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Xenobiotica; the Fate of Foreign Compounds in Biological Systems

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https://www.readbyqxmd.com/read/30132394/comparison-of-uptake-transporter-functions-in-hepatocytes-in-different-species-to-determine-the-optimal-model-for-evaluating-drug-transporter-activities-in-humans
#1
Mingxiang Liao, Qing Zhu, Andy Zhu, Christopher Gemski, Bingli Ma, Emily Guan, Albert P Li, Guangqing Xiao, Cindy Q Xia
A thorough understanding of species-dependent differences in hepatic uptake transporters is critical for predicting human pharmacokinetics (PKs) from preclinical data. In this study, the activities of organic anion transporting polypeptide (OATP/Oatp), organic cation transporter 1 (OCT1/Oct1), and sodium-taurocholate cotransporting polypeptide (NTCP/Ntcp) in cultured rat, dog, monkey and human hepatocytes were compared. The activities of hepatic uptake transporters were evaluated with respect to culture duration, substrate and species-dependent differences in hepatocytes...
September 21, 2018: Xenobiotica; the Fate of Foreign Compounds in Biological Systems
https://www.readbyqxmd.com/read/30124359/in-vivo-hepatic-clearance-of-lipophilic-drugs-predicted-by-in-vitro-uptake-data-into-cryopreserved-hepatocytes-suspended-in-sera-of-rats-guinea-pigs-monkeys-and-humans
#2
Takashi Koyanagi, Koji Yano, Soonih Kim, Norie Murayama, Hiroshi Yamazaki, Ikumi Tamai
Evaluation of uptake of lipophilic acid compounds into hepatocytes was an unresolved drug development issue because of their adsorption to cells and materials and low analytical sensitivity and accuracy in assessment of protein bindings. Uptake assays of compounds using hepatocytes suspended in serum were expected to solve these problems for prediction of in vivo hepatic clearance. Here, for compounds with high protein binding (>99%), diflunisal, montelukast, cerivastatin, telmisartan, fluvastatin and six new drug candidates, in vivo hepatic clearance predicted based on hepatic depletion and uptake (CLh, uptake, predicted ) data using hepatocytes in the absence and presence of sera was investigated...
September 21, 2018: Xenobiotica; the Fate of Foreign Compounds in Biological Systems
https://www.readbyqxmd.com/read/30118378/microbial-biotransformation-an-important-tool-for-the-study-of-drug-metabolism
#3
Rhys Salter, Douglas C Beshore, Steven L Colletti, Liam Evans, Yong Gong, Roy Helmy, Yong Liu, Cheri M Maciolek, Gary Martin, Natasa Pajkovic, Richard Phipps, James Small, Jonathan Steele, Ronald de Vries, Headley Williams, Iain J Martin
Metabolite identification is an integral part of both preclinical and clinical drug discovery and development. Synthesis of drug metabolites is often required to support definitive identification, preclinical safety studies and clinical trials. Here we describe the use of microbial biotransformation as a tool to produce drug metabolites, complementing traditional chemical synthesis and other biosynthetic methods such as hepatocytes, liver microsomes and recombinant human drug metabolizing enzymes. A workflow is discussed whereby microbial strains are initially screened for their ability to form the putative metabolites of interest, followed by a scale-up to afford quantities sufficient to perform definitive identification and further studies...
September 21, 2018: Xenobiotica; the Fate of Foreign Compounds in Biological Systems
https://www.readbyqxmd.com/read/30231665/absorption-disposition-and-metabolic-pathway-of-amiselimod-mt-1303-in-healthy-volunteers-in-a-mass-balance-study
#4
Takayuki Kifuji, Shinsuke Inoue, Megumi Furukawa, Begonya Perez Madera, Takahiro Goto, Hiroshi Kumagai, Stuart J Mair, Atsuhiro Kawaguchi
1. The absorption, metabolism and excretion of MT-1303 were investigated in healthy male subjects after a single oral dose of 0.4 mg [14C]-MT-1303 (ClinicalTrials.gov NCT02293967). 2. The MT-1303 concentration in the plasma reached a maximum at 12 h after administration. Thereafter, the concentration declined with a half-life of 451 h. At the final assessment on Day 57, 91.16% of the administered radioactivity was excreted, and the cumulative excretion in the urine and faeces was 35.32% and 55.84%, respectively...
