinetics of (S)-MP3950 in normal and gastrointestinal motility disorders rats. 2...
August 8, 2017: Xenobiotica; the Fate of Foreign Compounds in Biological Systems
https://www.readbyqxmd.com/read/28783419/effects-of-safflower-injection-on-the-pharmacodynamics-and-pharmacokinetics-of-warfarin-in-rats
#19
Yan Liu, Shuang Liu, Yuan Shi, Mengnan Qin, Zhidan Sun, Gaofeng Liu
1. Safflower injection (SI) is extracted from Chinese herbal medicine safflower which comprises many active components. Warfarin is a common anticoagulant and has exhibited drug interactions with several herbal products. This study aimed to investigate the effects of SI on pharmacodynamics and pharmacokinetics of warfarin in rats. 2. Wistar rats were randomly divided into blank control group, SI group, warfarin control group, and SI+warfarin group, respectively. In SI and SI+warfarin groups, rats were injected with SI (1...
August 7, 2017: Xenobiotica; the Fate of Foreign Compounds in Biological Systems
https://www.readbyqxmd.com/read/28783416/toluene-and-methylethylketone-effect-of-combined-exposure-on-their-metabolism-in-rat
#20
Frédéric Cosnier, Hervé Nunge, Élodie Bonfanti, Stéphane Grossmann, Anne-Marie Lambert-Xollin, Samuel Muller, Sylvie Sébillaud, Aurélie Thomas, Laurent Gaté, Pierre Campo
Multiple exposures are ubiquitous in industrial environments. In this article, we highlight the risks faced by workers and complete the data available on the metabolic impact of a common mixture: toluene (TOL) and methylethylketone (MEK). Rats were exposed by inhalation under controlled conditions either to each solvent individually, or to mixtures of the two. How the interaction between the two solvents affected their fate in the blood and brain, their main relevant urinary metabolites (o-cresol, benzylmercapturic acid for TOL and 2,3-butanediols for MEK) and their hepatic metabolism were investigated...
August 7, 2017: Xenobiotica; the Fate of Foreign Compounds in Biological Systems
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