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Xenobiotica; the Fate of Foreign Compounds in Biological Systems

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https://www.readbyqxmd.com/read/28648140/oxidation-of-1-chloropyrene-by-human-cyp1-family-and-cyp2a-subfamily-cytochrome-p450-enzymes-catalytic-roles-of-two-cyp1b1-and-five-cyp2a13-allelic-variants
#1
Tsutomu Shimada, Norie Murayama, Kensaku Kakimoto, Shigeo Takenaka, Young-Ran Lim, Sora Yeom, Donghak Kim, Hiroshi Yamazaki, F Peter Guengerich, Masayuki Komori
1. Chloropyrene, one of the major chlorinated polycyclic aromatic hydrocarbon contaminants, was incubated with human cytochrome P450 (P450 or CYP) enzymes including CYP1A1, 1A2, 1B1, 2A6, 2A13, 2B6, 2C9, 2D6, 2E1, 3A4, and 3A5. Catalytic differences in 1-chloropyrene oxidation by polymorphic two CYP1B1 and five CYP2A13 allelic variants were also examined. 2. CYP1A1 oxidized 1-chloropyrene at the 6- and 8-positions more actively than at the 3-position, while both CYP1B1.1 and 1B1.3 preferentially catalyzed 6-hydroxylation...
June 26, 2017: Xenobiotica; the Fate of Foreign Compounds in Biological Systems
https://www.readbyqxmd.com/read/28648122/phase-1-study-to-investigate-the-pharmacokinetic-properties-of-dacomitinib-in-healthy-adult-chinese-subjects-genotyped-for-cyp2d6
#2
Xia Chen, Ji Jiang, Nagdeep Giri, Pei Hu
1. This study aimed to characterise the pharmacokinetics of dacomitinib, a pan-human epidermal growth factor receptor tyrosine kinase inhibitor, and its metabolite, PF-05199265, in healthy Chinese subjects. 2. In this open-label, single-centre, nonrandomised study (NCT02097433), 14 subjects received a single dacomitinib 45-mg oral dose. Pharmacokinetic samples for dacomitinib and PF-05199265 were collected pre- and postdose. Subjects were genotyped for cytochrome P450 (CYP)2D6 metaboliser status. Safety was assessed throughout the study...
June 26, 2017: Xenobiotica; the Fate of Foreign Compounds in Biological Systems
https://www.readbyqxmd.com/read/28644704/numerical-analysis-of-time-dependent-inhibition-kinetics-comparison-between-rat-liver-microsomes-and-rat-hepatocyte-data-for-mechanistic-model-fitting
#3
Chuong Pham, Swati Nagar, Ken Korzekwa
Time dependent inhibition (TDI) may confound drug interaction predictions. Recently, models were generated for an array of TDI kinetic schemes using numerical analysis of microsomal assays. Additionally, a distinct terminal inactivation step was identified for certain mechanism based inhibitors (MBI) following reversible metabolite intermediate complex (MIC) formation. Longer hepatocyte incubations potentially allow analysis of slow TDI and terminal inactivation. In the experiments presented here, we compared the quality of TDI parameterization by numerical analysis between hepatocyte and microsomal data...
June 23, 2017: Xenobiotica; the Fate of Foreign Compounds in Biological Systems
https://www.readbyqxmd.com/read/27458090/polychlorinated-biphenyls-disrupt-hepatic-epidermal-growth-factor-receptor-signaling
#4
Josiah E Hardesty, Banrida Wahlang, K Cameron Falkner, Heather B Clair, Barbara J Clark, Brian P Ceresa, Russell A Prough, Matthew C Cave
1. Polychlorinated biphenyls (PCBs) are persistent environmental pollutants that disrupt hepatic xenobiotic and intermediary metabolism, leading to metabolic syndrome and nonalcoholic steatohepatitis (NASH). 2. Since phenobarbital indirectly activates Constitutive Androstane Receptor (CAR) by antagonizing growth factor binding to the epidermal growth factor receptor (EGFR), we hypothesized that PCBs may also diminish EGFR signaling. 3. The effects of the PCB mixture Aroclor 1260 on the protein phosphorylation cascade triggered by EGFR activation were determined in murine (in vitro and in vivo) and human models (in vitro)...
