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Drug Metabolism and Disposition: the Biological Fate of Chemicals

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https://www.readbyqxmd.com/read/28607029/age-dependent-protein-abundance-of-cytosolic-alcohol-and-aldehyde-dehydrogenases-in-human-liver
#1
Deepak Kumar Bhatt, Andrea Gaedigk, Robin E Pearce, J Steven Leeder, Bhagwat Prasad
Hepatic cytosolic alcohol and aldehyde dehydrogenases (ADHs and ALDHs) catalyze the biotransformation of xenobiotics (e.g., cyclophosphamide and ethanol) and vitamin A. Because age-dependent hepatic abundance of these proteins is unknown, we quantified protein expression of ADHs and ALDH1A1 in a large cohort of pediatric and adult human livers by LC-MS/MS proteomics. Purified proteins were used as calibrators. Two to three surrogate peptides per protein were quantified in trypsin digests of liver cytosolic samples and calibrator proteins under optimal conditions of reproducibility...
June 12, 2017: Drug Metabolism and Disposition: the Biological Fate of Chemicals
https://www.readbyqxmd.com/read/28600384/oxetane-substrates-of-human-microsomal-epoxide-hydrolase
#2
Francesca Toselli, Marlene Fredenwall, Peder Svensson, Xue-Qing Li, Anders Johansson, Lars Weidolf, Martin A Hayes
Oxetanyl building blocks are increasingly used in drug discovery because of the improved drug-like properties they confer on drug candidates, yet little is currently known about their biotransformation. A series of oxetane-containing analogues was studied and we provide the first direct evidence of oxetane hydrolysis by human recombinant microsomal epoxide hydrolase (mEH). Incubations with human liver fractions and hepatocytes were performed with and without inhibitors of P450s, mEH and soluble EH (sEH). Reaction dependence on NADPH was investigated in subcellular fractions...
June 9, 2017: Drug Metabolism and Disposition: the Biological Fate of Chemicals
https://www.readbyqxmd.com/read/28588050/development-of-a-novel-maternal-fetal-physiologically-based-pharmacokinetic-model-i-insights-into-factors-that-determine-fetal-drug-exposure-through-simulations-and-sensitivity-analyses
#3
Zufei Zhang, Marjorie Z Imperial, Gabriela I Patilea-Vrana, Janak Wedagedera, Lu Gaohua, Jashvant D Unadkat
Determining fetal drug exposure (except at the time of birth) is not possible for both logistical and ethical reasons. Therefore, we developed a novel maternal-fetal physiologically based pharmacokinetic (m-f-PBPK) model to predict fetal exposure to drugs and populated this model with gestational age-dependent changes in maternal-fetal physiology. Then, we used this m-f-PBPK to: (1) perform a series of sensitivity analyses to quantitatively demonstrate the impact of fetoplacental metabolism and placental transport on fetal drug exposure for various drug dosing regimens administered to the mother; (2) predict the impact of gestational age on fetal drug exposure; and (3) demonstrate that a single umbilical venous: maternal plasma (UV:MP) ratio (even after multiple oral dose administration to steady-state) does not necessarily reflect fetal drug exposure...
June 6, 2017: Drug Metabolism and Disposition: the Biological Fate of Chemicals
https://www.readbyqxmd.com/read/28576766/comparative-evaluation-of-plasma-bile-acids-dehydroepiandrosterone-sulfate-hexadecanedioate-and-tetradecanedioate-with-coproporphyrins-i-and-iii-as-markers-of-oatp-inhibition-in-healthy-subjects
#4
Hong Shen, Weiqi Chen, Dieter M Drexler, Sandhya Mandlekar, Vinay K Holenarsipur, Eric E Shields, Robert Langish, Kurex Sidik, Jinping Gan, W Griffith Humphreys, Punit Marathe, Yurong Lai
Multiple endogenous compounds have been proposed as candidate biomarkers to monitor organic anion transporting polypeptide (OATP) function in preclinical species or humans. Recently we have demonstrated that coproporphyrins (CPs) I and III are appropriate clinical markers to evaluate OATP inhibition and recapitulate clinical drug-drug interactions (DDIs). In the present studies, we investigated bile acids (BAs), dehydroepiandrosterone sulfate (DHEAS), hexadecanedioate (HDA), and tetradecanedioate (TDA) in plasma as endogenous probes for OATP inhibition and compared these candidate probes to CPs...
