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https://www.readbyqxmd.com/read/29785610/evaluation-of-strategies-for-the-assessment-of-drug-drug-interactions-involving-cytochrome-p450-enzymes
#1
Jelle Reinen, Martijn Smit, Mira Wenker
BACKGROUND AND OBJECTIVES: Drug-drug interactions (DDIs) can occur when one drug alters the metabolism of another drug. Drug metabolism mediated by cytochrome P450 enzymes (CYPs) is responsible for the majority of metabolism of known drugs and inhibition of CYP enzymes is a well-known cause of DDIs. In the current study, the use of various human liver microsomes (HLM)-based methods to determine occurrence of CYP-mediated metabolism-dependent inhibition (MDI) and possible follow-up studies were evaluated...
May 21, 2018: European Journal of Drug Metabolism and Pharmacokinetics
https://www.readbyqxmd.com/read/29784381/synthesis-of-a-selective-ratiometric-fluorescent-probe-based-on-naphthalimide-and-its-application-in-human-cytochrome-p450-1a
#2
Xiuxuan Zhang, Yan Zhou, Xiaofei Gu, Yu Cheng, Manxin Hong, Liqiang Yan, Fulong Ma, Zhengjian Qi
Cytochrome P450s have brought considerable attention to researchers for their significant correlations with metabolic behaviors of procarcinogenic chemicals. To better understand the roles of CYP1A in biological and physiological systems, we developed a novel ratiometric fluorescence probe N-((2-hydroxyl ethoxy) ethyl)- 4-methoxy-1, 8-naphthalimide (NEMN) allowing for selectively and sensitively monitoring the target enzymes under physiological conditions and living cells. The probe was designed based on substrate predilection of CYP1A and its outstanding O-dealkylation capacity, and 1, 8-naphthalimide was chosen as fluorophore on account of its desirable photophysical properties...
August 15, 2018: Talanta
https://www.readbyqxmd.com/read/29779669/synthesis-and-profiling-of-benzylmorpholine-1-2-4-5-tetraoxane-analogue-n205-towards-tetraoxane-scaffolds-with-potential-for-single-dose-cure-of-malaria
#3
Paul M O' Neill, Paul A Stocks, Sunil Sabbani, Natalie L Roberts, Richard K Amewu, Emma R Shore, Ghaith Aljayyoussi, Iñigo Angulo-Barturén, María Belén, Jiménez-Díaz, Santiago Ferrer Bazaga, María Santos Martínez, Brice Campo, Raman Sharma, Susan A Charman, Eileen Ryan, Gong Chen, David M Shackleford, Jill Davies, Gemma L Nixon, Giancarlo A Biagini, Stephen A Ward
A series of aryl carboxamide and benzylamino dispiro 1,2,4,5-tetraoxane analogues have been designed and synthesized in a short synthetic sequence from readily available starting materials. From this series of endoperoxides, molecules with in vitro IC50s versus Plasmodium falciparum (3D7) as low as 0.84 nM were identified. Based on an assessment of blood stability and in vitro microsomal stability, N205 (10a) was selected for rodent pharmacokinetic and in vivo antimalarial efficacy studies in the mouse Plasmodium berghei and Plasmodium falciparum Pf3D70087/N9 severe combined immunodeficiency (SCID) mouse models...
May 17, 2018: Bioorganic & Medicinal Chemistry
https://www.readbyqxmd.com/read/29779438/metabolism-of-deltamethrin-and-cis-and-trans-permethrin-by-human-expressed-cytochrome-p450-and-carboxylesterase-enzymes
#4
Laura Hedges, Susan Brown, A Kenneth MacLeod, Audrey Vardy, Edward Doyle, Gina Song, Marjory Moreau, Miyoung Yoon, Thomas G Osimitz, Brian G Lake
1. The metabolism of the pyrethroids deltamethrin (DLM), cis-permethrin (CPM) and trans-permethrin (TPM) was studied in human expressed cytochrome P450 (CYP) and carboxylesterase (CES) enzymes. 2. DLM, CPM and TPM were metabolised by human CYP2B6 and CYP2C19, with the highest apparent intrinsic clearance (CLint ) values for pyrethroid metabolism being observed with CYP2C19. Other CYP enzymes contributing to the metabolism of one or more of the three pyrethroids were CYP1A2, CYP2C8, CYP2C9*1, CYP2D6*1, CYP3A4 and CYP3A5...