June 21, 2017: Xenobiotica; the Fate of Foreign Compounds in Biological Systems
https://www.readbyqxmd.com/read/28629263/mass-spectrometry-based-analysis-of-murine-bronchoalveolar-lavage-fluid-following-respiratory-exposure-to-4-4-methylene-diphenyl-diisocyanate-aerosol
#5
Justin M Hettick, Brandon F Law, Chen-Chung Lin, Adam V Wisnewski, Paul D Siegel
Diisocyanates are highly reactive electrophiles utilized in the manufacture of a wide range of polyurethane products, and have been identified as causative agents of occupational allergic respiratory disease. However, in spite of the significant occupational health burden associated with diisocyanate-induced asthma, the mechanism of disease pathogenesis remains largely unknown. To better understand the fate of inhaled diisocyanates, a nose-only aerosol exposure system was constructed and utilized to expose a BALB/c mouse model to aerosol generated from 4,4'-methylene diphenyl diisocyanate (MDI)...
June 20, 2017: Xenobiotica; the Fate of Foreign Compounds in Biological Systems
https://www.readbyqxmd.com/read/28627269/profiling-and-identification-of-chlorogenic-acid-metabolites-in-rats-by-ultra-high-performance-liquid-chromatography-coupled-with-linear-ion-trap-orbitrap-mass-spectrometer
#6
Fei Wang, Zhanpeng Shang, Lulu Xu, Zhibin Wang, Wenjing Zhao, XiaoDan Mei, Jianqiu Lu, Jiangyu Zhang
1. Chlorogenic acids (CGAs), one kind of major bioactive constituents isolated from Flos Lonicerae Japonicae, possess many biological activities, such as antibacterial, antioxidant, and antiviral activities. In this study, we established an efficient strategy using ultra-high-performance liquid chromatography coupled with linear ion trap-Orbitrap mass spectrometry (UHPLC-LTQ-Orbitrap MS) to profile the in vivo metabolic fate of CGAs in rat urine and plasma. 2. The extract from Flos Lonicerae Japonicae was orally administrated to Sprague-Dawley (SD) rats at a dose of 1000 mg/kg body weight...
June 19, 2017: Xenobiotica; the Fate of Foreign Compounds in Biological Systems
https://www.readbyqxmd.com/read/28627264/utility-of-in-vitro-and-in-vivo-systems-for-studying-the-permeability-of-capsaicin-and-nonivamide-through-different-intestinal-regions
#7
Lian Duan, Huaidong Peng, Guangcan Li, Ruolun Wang, Yanfang Chen
1. The present study determined and compared the permeability of capsaicin and nonivamide along the length of the intestine in rats. Accordingly, to evaluate this synthetic analog as a clinical substitute for capsaicin. 2. Permeabilities of capsaicin and nonivamide were measured in experiments utilizing Ussing chambers and in vivo methods. Capsaicin concentrations were examined by Liquid chromatography tandem mass spectrometry (LC-MS/MS). 3. Both capsaicin (0.80 × 10(-6) cm/s) and nonivamide (0.22 × 10(-6) cm/s, P > 0...
June 19, 2017: Xenobiotica; the Fate of Foreign Compounds in Biological Systems
https://www.readbyqxmd.com/read/28608757/the-effect-of-ethanol-and-n-nitrosodimethylamine-on-the-inos-dependent-no-production-in-human-neutrophils-role-of-nf-%C3%AE%C2%BAb
#8
Karolina Nowak, Wioletta Ratajczak-Wrona, Marzena Garley, Ewa Jabłońska
The objective of study was to determine the influence of ethanol and/or N-nitrosodimethyloamine (NDMA) on the inducible nitric oxide synthase (iNOS) expression and nitric oxide (NO) production by human neutrophils and determination of the role of NF-κB in this process. Isolated PMNs derived from 15 human volunteers were incubated in the presence of ethanol and/or NDMA. Expression of the tested proteins were evaluated using the Western blot method. Total NO metabolites was assayed in the cell cultures by Griess reaction...