June 2, 2017: Drug Metabolism and Disposition: the Biological Fate of Chemicals
https://www.readbyqxmd.com/read/28572241/pkc-nedd4-2-signaling-pathway-regulates-the-cell-surface-expression-of-drug-transporter-hoat1
#5
Da Xu, Jinghui Zhang, Qiang Zhang, Yunzhou Fan, Chenchang Liu, Guofeng You
Human organic anion transporter-1 (hOAT1) regulates the absorption, distribution, and excretion of a wide range of clinically important drugs. Our previous work demonstrated that hOAT1 is a dynamic membrane transporter, constitutively internalizing from and recycling back to cell plasma membrane. Short-term activation (<30 min) of protein kinase C (PKC) promotes the attachment of a lysine 48-linked polyubiquitin chain to hOAT1, a process catalyzed by ubiquitin ligase Nedd4-2. The Ubiquitination of hOAT1 then triggers an accelerated endocytosis of the transporter from plasma membrane, which results in a reduced hOAT1 expression at the cell surface and a decreased hOAT1 transport activity...
June 1, 2017: Drug Metabolism and Disposition: the Biological Fate of Chemicals
https://www.readbyqxmd.com/read/28566285/comparison-of-19f-nmr-and-14c-measurements-for-the-assessment-of-adme-of-byl719-alpelisib-in-humans
#6
Alexander D James, Cyrille Marvalin, Alexandre Luneau, Axel Meissner, Gian Camenisch
The human mass balance study is the definitive study for the assessment of absorption, distribution, metabolism and excretion (ADME) properties of a new chemical entity (NCE) in humans. Traditionally this has been carried out by the administration of radiolabeled drug substances, typically 14C or occasionally 3H, as detection methods for these isotopes allow the absolute quantification of drug related material (DRM) in blood, plasma and excreta. Coupled with the use of analytical techniques such as liquid chromatography-mass spectrometry, a picture of the metabolic fate of a compound can be elucidated...
May 31, 2017: Drug Metabolism and Disposition: the Biological Fate of Chemicals
https://www.readbyqxmd.com/read/28546505/role-of-cyp2b-in-phenobarbital-induced-hepatocyte-proliferation-in-mice
#7
Lei Li, Xiaochen Bao, Qing-Yu Zhang, Masahiko Negishi, Xinxin Ding
Phenobarbital (PB) promotes liver tumorigenesis in rodents, in part through activation of the constitutive androstane receptor (CAR) and the consequent changes in hepatic gene expression and increases in hepatocyte proliferation. A typical effect of CAR activation by PB is a marked induction of Cyp2b10 expression in the liver; the latter has been suspected to be vital for PB-induced hepatocellular proliferation. This hypothesis was tested here, by using a Cyp2a(4/5)bgs-null (null) mouse model, in which all Cyp2b genes are deleted...
May 25, 2017: Drug Metabolism and Disposition: the Biological Fate of Chemicals
https://www.readbyqxmd.com/read/28536098/rosuvastatin-and-atorvastatin-are-ligands-of-the-human-car-rxr%C3%AE-complex
#8
Tadeja Rezen, Mateja Hafner, Sandhya Kortagere, Sean Ekins, Vesna Hodnik, Damjana Rozman
Statins are well known lipid lowering agents that inhibit the enzyme HMG-CoA reductase. They also activate drug metabolism but their exact receptor-mediated action has not been proven so far. The aim of this study was to test if atorvastatin and rosuvastatin are direct ligands of human CAR. We measured binding activities of atorvastatin and rosuvastatin to the human CAR/RXRα-LBD heterodimer with surface plasmon resonance (SPR). Additionally, three-dimensional models of CAR/RXRα-LBD were constructed by ligand-based and structure-based in silico modelling...
