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Xenobiotica; the Fate of Foreign Compounds in Biological Systems

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https://www.readbyqxmd.com/read/28812950/expression-of-cytochrome-p450-regulators-in-cynomolgus-macaque
#1
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
#2
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
#3
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
#4
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
#5
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
#6
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
https://www.readbyqxmd.com/read/28776489/pharmacokinetic-study-of-methylnaltrexone-after-single-and-multiple-subcutaneous-administrations-in-healthy-chinese-subjects
#7
Dan Zhang, Jing-Yi Ma, Man Yang, Ming Deng, Huichen Liu
1. Pharmacokinetics of methylnaltrexone (MNTX) were evaluated after subcutaneous administrations (s.c.) in healthy Chinese subjects. 2. In a cross-over single dose study, 12 subjects were given 0.075, 0.15, and 0.3 mg/kg of MNTX bromide injection. In a multiple doses study, another 12 subjects subcutaneously received 0.15 mg/kg of MNTX bromide injection every 48 hours, in total 5 administrations. The concentrations of MNTX in plasma were quantified by LC-MS/MS. 3. After single s.c. administrations of 0...
August 4, 2017: Xenobiotica; the Fate of Foreign Compounds in Biological Systems
https://www.readbyqxmd.com/read/28762864/progesterone-hydroxylation-by-cytochromes-p450-2c-and-3a-enzymes-in-marmoset-liver-microsomes
#8
Kazuyuki Nakanishi, Shotaro Uehara, Yasuhiro Uno, Takashi Inoue, Erika Sasaki, Hiroshi Yamazaki
1. Common marmosets (Callithrix jacchus) are potentially useful nonhuman primate models for preclinical drug metabolism studies. However, the roles of marmoset cytochrome P450 (P450) isoforms in the oxidation of endobiotic progesterone have not been fully investigated. In this study, the roles of marmoset P450 isoforms in progesterone hydroxylation were extensively determined. 2. The activities of liver microsomes from individual marmosets with respect to progesterone 21/17α- and 16α/6β-hydroxylation were significantly correlated with those for flurbiprofen 4-hydroxylation and midazolam 1'-hydroxylation, respectively, as similar correlations have been found in humans...
August 1, 2017: Xenobiotica; the Fate of Foreign Compounds in Biological Systems
https://www.readbyqxmd.com/read/28756727/effects-of-m-nisoldipine-on-the-activity-and-mrna-expression-of-four-cyp-isozymes-in-rats
#9
Yupeng Sun, Yanyan Liu, Xia Zhang, Changchen Wan, Tao Lyu, Lantong Zhang
1. For the first time, a systemic in vivo investigation was employed to evaluate the potential effects of m-nisoldipine on activities of rat cytochrome P450 enzymes (CYP1A2, CYP2C11, CYP2D1 and CYP3A1) by both cocktail probe drugs and the quantitative real-time reverse-transcription polymerase chain reaction (RT-qPCR). 2. m-Nisoldipine-treated and blank control groups were respectively administered m-nisoldipine at the dosage of 2.5, 5 and 12.5 mg/kg and CMC-Na solution for 15 days consecutively, then they were given the probe drugs of caffeine, diclofenac, dextromethorphan and midazolam (all probes were 5 mg/kg) by p...
July 31, 2017: Xenobiotica; the Fate of Foreign Compounds in Biological Systems
https://www.readbyqxmd.com/read/28745128/the-permeability-characteristics-and-interaction-of-main-components-from-si-ni-san-in-a-mdck-epithelial-cell-monolayer-model
#10
Ruonan Chen, Chenlin Shen, Qingqing Xu, Yaru Liu, Bo Li, Cheng Huang, Taotao Ma, Xiaoming Meng, Maomao Wu, Jun Li
1. Si-Ni-San (SNS) possesses extensive therapeutic effects, however, the extent to which main components are absorbed and the mechanisms involved are controversial. 2. In this study, MDCK cell model was used to determine the permeability characteristics and interaction between the major components of Si-Ni-San, including saikosaponin a, paeoniflorin, naringin and glycyrrhizic acid. 3. The transport of the major components was concentration-dependent in both directions. Moreover, the transport of paeoniflorin, naringin and glycyrrhizic acid was significantly reduced at 4°C or in the presence of NaN3...