June 13, 2017: Xenobiotica; the Fate of Foreign Compounds in Biological Systems
https://www.readbyqxmd.com/read/28608746/new-insights-in-the-metabolism-of-oxybutynin-evidence-of-n-oxidation-of-propargylamine-moiety-and-rearrangement-to-enaminoketone
#9
Silvio Aprile, Rossana Canavesi, Rosanna Matucci, Cristina Bellucci, Erika Del Grosso, Giorgio Grosa
1. Oxybutynin hydrochloride is an antimuscarinic agent prescribed to patients with an overactive bladder and symptoms of urinary urge incontinence. Oxybutynin undergoes pre-systemic metabolism, and the N-desethyloxybutynin (Oxy-DE), is reported to have similar anticholinergic effects. 2. We revisited the oxidative metabolic fate of oxybutynin by liquid chromatography tandem mass spectrometry analysis of incubations with rat and human liver fractions, and by measuring plasma and urine samples collected after oral administration of oxybutynin in rats...
June 13, 2017: Xenobiotica; the Fate of Foreign Compounds in Biological Systems
https://www.readbyqxmd.com/read/28532270/predominant-contributions-of-carboxylesterase-1-and-2-in-hydrolysis-of-anordrin-in-humans
#10
Jinfang Jiang, Xiaoyan Chen, Dafang Zhong
1. Anordrin (2α, 17α-diethynyl-A-nor-5α-androstane-2β, 17β-diol diproprionate) is post-coital contraceptive drug that is on the market in China for more than 30 years. This study aims to elucidate enzymes involved in anordrin hydrolysis, and to evaluate the significant role of carboxylesterases in anordrin hydrolysis in humans. 2. Human liver and intestinal microsomes, recombinant human carboxylesterase were selected as enzyme sources. In human liver microsomes, intrinsic clearance was 684 ± 83 μL/min/mg protein, which was considerably higher than the value of intestine microsomes (94...
June 7, 2017: Xenobiotica; the Fate of Foreign Compounds in Biological Systems
https://www.readbyqxmd.com/read/28532263/establishment-and-assessment-of-a-novel-in-vitro-bio-pk-pd-system-in-predicting-the-in-vivo-pharmacokinetics-and-pharmacodynamics-of-cyclophosphamide
#11
Shanshan Tong, Hong Sun, Caifu Xue, Hanmei Chen, Jing Liu, Huiying Yang, Ning Zhou, Xiaoqiang Xiang, Weimin Cai
1. A novel bio-pharmacokinetic/pharmacodynamic (PK/PD) system was established and assessed in predicting the PK parameters and PD effects of the model drug cyclophosphamide (CP) considering the interrelationships between drug metabolism, pharmacological effects and dynamic blood circulation processes in vitro. 2. The system contains a peristaltic pump, a reaction chamber with rat liver microsomes (RLMs) encapsulated in pluronic F127-acrylamide-bisacrylamide (FAB) hydrogels, an effector cell chamber and a recirculating pipeline...
June 6, 2017: Xenobiotica; the Fate of Foreign Compounds in Biological Systems
https://www.readbyqxmd.com/read/28489470/reaction-products-of-hexamethylene-diisocyanate-vapors-with-self-molecules-in-the-airways-of-rabbits-exposed-via-tracheostomy
#12
Adam V Wisnewski, Jean Kanyo, Jennifer Asher, James A Goodrich, Grace Barnett, Lyn Patrylak, Jian Liu, Carrie A Redlich, Ala F Nassar
1. Hexamethylenediisocyanate (HDI) is a widely used aliphatic diisocyanate and a well-recognized cause of occupational asthma. 2. "Self" molecules (peptides/proteins) in the lower airways, susceptible to chemical reactivity with HDI, have been hypothesized to play a role in asthma pathogenesis and/or chemical metabolism, but remain poorly characterized. 3. This study employed unique approaches to identify and characterize "self" targets of HDI reactivity in the lower airways. Anesthetized rabbits free breathed through a tracheostomy tube connected to chambers containing either, O2, or O2 plus ∼200 ppb HDI vapors...