May 23, 2017: Drug Metabolism and Disposition: the Biological Fate of Chemicals
https://www.readbyqxmd.com/read/28533324/crispr-cas9-genetic-modification-of-cyp3a5-3-in-huh-7-human-hepatocyte-cell-line-leads-to-cell-lines-with-increased-midazolam-and-tacrolimus-metabolism
#9
Casey R Dorr, Rory P Remmel, Amutha Muthusamy, James Fisher, Branden Moriarity, Kazuto Yasuda, Baolin Wu, Weihua Guan, Erin G Schuetz, William S Oetting, Pamala A Jacobson, Ajay K Israni
CRISPR/Cas9 engineering of the CYP3A5 *3 locus (rs776746) in human liver cell line HuH-7 (CYP3A5 *3/*3) led to three CYP3A5 *1 cell lines by deletion of the exon 3B splice junction or point mutation. Cell lines CYP3A5 *1/*3 sd (single deletion), CYP3A5 *1/*1 dd (double deletion) or CYP3A5 *1/*3 pm (point mutation) expressed the CYP3A5 *1 mRNA, had elevated CYP3A5 mRNA (p<0.0005 for all engineered cell lines) and protein expression compared with HuH-7. In metabolism assays, HuH-7 had less tacrolimus (Tac) (all p-values < 0...
May 22, 2017: Drug Metabolism and Disposition: the Biological Fate of Chemicals
https://www.readbyqxmd.com/read/28526768/direct-comparison-of-the-enzymatic-characteristics-and-superoxide-production-of-the-four-aldehyde-oxidase-enzymes-present-in-mouse
#10
Gokhan Kucukgoze, Mineko Terao, Enrico Garattini, Silke Leimkuhler
Aldehyde oxidases (AOXs) are molybdoflavoenzymes with an important role in the metabolism and detoxification of heterocyclic compounds and aliphatic as well as aromatic aldehydes. The enzymes use oxygen as the terminal electron acceptor and produce reduced oxygen species during turnover. Four different enzymes, mAOX1, mAOX3, mAOX4 and mAOX2, which are the products of distinct genes, are present in the mouse. A direct and simultaneous comparison of the enzymatic properties and characteristics of the four enzymes has never been performed...
May 19, 2017: Drug Metabolism and Disposition: the Biological Fate of Chemicals
https://www.readbyqxmd.com/read/28495902/regio-and-stereo-selective-oxidation-of-a-cardiovascular-drug-metoprolol-mediated-by-cytochrome-p450-2d-and-3a-enzymes-in-marmoset-livers
#11
Shotaro Uehahara, Sakura Ishii, Yasuhiro Uno, Takashi Inoue, Erika Sasaki, Hiroshi Yamazaki
A β-blocker metoprolol is one of the in vivo probes for human cytochrome P450 (P450) 2D6. Investigation of non-human primate P450 enzymes helps improve accuracy of the extrapolation of pharmacokinetic data from animals into humans. Common marmosets (Callithrix jacchus) are a potential primate model for preclinical research, but detailed roles of marmoset P450 enzymes in metoprolol oxidations remained unknown. In this study, regio- and stereo-selectivity of metoprolol oxidations by a variety of P450 enzymes in marmoset and human livers were investigated in vitro...
May 11, 2017: Drug Metabolism and Disposition: the Biological Fate of Chemicals
https://www.readbyqxmd.com/read/28487309/molecular-cloning-and-characterization-of-marmoset-aldehyde-oxidase
#12
Shotaro Uehara, Yasuhiro Uno, Eriko Okamoto, Takashi Inoue, Erika Sasaki, Hiroshi Yamazaki
Common marmosets (Callithrix jacchus), New world monkeys, are a promising primate model for preclinical drug metabolism studies due to the similarities of cytochrome P450 (P450) enzyme function to those of humans. Despite an increasing number of drug candidates catalyzed by non-P450 enzymes, drug metabolizing enzymes other than P450s have been hardly identified or characterized in marmosets. In this study, we identified aldehyde oxidase (AOX) 1 gene by marmoset genome analysis. AOX1 cDNA was cloned from marmoset livers by reverse transcription-polymerase chain reaction...