September 20, 2018: Xenobiotica; the Fate of Foreign Compounds in Biological Systems
https://www.readbyqxmd.com/read/30231664/effects-of-shuanghuanglian-injection-on-the-activities-of-cyp1a2-2c9-2d6-and-3a1-2-in-rats-in-vivo-and-in-vitro
#5
Yuan Shi, Juan Xu, Yan Qiao, Wenlong Zhang, Duo Liu, Mengnan Qin, Mei Dong, Gaofeng Liu
Shuanghuanglian Injection (SHLI), one of the most popular herbal prescription in China, has been commonly used to treat pneumonia, tonsillitis, and other respiratory diseases caused by bacterium and virus. This study is to investigate the effects of SHLI on the activities of Cytochrome P450 (CYP) 1A2, 2C11, 2D1 and 3A1/2 in rats. Sixteen rats were randomly divided into two groups (SHLI-treated and blank control). They were administered SHLI or physiological saline for consecutive seven days. On day eight, sixteen animals were administrated cocktail drugs as probe substrates of the four CYP in vivo...
September 20, 2018: Xenobiotica; the Fate of Foreign Compounds in Biological Systems
https://www.readbyqxmd.com/read/30227770/minor-contribution-of-cyp3a5-to-the-metabolism-of-hepatitis-c-protease-inhibitor-paritaprevir-in-vitro
#6
Su Nwe San, Jun Matsumoto, Yumi Saito, Masako Koike, Hiroaki Sakaue, Yoshinori Kato, Masachika Fujiyoshi, Noritaka Ariyoshi, Harumi Yamada
1. Paritaprevir (PTV) is a non-structural protein 3/4A protease inhibitor developed for the treatment of hepatitis C disease as a fixed dose combination of ombitasvir (OBV) and ritonavir (RTV) with or without dasabuvir. 2. The aim of this study was to evaluate the effects of cytochrome P450 (CYP) 3A5 on in vitro PTV metabolism using human recombinant CYP3A4, CYP3A5 (rCYP3A4, rCYP3A5), and human liver microsomes (HLMs) genotyped as either CYP3A5*1/*1, CYP3A5*1/*3, or CYP3A5*3/*3. 3. The intrinsic clearance (CLint , Vmax /Km ) for the production of a metabolite from PTV in rCYP3A4 was 1...
September 19, 2018: Xenobiotica; the Fate of Foreign Compounds in Biological Systems
https://www.readbyqxmd.com/read/30216105/functionally-relevant-genetic-variants-of-glutathione-s-transferase-gstm5-in-cynomolgus-and-rhesus-macaques
#7
Yasuhiro Uno, Norie Murayama, Kazuaki Tamura, Hiroshi Yamazaki
1. Glutathione S-transferase (GST) is a family of enzymes important for conjugation with glutathione of endogenous and exogenous compounds. Human GSTM1 null allele is associated with toxicity and cancers. Cynomolgus and rhesus macaques have molecular and enzymatic similarities of GSTs to humans; however, genetic variants have not been investigated. In macaques, instead of pseudogenized GSTM1, GSTM5 is a predominant GSTM isoform. 2. In this study, resequencing of GSTM5 in 64 cynomolgus and 31 rhesus macaques found 6 non-synonymous variants, and 1 variant (IVS5 + 1) causing exon skip...
September 14, 2018: Xenobiotica; the Fate of Foreign Compounds in Biological Systems
https://www.readbyqxmd.com/read/30216103/pharmacokinetic-modeling-and-simulation-of-etodolac-following-single-oral-administration-in-dogs
#8
In-Hwan Baek
1. Etodolac is a nonsteroidal anti-inflammatory drug with selective cyclooxigenase-2 inhibition to treat pain and inflammation associated with osteoarthritis in humans and dogs. The aim of the study was to investigate the pharmacokinetics of etodolac following single oral administration of 200 mg to 10 heathy beagle dogs. 2. The plasma concentrations of etodolac were detected using liquid chromatography-tandem mass spectrometry. Pharmacokinetic analysis was conducted using noncompartmental method and modeling approaches...