July 26, 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
#11
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 honey flavonoids (namely galangin, myricetin, pinocembrin, pinobanksin, chrysin, fisetin) towards hOATP2B1 and hOATP1A2 as well as at examining their effect on the cellular uptake of the known OATP substrate rosuvastatin...
July 26, 2017: Xenobiotica; the Fate of Foreign Compounds in Biological Systems
https://www.readbyqxmd.com/read/27460866/an-open-label-single-dose-phase-1-study-of-the-absorption-metabolism-and-excretion-of-quizartinib-a-highly-selective-and-potent-flt3-tyrosine-kinase-inhibitor-in-healthy-male-subjects-for-the-treatment-of-acute-myeloid-leukemia
#12
Madhu Sanga, Joyce James, Joseph Marini, Guy Gammon, Christine Hale, Jianke Li
1. Quizartinib absorption, metabolism and excretion were characterized in six healthy men receiving a single oral dose of 60 mg (≈100 μCi) of [(14)C]-quizartinib. Blood, plasma, urine and faeces were collected ≤336 h postdose. 2. Four hours postdose, maximum mean ± SD blood radioactivity concentrations were 296 ± 67.4 ng equivalents/g. A mean ± SD of 1.64 ± 0.482% and 76.3 ± 6.23% of the dose was recovered in urine and faeces, respectively, within 336 h postdose. 3. Radio-detector high-performance liquid chromatography (radio-HPLC) and liquid chromatography-mass spectrometry (LC-MS) showed two main radioactive peaks in plasma, unchanged quizartinib and mono-oxidative metabolite, AC886...
July 25, 2017: Xenobiotica; the Fate of Foreign Compounds in Biological Systems
https://www.readbyqxmd.com/read/28737453/the-metabolism-and-drug-drug-interaction-potential-of-the-selective-prostacyclin-receptor-agonist-selexipag
#13
Carmela Gnerre, Jérôme Segrestaa, Swen Seeland, Päivi Äänismaa, Thomas Pfeifer, Stephane Delahaye, Ruben de Kanter, Tomohiko Ichikawa, Tetsuhiro Yamada, Alexander Treiber
- The metabolism of selexipag has been studied in vivo in man and the main excreted metabolites were identified. Also, metabolites circulating in human plasma have been structurally identified and quantified. - The main metabolic pathway of selexipag in man is the formation of the active metabolite ACT-333679. Other metabolic pathways include oxidation and dealkylation reactions. All primary metabolites undergo subsequent hydrolysis of the sulphonamide moiety to their corresponding acids. ACT-333679 undergoes conjugation with glucuronic acid and aromatic hydroxylation to P10, the main metabolite detected in human faeces...
July 24, 2017: Xenobiotica; the Fate of Foreign Compounds in Biological Systems
https://www.readbyqxmd.com/read/28737446/quantitative-in-vitro-phenotyping-and-prediction-of-drug-interaction-potential-of-cyp2b6-substrates-as-victims
#14
Raghava Choudary Palacharla, Ramakrishna Nirogi, Venkatesham Uthukam, Arunkumar Manoharan, Ranjith Kumar Ponnamaneni, Ilayaraja Kalaikadhiban
1. Determination of fm, CYP for a compound is critical to assess the potential risk of a drug candidate as a victim of DDI. Several compounds are identified as CYP2B6 substrates but the fm, CYP2B6 values are not determined quantitatively 2. Two methods of reaction phenotyping, the chemical inhibition method, and metabolism in rCYP enzymes, were used to determine the relative contributions of the enzymes. Chemical inhibition method was also conducted in the presence of BSA (0.5% w/v) 3. The results confirm with the earlier studies concerning the identity of the CYP2B6 enzyme...
July 24, 2017: Xenobiotica; the Fate of Foreign Compounds in Biological Systems
https://www.readbyqxmd.com/read/28730856/in-vitro-drug-drug-interactions-of-budesonide-inhibition-and-induction-of-transporters-and-cytochrome-p450-enzymes
#15
Nancy Chen, Donghui Cui, Qing Wang, Zhiming Wen, Richard D Finkelman, Devin Welty
1. Budesonide is a glucocorticoid used in the treatment of several respiratory and gastrointestinal inflammatory diseases. Glucocorticoids have been demonstrated to induce cytochrome P450 (CYP) 3A and the efflux transporter P-glycoprotein (P-gp). This study aimed to evaluate the potential of budesonide to act as a perpetrator or a victim of transporter- or CYP-mediated drug-drug interactions (DDIs). 2. In vitro studies were conducted for P-gp, breast cancer resistance protein and organic anion and cation transporters (OATP1B1, OATP1B3, OAT1, OAT3, OCT2) in transporter-transfected cells...