May 9, 2017: Drug Metabolism and Disposition: the Biological Fate of Chemicals
https://www.readbyqxmd.com/read/28450579/quantitative-polymerase-chain-reaction-analysis-of-the-mouse-cyp2c-subfamily-and-characterization-of-their-tissue-distribution
#13
Joan P Graves, Artiom Gruzdev, J Alyce Bradbury, Laura M DeGraff, Matthew L Edin, Darryl C Zeldin
The cytochrome P450 superfamily encompasses a diverse group of enzymes that catalyze the oxidation of various substrates. CYP2C proteins detoxify xenobiotics and metabolize endogenous lipids such as arachidonic acid to bioactive eicosanoids. We report new methods and results for the quantitative polymerase reaction (qPCR) analysis for the 15 members of the mouse Cyp2c subfamily (Cyp2c29, Cyp2c37, Cyp2c38, Cyp2c39, Cyp2c40, Cyp2c44, Cyp2c50, Cyp2c54, Cyp2c55, Cyp2c65, Cyp2c66, Cyp2c67, Cyp2c68, Cyp2c69 and Cyp2c70)...
April 27, 2017: Drug Metabolism and Disposition: the Biological Fate of Chemicals
https://www.readbyqxmd.com/read/28442499/absorption-distribution-metabolism-and-excretion-of-the-oral-prostaglandin-d2-receptor-2-dp2-antagonist-fevipiprant-qaw039-in-healthy-volunteers-and-in-vitro
#14
David Pearson, H Markus Weiss, Yi Jin, Jan Jaap van Lier, Veit J Erpenbeck, Ulrike Glaenzel, Peter End, Ralph Woessner, Fabian Eggimann, Gian Camenisch
Fevipiprant is a novel oral prostaglandin D2 receptor 2 (DP2; also known as CRTh2) antagonist, which is currently in development for the treatment of severe asthma and atopic dermatitis. We investigated the absorption, distribution, metabolism, and excretion properties of fevipiprant in healthy subjects after a single 200 mg oral dose of [(14)C]-radiolabeled fevipiprant. Fevipiprant and metabolites were analyzed by liquid chromatography coupled to tandem mass spectrometry and radioactivity measurements, and mechanistic in vitro studies were performed to investigate clearance pathways and covalent plasma protein binding...
April 25, 2017: Drug Metabolism and Disposition: the Biological Fate of Chemicals
https://www.readbyqxmd.com/read/28411280/interrelationships-between-infliximab-and-rhtnf-%C3%AE-in-plasma-using-minimal-physiologically-based-pharmacokinetic-mpbpk-models
#15
Xi Chen, Debra C DuBois, Richard R Almon, William J Jusko
The soluble cytokine TNF-α is an important target for many therapeutic proteins used in the treatment of rheumatoid arthritis (RA). Biologics targeting TNF-α exert their pharmacological effects through binding and neutralizing this cytokine and preventing it from binding to its cell surface receptors. The magnitude of their pharmacological effects directly corresponds to the extent and duration of free TNF-α suppression. However, endogenous TNF-α is of low abundance and therefore it is quite challenging to assess the free TNF-α suppression experimentally...
April 14, 2017: Drug Metabolism and Disposition: the Biological Fate of Chemicals
https://www.readbyqxmd.com/read/28411279/characterization-and-interspecies-scaling-of-rhtnf-%C3%AE-pharmacokinetics-with-minimal-physiologically-based-pharmacokinetic-mpbpk-models
#16
Xi Chen, Debra C DuBois, Richard R Almon, William J Jusko
Tumor necrosis factor-α (TNF-α) is a soluble cytokine and target of specific monoclonal antibodies (mAbs) and other biological agents used for the treatment of inflammatory diseases. These biologics exert their pharmacological effects through binding and neutralizing TNF-α, and thus prevent TNF-α from interacting with its cell surface receptors. The magnitude of pharmacological effects is governed not only by the pharmacokinetics of mAbs, but also the kinetic fate of TNF-α. We have examined the pharmacokinetics of rhTNF-α in rats at low doses and quantitatively characterized its pharmacokinetic features with a minimal physiologically-based pharmacokinetic (mPBPK) model...