September 14, 2018: Xenobiotica; the Fate of Foreign Compounds in Biological Systems
https://www.readbyqxmd.com/read/30216099/evaluation-of-pharmacokinetic-interactions-between-bicyclol-and-co-administered-drugs-in-rat-and-human-liver-microsomes-in-vitro-and-in-rats-in-vivo
#9
Shu Yang, Jinping Hu, Yan Li, Zhigang Zhao
1. Bicyclol is a new synthetic anti-hepatitic drug and primarily metabolized by CYP3A. The aim of this study was to evaluate the pharmacokinetic interactions between bicyclol and co-administered drugs including metformin, pioglitazone, atorvastatin, fenofibrate, Cyclosporin A (CsA) and tacrolimus in rat and human liver microsomes (RLMs/HLMs) in vitro and in rats in vivo. 2. The depletion rate of bicyclol in RLMs was significantly inhibited by 44.8% and 35.5% after preincubation with pioglitazone and fenofibrate while the metabolite formation rate of bicyclol in HLMs was inhibited by 26...
September 14, 2018: Xenobiotica; the Fate of Foreign Compounds in Biological Systems
https://www.readbyqxmd.com/read/30216091/pharmacokinetics-of-anticoagulants-apixaban-dabigatran-edoxaban-and-rivaroxaban-in-elderly-japanese-patients-with-atrial-fibrillation-treated-in-one-general-hospital
#10
Miho Yamazaki-Nishioka, Minoru Kogiku, Masayuki Noda, Sumio Endo, Mitsuru Takekawa, Hirohisa Kishi, Miki Ota, Yuki Notsu, Makiko Shimizu, Hiroshi Yamazaki
1. Steady-state plasma concentrations of anticoagulants and the time since the previous administration in mainly outpatients with atrial fibrillation administered standard or reduced doses were analyzed for 110 elderly Japanese subjects (mean age, 76 years) treated with apixaban (2.5 or 5.0 mg twice daily), dabigatran etexilate (110 or 150 mg twice daily), edoxaban (30 or 60 mg once daily), or rivaroxaban (10 or 15 mg once daily) at one general hospital. 2. The pharmacokinetics in patients treated with standard and reduced doses of the four anticoagulants using liquid chromatography-tandem mass spectrometry were compared with the concentration ranges estimated using physiologically based pharmacokinetic modelling...
September 14, 2018: Xenobiotica; the Fate of Foreign Compounds in Biological Systems
https://www.readbyqxmd.com/read/30215545/-19-f-nmr-based-determination-of-the-absorption-metabolism-and-excretion-of-the-oral-phosphatidylinositol-3-kinase-pi3k-delta-inhibitor-leniolisib-cdz173-in-healthy-volunteers
#11
David Pearson, Maxime Garnier, Alexandre Luneau, Alexander David James, Markus Walles
1. Leniolisib is a novel oral phosphatidylinositol-3-kinase (PI3K) delta inhibitor, currently in clinical development for the treatment of inflammatory and autoimmune diseases. 2. We investigated the absorption, metabolism, and excretion of leniolisib in healthy subjects after a single oral 400 mg dose as part of a first-in-human clinical study. The parent drug and metabolites were quantified by 19 F-NMR in plasma, urine and faeces after liquid chromatography separation, and structures were determined by liquid chromatography coupled to tandem mass spectrometry...
September 14, 2018: Xenobiotica; the Fate of Foreign Compounds in Biological Systems
https://www.readbyqxmd.com/read/30215542/in-vitro-phase-i-metabolism-of-vinclozolin-by-human-liver-microsomes
#12
Marycarmen Cruz-Hurtado, Ma de Lourdes López-González, Victor Mondragón, Adolfo Sierra-Santoyo
1. Vinclozolin (Vin) is a fungicide used in agricultural settings and is classified as an endocrine disruptor. Vin is non-enzymatically hydrolyzed to 2-[[(3,5-dichlorophenyl)-carbamoyl]oxy]-2-methyl-3-butenoic acid (M1) and 3',5'-dichloro-2-hydroxy-2-methylbut-3-enanilide (M2) metabolites. There is no information about Vin biotransformation in humans, therefore, the aim of this study was to characterize its in vitro metabolism using human liver microsomes. 2. Vin was metabolized to the [3-(3,5-dichlorophenyl)-5-methyl-5-(1,2-dihydroxyethyl)-1,3-oxazolidine-2,4-dione] (M4) and N-(2,3,4-trihydroxy-2-methyl-1-oxo)-3,5-dichlorophenyl-1-carbamic acid (M7) metabolites, which are unstable and gradually converted to 3',5'-dichloro-2,3,4-trihydroxy-2-methylbutyranilide (DTMBA, formerly denoted as M5)...