May 21, 2018: Xenobiotica; the Fate of Foreign Compounds in Biological Systems
https://www.readbyqxmd.com/read/29779033/genome-wide-association-study-of-renal-function-traits-results-from-the-japan-multi-institutional-collaborative-cohort-study
#5
Asahi Hishida, Masahiro Nakatochi, Masato Akiyama, Yoichiro Kamatani, Takeshi Nishiyama, Hidemi Ito, Isao Oze, Yuichiro Nishida, Megumi Hara, Naoyuki Takashima, Tanvir Chowdhury Turin, Miki Watanabe, Sadao Suzuki, Rie Ibusuki, Ippei Shimoshikiryo, Yohko Nakamura, Haruo Mikami, Hiroaki Ikezaki, Norihiro Furusyo, Kiyonori Kuriki, Kaori Endoh, Teruhide Koyama, Daisuke Matsui, Hirokazu Uemura, Kokichi Arisawa, Tae Sasakabe, Rieko Okada, Sayo Kawai, Mariko Naito, Yukihide Momozawa, Michiaki Kubo, Kenji Wakai
BACKGROUND: Chronic kidney disease (CKD) is a rapidly growing, worldwide public health problem. Recent advances in genome-wide-association studies (GWAS) revealed several genetic loci associated with renal function traits worldwide. METHODS: We investigated the association of genetic factors with the levels of serum creatinine (SCr) and the estimated glomerular filtration rate (eGFR) in Japanese population-based cohorts analyzing the GWAS imputed data with 11,221 subjects and 12,617,569 variants, and replicated the findings with the 148,829 hospital-based Japanese subjects...
May 18, 2018: American Journal of Nephrology
https://www.readbyqxmd.com/read/29777509/improving-the-oral-bioavailability-of-tapentadol-via-a-carbamate-prodrug-approach-synthesis-bioactivation-and-pharmacokinetics
#6
Yingchao Li, Yongjun Wang, Ran Zhang, Cuiru Liu, Yue Wei, Jin Sun, Zhonggui He, Youjun Xu, Tianhong Zhang
Tapentadol suffers from rapid clearance due to extensive metabolism in vivo, which results in low oral bioavailability. In the present study, three novel prodrugs of tapentadol (WWJ01, WWJ02, and WWJ03) were synthesized to improve its metabolic stability and thereby improve its oral bioavailability. They all exhibited good stability in phosphate buffers, simulated gastrointestinal fluids, rat plasma, and intestinal and liver homogenates. Disappointingly, the N,N-diethylcarbamate prodrug of tapentadol (WWJ02) and the N,N-diisopropylcarbamate prodrug of tapentadol (WWJ03) were metabolized into inactive metabolites when incubated with liver microsomes...
May 17, 2018: Drug Delivery and Translational Research
https://www.readbyqxmd.com/read/29775936/from-hit-to-lead-structure-based-discovery-of-naphthalene-1-sulfonamide-derivatives-as-potent-and-selective-inhibitors-of-fatty-acid-binding-protein-4
#7
Ding-Ding Gao, Hui-Xia Dou, Hai-Xia Su, Ming-Ming Zhang, Ting Wang, Qiu-Feng Liu, Hai-Yan Cai, Hai-Peng Ding, Zhuo Yang, Wei-Liang Zhu, Ye-Chun Xu, He-Yao Wang, Ying-Xia Li
Fatty acid binding protein 4 (FABP4) plays a critical role in metabolism and inflammatory processes and therefore is a potential therapeutic target for immunometabolic diseases such as diabetes and atherosclerosis. Herein, we reported the identification of naphthalene-1-sulfonamide derivatives as novel, potent and selective FABP4 inhibitors by applying a structure-based design strategy. The binding affinities of compounds 16dk, 16do and 16du to FABP4, at the molecular level, are equivalent to or even better than that of BMS309403...