July 21, 2017: Xenobiotica; the Fate of Foreign Compounds in Biological Systems
https://www.readbyqxmd.com/read/28657423/in-vitro-metabolism-of-alectinib-a-novel-potent-alk-inhibitor-in-human-contribution-of-cyp3a-enzymes
#16
Toshito Nakagawa, Stephen Fowler, Kenji Takanashi, Kuresh Youdim, Tsuyoshi Yamauchi, Kosuke Kawashima, Mika Sato-Nakai, Li Yu, Masaki Ishigai
1. The in vitro metabolism of alectinib, a potent and highly selective oral anaplastic lymphoma kinase inhibitor, was investigated. 2. The main metabolite (M4) in primary human hepatocytes was identified, which is produced by deethylation at the morpholine ring. Three minor metabolites (M6, M1a, and M1b) were also identified, and a minor peak of hydroxylated alectinib (M5) was detected as a possible precursor of M4, M1a, and M1b. 3. M4, an important active major metabolite, was produced and further metabolized to M6 by CYP3A, indicating that CYP3A enzymes were the principal contributors to this route...
July 21, 2017: Xenobiotica; the Fate of Foreign Compounds in Biological Systems
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
#17
Tsutomu Shimada, Norie Murayama, Kensaku Kakimoto, Shigeo Takenaka, Young-Ran Lim, Sora Yeom, Donghak Kim, Hiroshi Yamazaki, F Peter Guengerich, Masayuki Komori
1. 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...
July 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
#18
Justin M Hettick, Brandon F Law, Chen-Chung Lin, Adam V Wisnewski, Paul D Siegel
1. 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. 2. 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 an aerosol generated from 4,4'-methylene diphenyl diisocyanate (MDI)...
July 21, 2017: Xenobiotica; the Fate of Foreign Compounds in Biological Systems
https://www.readbyqxmd.com/read/28707509/intestinal-absorption-of-pallidifloside-d-are-limited-by-p-glycoprotein-in-mice
#19
Ming-Yu Wang, Ming Yang, Pi-Yong Hou, Xiu-Bo Chen, Hong-Gang Li, Jiu-Xing Yan, Jun Zhang, Yan-Wen Zhang, Xiao-Hui Wu
1. Pallidifloside D, a saponin glycoside constituent from the total saponins of Smilax riparia, had been proved to be very effective in hyperuricemic control. But it is poorly bioavailable after oral administration. Here, we determined the role of P-glycoprotein (P-gp) in the intestinal absorption of Pallidifloside D. 2. We found that Pallidifloside D significantly stimulated P-gp ATPase activity in vitro ATPase assay with a small EC50 value of 0.46 µM. 3. In the single-pass perfused mouse intestine model, the absorption of Pallidifloside D was not favored in the small intestine (duodenum, jejunum and ileum) with a P*w value of 0...
July 14, 2017: Xenobiotica; the Fate of Foreign Compounds in Biological Systems
https://www.readbyqxmd.com/read/28691554/uptake-and-metabolism-of-carbamazepine-cbz-by-clam-ruditapes-decussatus-and-its-effects-in-biochemical-responses
#20
Abdelhafidh Khazri, Ali Mezni, Hassen Khazri, Badreddine Sellami, Jaume Aceña, Sandra Pérez, Ethel Eljarrat, Damià Barceló, Hamouda Beyrem, Ezzeddine Mahmoudi
Laboratory experiments were carried out to assess uptake and metabolism of the epilepsy drug, carbamazepine and its consequent biological responses in marine clam (Ruditapes decussatus) a model non-target organism in ecotoxicology. Clams were exposed to two nominal concentrations (C1= 30 µg/L and C2= 50 µg/L) of CBZ for a maximum period of 14 days. Analysis of CBZ and their metabolites in clam and water after exposure to two nominal concentrations of the pharmaceutical drug were performed using UPLC-HRMS analysis...
July 10, 2017: Xenobiotica; the Fate of Foreign Compounds in Biological Systems
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