April 14, 2017: Drug Metabolism and Disposition: the Biological Fate of Chemicals
https://www.readbyqxmd.com/read/28396528/human-enterocytes-as-an-in-vitro-model-for-the-evaluation-of-intestinal-drug-metabolism-characterization-of-drug-metabolizing-enzyme-activities-of-cryopreserved-human-enterocytes-from-twenty-four-donors
#17
Ming-Chih David Ho, Nick Ring, Kirsten Amaral, Utkarsh Doshi, Albert Li
We report here successful isolation and cryopreservation of enterocytes from human small intestine. The enterocytes were isolated by enzyme digestion of the intestinal lumen followed by partial purification via differential centrifugation. The enterocytes were cryopreserved directly after isolation without culturing to maximize retention of in vivo drug metabolizing enzyme activities. Post-thaw viability of the cryopreserved enterocytes was consistently over 80% based on trypan blue exclusion. Cryopreserved enterocytes pooled from 8 donors (4 male and 4 female) were evaluated for their metabolism of 14 pathway-selective substrates: CYP1A2 (phenacetin hydroxylation), CYP2A6 (coumarin 7-hydroxylation), CYP2B6 (bupropion hydroxylation), CYP2C8 (paclitaxel 6α-hydroxylation), CYP2C9 (diclofenac 4-hydroxylation), CYP2C19 (s-mephenytoin 4-hydroxylation), CYP2D6 (dextromethorphan hydroxylation), CYP2E1 (chlorzoxazone 6-hydroxylation), CYP3A4 (midazolam 1'-hydroxylation and testosterone 6β-hydroxylation), CYP2J2 (astemizole O-demethylation), UDP-glucuronosyltransferase (UGT; 7-hydroxycoumarin glucuronidation), sulfotransferase (SULT; 7-hydroxycoumarin sulfation), and carboxylesterase 2 (CES2; irinotecan hydrolysis) activities...
April 10, 2017: Drug Metabolism and Disposition: the Biological Fate of Chemicals
https://www.readbyqxmd.com/read/28373266/global-proteomic-analysis-of-human-liver-microsomes-rapid-characterization-and-quantification-of-hepatic-drug-metabolizing-enzymes
#18
Brahim Achour, Hajar Al-Feteisi, Francesco Lanucara, Amin Rostami-Hodjegan, Jill Barber
Many genetic and environmental factors lead to inter-individual variations in metabolism and transport of drugs, profoundly affecting efficacy and toxicity. Precision dosing, targeting drug dose to a well-characterised sub-population, is dependent on quantitative models of the profiles of drug-metabolizing enzymes and transporters within that sub-population, informed by quantitative proteomics. We report the first use of ion mobility-mass spectrometry for this purpose, allowing rapid, robust, label-free quantification of human liver microsomal (HLM) proteins from distinct individuals...
April 3, 2017: Drug Metabolism and Disposition: the Biological Fate of Chemicals
https://www.readbyqxmd.com/read/28356314/high-throughput-and-reliable-isotope-label-free-approach-for-profiling-24-metabolic-enzymes-in-fvb-mice-and-gender-differences
#19
Jiamei Chen, Lijun Zhu, Xiaoyan Li, Haihui Zheng, Tongmeng Yan, Cong Xie, Sijing Zeng, Jia Yu, Huangyu Jiang, Linlin Lu, Xiaoxiao Qi, Ying Wang, Ming Hu, Zhongqiu Liu
FVB mice are extensively used in transgenic and pharmacokinetic research. In this study, a validated isotope label-free method of using ultrahigh-performance liquid chromatography (UHPLC)-MS/MS was established for quantifying 24 drug-metabolizing enzymes (DMEs) in FVB mice. The DMEs include cytochrome P450 (CYPs/Cyps), UDP-glucuronsyltransferases (UGTs/Ugts), and sulfotransferases (SULTs/Sults), which are the major phase I and II metabolic enzymes responsible for clearing and detoxifying xenobiotic and endogenous substances...
March 29, 2017: Drug Metabolism and Disposition: the Biological Fate of Chemicals
https://www.readbyqxmd.com/read/28559373/correction-to-tramadol-metabolism-to-o-desmethyl-tramadol-m1-and-n-desmethyl-tramadol-m2-by-dog-liver-microsomes-species-comparison-and-identification-of-responsible-canine-cytochrome-p450s
#20
(no author information available yet)
No abstract text is available yet for this article.
July 2017: Drug Metabolism and Disposition: the Biological Fate of Chemicals
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