May 9, 2018: European Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/29775722/inflammatory-and-oxidative-mechanisms-potentiate-bifenthrin-induced-neurological-alterations-and-anxiety-like-behavior-in-adult-rats
#8
Brahim Gargouri, Harsharan S Bhatia, Michèle Bouchard, Bernd L Fiebich, Hamadi Fetoui
Bifenthrin (BF) is a synthetic pyrethroid pesticide widely used in several countries to manage insect pests on diverse agricultural crops. Growing evidence indicates that BF exposure is associated with an increased risk of developing neurodegenerative disorders. However, the mechanisms by which BF induces neurological and anxiety alterations in the frontal cortex and striatum are not well known. The present in vivo study was carried out to determine whether reactive oxygen species (ROS)-mediated oxidative stress (OS) and neuroinflammation are involved in such alterations...
May 15, 2018: Toxicology Letters
https://www.readbyqxmd.com/read/29774371/prediction-of-deoxynivalenol-toxicokinetics-in-humans-by-in-vitro-to-in-vivo-extrapolation-and-allometric-scaling-of-in-vivo-animal-data
#9
Christiane Kruse Fæste, Lada Ivanova, Amin Sayyari, Ulrik Hansen, Tore Sivertsen, Silvio Uhlig
Deoxynivalenol (DON) is the most prevalent mycotoxin in cereals worldwide. It can cause adverse health effects in humans and animals, and maximum levels in food and feed have been implemented by food authorities based on risk assessments derived from estimated intake levels. The lack of human toxicokinetic data such as absorption, distribution, and elimination characteristics hinders the direct calculation of DON plasma levels and exposure. In the present study, we have, therefore, used in vitro-to-in vivo extrapolation of depletion constants in hepatic microsomes from different species and allometric scaling of reported in vivo animal parameters to predict the plasma clearance [0...
May 17, 2018: Archives of Toxicology
https://www.readbyqxmd.com/read/29773554/nitidine-chloride-is-a-mechanism-based-inactivator-of-cyp2d6
#10
Xu Mao, Zi Xia Hu, Qian Wang, Na Zhang, Shen Zhi Zhou, Ying Peng, Jiang Zheng
Nitidine chloride (NC) is a benzophenanthridine alkaloid isolated from the roots of Zanthoxylum nitidum (Roxb.) DC, a widely used traditional herbal medicine. NC has been reported to reveal multiple pharmacologic properties. The inhibitory effects of NC on human cytochrome P450 enzymes were investigated in the present study. We found that NC caused time- and concentration-dependent inhibition of CYP2D6, and more than 50% of CYP2D6 activity was suppressed after 15 min incubation with NC at 100 μM in the primary incubation mixtures, with KI of 4...
May 17, 2018: Drug Metabolism and Disposition: the Biological Fate of Chemicals
https://www.readbyqxmd.com/read/29772747/involvement-of-cyp4f2-in-the-metabolism-of-a-novel-monophosphate-ester-prodrug-of-gemcitabine-and-its-interaction-potential-in-vitro
#11
Yedong Wang, Yuan Li, Jia Lu, Huixin Qi, Isabel Cheng, Hongjian Zhang
Compound- 3 is an oral monophosphate prodrug of gemcitabine. Previous data showed that Compound- 3 was more potent than gemcitabine and it was orally active in a tumor xenograft model. In the present study, the metabolism of Compound- 3 was investigated in several well-known in vitro matrices. While relatively stable in human and rat plasma, Compound- 3 demonstrated noticeable metabolism in liver and intestinal microsomes in the presence of NADPH and human hepatocytes. Compound- 3 could also be hydrolyzed by alkaline phosphatase, leading to gemcitabine formation...
May 16, 2018: Molecules: a Journal of Synthetic Chemistry and Natural Product Chemistry
https://www.readbyqxmd.com/read/29772541/myeloid-heme-oxygenase-1-a-new-therapeutic-target-in-anti-inflammation
#12
Mingyi Zhao, Minghua Yang, Weitao Que, Lin Zhong, Masayuki Fujino, Xiao-Kang Li
An increasing amount of evidence reveals that an orchestrated interplay between myeloid subpopulations in the hematopoietic system plays a significant role in supporting normal functions of the immune system and facilitating homeostatic restoration upon exogenous or endogenous insults. Heme oxygenase-1 (HO-1), a microsomal enzyme discovered decades ago, can metabolize pro-oxidant heme into biliverdin, free iron, and carbon monoxide. This enzymatic reaction produces biological materials, contributing to major immunomodulatory effects...