September 14, 2018: Xenobiotica; the Fate of Foreign Compounds in Biological Systems
https://www.readbyqxmd.com/read/30215539/effect-of-diammonium-glycyrrhizinate-on-pharmacokinetics-of-omeprazole-by-regulating-cytochrome-p450-enzymes-and-plasma-protein-binding-rate
#13
Lu Han, Rong Wang, Bin Wu, Yanqiu Gu, Yongfang Yuan
1. In clinical practice, diammonium glycyrrhizinate is usually used with omeprazole in patients with viral hepatitis and cirrhosis accompanied by peptic ulcers. However, the drug interaction between diammonium glycyrrhizinate and omeprazole remains unclear. 2. In this study, the effects of diammonium glycyrrhizinate on the pharmacokinetics of omeprazole was investigated by liquid chromatography-tandem mass spectrometry (LC-MS/MS) analytical method. Male Sprague-Dawley rats were randomly assigned to two groups: omeprazole and omeprazole+diammonium glycyrrhizinate, and the main pharmacokinetic parameters were estimated after oral administration...
September 14, 2018: Xenobiotica; the Fate of Foreign Compounds in Biological Systems
https://www.readbyqxmd.com/read/30207187/deciphering-the-absorption-profile-and-interaction-of-multi-components-of-zhi-zi-da-huang-decoction-based-on-in-vitro-in-silico-in-vivo-integrated-strategy
#14
Qing Hu, Xixi Li, Qingshui Shi, Gongjun Yang, Fang Feng
Zhi-Zi-Da-Huang decoction (ZZDHD) has been acknowledged with striking therapeutic effects for hepatobiliary disorders in the history of China. As decoctions are usually administrated orally, intestinal absorption, the prerequisite task of exerting therapeutic effects, is of utmost significance for screening potential active compounds and understanding the mechanism of drug action. In this work, an in vitro-in silico-in vivo strategy based on HPLC-DAD-ESI-TOF/MS was adopted for precisely profiling the intestinal absorption of ZZDHD, which integrated information obtained from rat everted gut sac model, octanol-water partition model, in silico prediction and in vivo experimental data...
September 12, 2018: Xenobiotica; the Fate of Foreign Compounds in Biological Systems
https://www.readbyqxmd.com/read/30117757/metabolism-and-disposition-of-lesinurad-a-uric-acid-reabsorption-inhibitor-in-humans
#15
Vishal Shah, Chun Yang, Zancong Shen, Bradley M Kerr, Kathy Tieu, David M Wilson, Jesse Hall, Michael Gillen, Caroline A Lee
The objectives of this study were to determine the absolute bioavailability of lesinurad and to characterized its disposition in humans. The oral bioavailability assessment was performed using a clinical design of simultaneous dosing of a therapeutic oral dose of lesinurad with an intravenous infusion of [14 C]lesinurad microdose. The bioavailability of lesinurad was determined to be 100%. The disposition of lesinurad in humans involves hepatic oxidation and renal elimination following administration of oral [14 C]lesinurad dose...
September 12, 2018: Xenobiotica; the Fate of Foreign Compounds in Biological Systems
https://www.readbyqxmd.com/read/30044673/investigation-of-disposition-for-tak-448-a-synthetic-peptide-of-kisspeptin-analog-in-rats-and-dogs-using-the-radiolabeled-tak-448-suitable-for-pharmacokinetic-study
#16
Yuu Moriya, Akifumi Kogame, Yoshihiko Tagawa, Akio Morohashi, Takahiro Kondo, Satoru Asahi
Disposition of 2-(N-acetyl-d-tyrosyl-trans-4-hydroxy-l-prolyl-l-asparaginyl-l-threonyl-l-phenylalanyl) hydrazinocarbonyl-L-leucyl-Nω -methyl-l-arginyl-l-tryptophanamide monoacetate (TAK-448, RVT-602), a synthetic kisspeptin analog, was investigated after parenteral dosing of radiolabeled TAK-448 ([d-Tyr-14 C]TAK-448) to rats and dogs, and it was confirmed if the radiolabeling position at d-Tyr was eligible for assessment of in vivo disposition. Dosed radioactivity was rapidly and well absorbed after subcutaneous administration and an appreciable amount of unchanged TAK-448 (TAK-448F) and a hydrolyzed metabolite, M-I, were detected in the plasma of rats and dogs...