June 1, 2017: Xenobiotica; the Fate of Foreign Compounds in Biological Systems
https://www.readbyqxmd.com/read/28485193/preclinical-absorption-distribution-metabolism-excretion-and-pharmacokinetics-of-a-novel-selective-inhibitor-of-breast-cancer-resistance-protein-bcrp
#13
Mingxiang Liao, Bei-Ching Chuang, Qing Zhu, Yuexian Li, Emily Guan, Shaoxia Yu, Johnny Yang, Shimoga Prakash, Cindy Q Xia
1. Breast cancer resistance protein (BCRP) plays an important role in drug absorption, distribution and excretion. It is challenging to evaluate BCRP functions in preclinical models because commonly used BCRP inhibitors are nonspecific or unstable in animal plasma. 2. In this work, in vitro absorption, distribution, metabolism and elimination (ADME) assays and pharmacokinetic (PK) experiments in Bcrp knockout (KO) (Abcg2(-/-)) and wild-type (WT) FVB mice and Wistar rats were conducted to characterize the preclinical properties of a novel selective BCRP inhibitor (ML753286, a Ko143 analog)...
May 31, 2017: Xenobiotica; the Fate of Foreign Compounds in Biological Systems
https://www.readbyqxmd.com/read/28489504/validation-of-the-cell-line-ls180-as-a-model-for-study-of-the-gastrointestinal-toxicity-of-mycophenolic-acid
#14
Svenja Heischmann, Uwe Christians
1. Gastrointestinal (GI) intolerability is a concern for drugs such as mycophenolic acid (MPA) and drug metabolism may play a role. Few in vitro models exist that allow for the preclinical evaluation of a potential role of drug metabolism in intestinal drug toxicity. Thus, we sought to develop an in vitro model based on the human colon adenocarcinoma cell line LS180 to investigate MPA's negative effects on intestinal cells. 2. Stability of expression of key enzymes of MPA metabolism (UGT1A7, UGT1A9, UGT1A10, UGT2B7, CYP3A4 and CYP3A5), transporters (OATP1B1, OATP1B3, OATP2B1, MRP1, MRP2 and MDR1) and the nuclear receptor PXR over 12 passages in combination with guanosine supplementation to counter MPA's antiproliferative effects (determined by western blot analysis and proliferation assays, respectively) was established...
May 30, 2017: Xenobiotica; the Fate of Foreign Compounds in Biological Systems
https://www.readbyqxmd.com/read/28489480/ponesimod-a-selective-sphingosine-1-phosphate-s1p1-receptor-modulator-for-autoimmune-diseases-review-of-clinical-pharmacokinetics-and-drug-disposition
#15
Ranjeet Prasad Dash, Rana Rais, Nuggehally R Srinivas
1. Ponesimod, a selective sphingosine 1-phosphate (S1P1) receptor modulator, is undergoing clinical development for the treatment of autoimmune diseases (multiple sclerosis/psoriasis). 2. Published literature data describing pharmacokinetic disposition of ponesimod were collected, reviewed and tabulated. 3. Across various clinical phase-I studies, ponesimod displayed consistent pharmacokinetics - relatively faster absorption peak time (approximately 2.5 h), elimination half-life of approximately 30 h and modest accumulation (2- to 2...
May 30, 2017: Xenobiotica; the Fate of Foreign Compounds in Biological Systems
https://www.readbyqxmd.com/read/28481715/efflux-proteins-at-the-blood-brain-barrier-review-and-bioinformatics-analysis
#16
Massoud Saidijam, Fatemeh Karimi Dermani, Sareh Sohrabi, Simon G Patching
1. Efflux proteins at the blood-brain barrier provide a mechanism for export of waste products of normal metabolism from the brain and help to maintain brain homeostasis. They also prevent entry into the brain of a wide range of potentially harmful compounds such as drugs and xenobiotics. 2. Conversely, efflux proteins also hinder delivery of therapeutic drugs to the brain and central nervous system used to treat brain tumours and neurological disorders. For bypassing efflux proteins, a comprehensive understanding of their structures, functions and molecular mechanisms is necessary, along with new strategies and technologies for delivery of drugs across the blood-brain barrier...