June 1, 2018: Frontiers in Bioscience (Landmark Edition)
https://www.readbyqxmd.com/read/29772457/in-vitro-and-in-vivo-metabolic-investigation-of-the-palbociclib-by-uhplc-q-tof-ms-ms-and-in-silico-toxicity-studies-of-its-metabolites
#13
Balasaheb B Chavan, Shristy Tiwari, Shankar G, Rakesh D Nimbalkar, Prabha Garg, Srinivas R, M V N Kumar Talluri
Palbociclib (PAB) is a CDK4/6 inhibitor and U. S Food and Drug Administration (FDA) granted regular approval for the treatment of hormone receptor (HR) positive, metastatic breast cancer in combination with an aromatase inhibitor in postmenopausal women. Metabolite identification is a crucial aspect during drug discovery and development as the drug metabolites may be pharmacologically active or possess toxicological activity. As there are no reports on the metabolism studies of the PAB, the present study focused on investigation of the in vitro and in vivo metabolic fate of the drug...
May 14, 2018: Journal of Pharmaceutical and Biomedical Analysis
https://www.readbyqxmd.com/read/29770723/the-impact-of-azole-antifungal-drugs-on-imatinib-metabolism-in-human-liver-microsomes
#14
Xingxian Luo, Taifeng Li, Ze Yu, Xuecai Xue, Haiyang Zhao, Na Li, Liping Ma, Changqing Yang, Lin Huanglin, Wangyu Feng
1. Imatinib is widely used for the treatment of hematologic malignancies. It is common that imatinib is clinically co-prescribed with azole antifungal agents since these patients are more prone to invasive antifungal infection. The present study was to investigate the effects of azole antifungal drugs, including ketoconazole, fluconazole, voriconazole, itraconazole and posaconazole on imatinib metabolism. 2. The main metabolites, 1-OH midazolam and N-desmethyl imatinib, were determined in the absence and in the presence of various levels of ketoconazole, fluconazole, voriconazole, itraconazole and posaconazole...
May 17, 2018: Xenobiotica; the Fate of Foreign Compounds in Biological Systems
https://www.readbyqxmd.com/read/29768080/effects-of-quercetin-on-the-pharmacokinetics-of-losartan-and-its-metabolite-exp3174-in-rats
#15
Qingling Zhao, Jinlan Wei, Hongying Zhang
1. This study investigates the influence of quercetin on the pharmacokinetics of losartan and its metabolite EXP3174 in rats. 2. The pharmacokinetic profiles of losartan and EXP3174 of orally administered losartan (10 mg/kg) with or without pretreatment with quercetin (20 mg/kg/day for 7 days) were investigated. Additionally, Caco-2 cell transwell model and rat liver microsome incubation experiments were also conducted to investigate its potential mechanism. 3. The results showed that when the rats were pretreated with quercetin, the Cmax (2...
May 16, 2018: Xenobiotica; the Fate of Foreign Compounds in Biological Systems
https://www.readbyqxmd.com/read/29766657/drug-drug-interaction-and-doping-effect-of-non-prohibited-drugs-on-the-urinary-excretion-profile-of-methandienone
#16
Monica Mazzarino, Franziska L Khevenhüller-Metsch, Ilaria Fiacco, Maria Kristina Parr, Xavier de la Torre, Francesco Botrè
The potential consequences of drug-drug interactions on the excretion profile of the anabolic androgenic steroid methandienone (17β-hydroxy-17α-methylandrosta-1,4-dien-3-one) are discussed here. More specifically, we have evaluated by in vitro and in vivo experiments the effects of seven non-prohibited drugs (fluconazole, ketoconazole, itraconazole, miconazole, fluoxetine, paroxetine and nefazodone) on the main metabolic pathways of methandienone. These are selected among those most commonly used by the athletes...