September 12, 2018: Xenobiotica; the Fate of Foreign Compounds in Biological Systems
https://www.readbyqxmd.com/read/30028220/the-current-understanding-of-the-interactions-between-nanoparticles-and-cytochrome-p450-enzymes-a-literature-based-review
#17
Yan Pan, Chin Eng Ong, Yuh Fen Pung, Jin Yu Chieng
Nanoparticles (NPs) have wide spectrum applications in the areas of industry and biomedicine. However, concerns about their toxic and negative impacts on the environments as well as human health have been raised. Cytochrome P450s (CYPs) are involved in endogenous and exogenous metabolism. Modulations of CYP can adversely damage drug metabolism, detoxification of xenobiotics and animal physiology functions. This article focused on NPs-CYP interactions for humans and animals available in the literature. It was found that different NPs process specific inhibitory potencies against CYPs involved in drug metabolism...
September 12, 2018: Xenobiotica; the Fate of Foreign Compounds in Biological Systems
https://www.readbyqxmd.com/read/30022699/inhibitor-selectivity-of-cnts-and-ents
#18
Balázs Vaskó, Viktória Juhász, Beáta Tóth, Anita Kurunczi, Zsolt Fekete, Joseph Krisjanis Zolnerciks, Emese Kis, Rémi Magnan, Axel Bidon-Chanal Badia, Marçal Pastor-Anglada, Eszter Hazai, Zsolt Bikadi, Ferenc Fülöp, Peter Krajcsi
The concentrative nucleoside transporters (CNT; solute carrier family 28 (SLC28)) and the equilibrative nucleoside transporters (ENT; solute carrier family 29 (SLC29)) are important therapeutic targets but may also mediate toxicity or adverse events. To explore the relative role of the base and the monosaccharide moiety in inhibitor selectivity we selected compounds that either harbor an arabinose moiety or a cytosine moiety, as these groups had several commercially available drug members. The screening data showed that more compounds harboring a cytosine moiety displayed potent interactions with the CNTs than compounds harboring the arabinose moiety...
September 12, 2018: Xenobiotica; the Fate of Foreign Compounds in Biological Systems
https://www.readbyqxmd.com/read/29962267/dose-proportionality-and-pharmacokinetics-of-dronedarone-following-intravenous-and-oral-administration-to-rat
#19
In-Hwan Baek
The aim of this study was to investigate the pharmacokinetic properties of dronedarone by using noncompartmental analysis and modeling approaches after intravenous and oral administration of dronedarone to rats. Twenty-eight male Sprague-Dawley rats were randomly divided into four groups, and dronedarone was administered intravenously (1 mg/kg) and orally (5, 10 and 40 mg/kg) based on a parallel design. Blood samples were collected before and 0.083 (intravenous administration only), 0.25, 0.5, 0.75, 1, 2, 4, 6, 8, 12 and 24 h after drug administration...
September 12, 2018: Xenobiotica; the Fate of Foreign Compounds in Biological Systems
https://www.readbyqxmd.com/read/29804490/aromatase-inhibition-by-2-methyl-indole-hydrazone-derivatives-evaluated-via-molecular-docking-and-in-vitro-activity-studies
#20
Senem Ozcan-Sezer, Elif Ince, Atilla Akdemir, Özlem Öztürk Ceylan, Sibel Suzen, Hande Gurer-Orhan
A causal association is reported between prolonged exposures to elevated levels of estrogen and breast cancer. Therefore inhibiting aromatase (CYP19A), which catalyses the conversion of androgens to estrogens, is an important approach in prevention and treatment of estrogen receptor positive (ER+) breast cancer. Melatonin, a natural indolic hormone, is reported to prevent free radical induced carcinogenesis and block local estrogen synthesis in breast tissue via aromatase inhibition. However several features of melatonin limit its therapeutic use...
September 12, 2018: Xenobiotica; the Fate of Foreign Compounds in Biological Systems
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