May 30, 2017: Xenobiotica; the Fate of Foreign Compounds in Biological Systems
https://www.readbyqxmd.com/read/28471331/study-on-the-pharmacokinetics-of-deoxyschizandrin-and-schizandrin-in-combination-with-epigallocatechin-gallate-a-component-of-green-tea-in-rats
#17
Yan Liu, Dong Zhang, Yingli Wang, Wenjuan Zhang, Xiaohong Liu
1. Green tea is commonly used worldwide due to its potential positive health benefits. We have examined the effects of epigallocatechin gallate (EGCG), the most abundant catechin in green tea, on the pharmacokinetics of deoxyschizandrin (DSD) and schizandrin (SD), which are the representative lignans in popular traditional Chinese medicines Fructus schisandrae, in rats. 2. The effects on the transport in Caco-2 cells and metabolism in human liver microsomes (HLMs) of DSD and SD by EGCG were determined to analyze their interactions thoroughly...
May 30, 2017: Xenobiotica; the Fate of Foreign Compounds in Biological Systems
https://www.readbyqxmd.com/read/28548030/everolimus-inhibited-multiple-isoforms-of-udp-glucuronosyltransferases-ugts
#18
Zuo Du, Guang Wang, Yun-Feng Cao, Cui-Min Hu, Kun Yang, Yong-Zhe Liu, Chun-Ze Zhang, Wei-Hua Zhang, Zhi-Tu Zhu, Hong-Zhi Sun, Xiao-Yu Sun, Mo Hong, Zhong-Ze Fang
1. Everolimus is an inhibitor of mammalian target of rapamycin (mTOR) and has been clinically utilized to prevent the rejection of organ transplants. This study aims to determine the inhibition of everolimus on the activity of phase II drug-metabolizing enzymes UDP-glucuronosyltransferases (UGTs). 2. The results showed that 100 uM of everolimus exerted more than 80% inhibition towards UGT1A1, -1A3, and -2B7. UGT1A3 and UGT2B7 were selected to elucidate the inhibition mechanism, and in silico docking showed that hydrogen bonds and hydrophobic interactions mainly contributed to the strong binding of everolimus towards the activity cavity of UGT1A3 and UGT2B7...
May 26, 2017: Xenobiotica; the Fate of Foreign Compounds in Biological Systems
https://www.readbyqxmd.com/read/28436712/disposition-and-metabolism-of-14-c-galunisertib-a-tgf-%C3%AE-ri-kinase-alk5-inhibitor-following-oral-administration-in-healthy-subjects-and-mechanistic-prediction-of-the-effect-of-itraconazole-on-galunisertib-pharmacokinetics
#19
Kenneth C Cassidy, Ivelina Gueorguieva, Colin Miles, Jessica Rehmel, Ping Yi, William J Ehlhardt
1. The disposition and metabolism of galunisertib (LY2157299 monohydrate, a TGF-βRI Kinase/ALK5 Inhibitor) was characterized following a single oral dose of 150 mg of [(14)C]-galunisertib (100 µCi) to six healthy human subjects. 2. The galunisertib plasma half-life was 8.6 h, while the (14)C half-life was 10.0 h. Galunisertib was abundant in circulation (40.3% of the (14)C AUC024 h), with 7 additional metabolites detected in plasma. Two metabolites LSN3199597 (M5, mono-oxidation), and M4 (glucuronide of M3) were the most abundant circulating metabolites (10...
May 16, 2017: Xenobiotica; the Fate of Foreign Compounds in Biological Systems
https://www.readbyqxmd.com/read/28443803/a-strategy-for-early-risk-predictions-of-clinical-drug-drug-interactions-involving-the-gastroplus-tm-ddi-module-for-time-dependent-cyp-inhibitors
#20
Anna-Karin Sohlenius-Sternbeck, Gabrielle Meyerson, Ann-Louise Hagbjörk, Sanja Juric, Ylva Terelius
1. A set of reference compounds for time-dependent inhibition (TDI) of cytochrome P450 with available literature data for kinact and KI was used to predict clinical implications using the GastroPlus(TM) software. Comparisons were made to in vivo literature interaction data. 2. The predicted AUC ratios (AUC+inhibitor/AUCcontrol) could be compared with the observed ratios from literature for all compounds with detailed information about in vivo administration, pharmacokinetics and in vivo interactions (N = 21)...
May 15, 2017: Xenobiotica; the Fate of Foreign Compounds in Biological Systems
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