May 15, 2018: Drug Testing and Analysis
https://www.readbyqxmd.com/read/29763945/leishmanicidal-effects-of-piperlongumine-piplartine-and-its-putative-metabolites
#17
Fernanda de Lima Moreira, Thalita Bachelli Riul, Marcela de Lima Moreira, Alan Cesar Pilon, Marcelo Dias-Baruffi, Márcio S S Araújo, Norberto Peporine Lopes, Anderson R M de Oliveira
Piperlongumine is an amide alkaloid found in Piperaceae species that shows a broad spectrum of biological properties, including antitumor and antiparasitic activities. Herein, the leishmanicidal effect of piperlongumine and its derivatives produced by a biomimetic model using metalloporphyrins was investigated. The results showed that IC50 values of piperlongumine in promastigote forms of Leishmania infantum and Leishmania amazonensis were 7.9 and 3.3 µM, respectively. The IC50 value of piperlongumine in the intracellular amastigote form of L...
May 15, 2018: Planta Medica
https://www.readbyqxmd.com/read/29763932/microvesicles-from-human-adipose-tissue-derived-mesenchymal-stem-cells-as-a-new-protective-strategy-in-osteoarthritic-chondrocytes
#18
Miguel Tofiño-Vian, Maria Isabel Guillén, María Dolores Pérez Del Caz, Antonio Silvestre, María José Alcaraz
BACKGROUND/AIMS: Chronic inflammation contributes to cartilage degeneration during the progression of osteoarthritis (OA). Adipose tissue-derived mesenchymal stem cells (AD-MSC) show great potential to treat inflammatory and degradative processes in OA and have demonstrated paracrine effects in chondrocytes. In the present work, we have isolated and characterized the extracellular vesicles from human AD-MSC to investigate their role in the chondroprotective actions of these cells. METHODS: AD-MSC were isolated by collagenase treatment from adipose tissue from healthy individuals subjected to abdominal lipectomy surgery...
May 9, 2018: Cellular Physiology and Biochemistry
https://www.readbyqxmd.com/read/29763636/inhibition-of-cox-2-mpges-1-and-5-lox-in-macrophages-by-leonurine-ameliorates-monosodium-urate-crystal-induced-inflammation
#19
Yanzhuo Liu, Chenfan Duan, Honglei Chen, Chenlong Wang, Xiaoxiao Liu, Miao Qiu, Honglin Tang, Feng Zhang, Xiaoyang Zhou, Jing Yang
Cyclooxygenase-2 (COX-2), 5-lipoxygenase (5-LOX) and microsomal prostaglandin E synthase-1 (mPGES-1)-derived eicosanoids play an essential role in human inflammatory disorders. Here, we investigated whether inhibition of COX-2/mPGES-1 and 5-LOX in macrophages by leonurine ameliorates monosodium urate (MSU) crystal-induced inflammation. Virtual screening assay and in vitro enzyme inhibition assay showed that leonurine was a potential inhibitor of COX-2, mPGES-1 and 5-LOX. Compared with COX-2 inhibitor celecoxib, leonurine (30 mg/kg) significantly decreased ankle perimeter, gait score and neutrophil number in synovial fluid in MSU crystal-treated rats, accompanied with the decreased expression of COX-2, mPGES-1 and 5-LOX and production of prostaglandin E2 (PGE2 ) and leukotriene B4 (LTB4 ) in the synovial fluid macrophages...
May 15, 2018: Toxicology and Applied Pharmacology
https://www.readbyqxmd.com/read/29759885/terfenadone-is-a-strong-inhibitor-of-cyp2j2-present-in-the-human-liver-and-intestinal-microsomes
#20
Eunyoung Lee, Ju-Hyun Kim, Jong Cheol Shon, Zhexue Wu, Hyun Ji Kim, Minsik Gim, Taeho Lee, Kwang-Hyeon Liu
Cytochrome P450 2J2 (CYP2J2) is involved in the metabolism of drugs, including albendazole, astemizole, ebastine, and endogenous substrates. In a previous study, we used recombinant CYP2J2 and determined whether danazol, hydroxyebastine, telmisartan, and terfenadone inhibited CYP2J2 by using four representative CYP2J2 substrates, namely albendazole, astemizole, ebastine, and terfenadine. In this study, we evaluated the inhibitory potential of these four chemicals on human liver and intestinal microsomes, which are commonly used in a reaction phenotyping study...
March 15, 2018: Drug Metabolism and Pharmacokinetics
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