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Drug Metabolism and Disposition: the Biological Fate of Chemicals

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https://www.readbyqxmd.com/read/28716828/creation-and-preliminary-characterization-of-pregnane-x-receptor-and-constitutive-androstane-receptor-knockout-rats
#1
Kevin P Forbes, Evguenia Kouranova, Daniel Tinker, Karen Janowski, Doug Cortner, Aaron McCoy, Xiaoxia Cui
The nuclear receptors pregnane X receptor (PXR) and constitutive androstane receptor (CAR) are closely related transcription factors that regulate the expression of Phase I (Cytochrome P450s), Phase II metabolizing enzymes and transporter genes in response to stimulation from xenobiotics, including prescription drugs. PXR and CAR are also involved in other endogenous processes, such as in inflammation, glucose homeostasis and lipid metabolism, and are thus potential drug targets themselves. PXR and CAR knockout and humanized mouse models have proven useful...
July 17, 2017: Drug Metabolism and Disposition: the Biological Fate of Chemicals
https://www.readbyqxmd.com/read/28698304/prediction-of-clinically-relevant-herb-drug-clearance-interactions-using-a-whole-cell-approach-schisandra-sphenanthera-case-study
#2
Jonathan P Jackson, Kimberly M Freeman, Weslyn W Friley, Ashley G Herman, Christopher B Black, Kenneth R Brouwer, Amy L Roe
The Schisandraceae family is reported to have a range of pharmacological activities, including anti-inflammatory effects. As with all herbal preparations, extracts of Schisandra species are mixtures composed of >50 lignans including schizandrins and deoxyschizandrins. In China, Schisandra sphenanthera extract (SSE) is often co-administered with immunosuppressant treatment of transplant recipients. In cases of co-administration, the potential for herb-drug interactions (HDI) increases. Clinical studies have been employed to assess HDI of extracts including SSE...
July 11, 2017: Drug Metabolism and Disposition: the Biological Fate of Chemicals
https://www.readbyqxmd.com/read/28698303/evaluation-of-expression-and-glycosylation-status-of-ugt1a10-in-supersomes-and-intestinal-epithelial-cells-with-a-novel-specific-ugt1a10-monoclonal-antibody
#3
Shingo Oda, Yukiko Kato, Masahiko Hatakeyama, Atsushi Iwamura, Tatsuki Fukami, Toshiyuki Kume, Tsuyoshi Yokoi, Miki Nakajima
UDP-Glucuronosyltransferases (UGTs) are major phase II drug-metabolizing enzymes. Each member of the UGT family exhibits a unique but occasionally overlapping substrate specificity and tissue-specific expression pattern. Earlier studies have reported that human UGT1A10 is expressed in the gastrointestinal tract at the mRNA level, but the evaluation at the protein level, especially tissue or cellular localization, has lagged behind because of the lack of a specific antibody. In this study, we prepared a monoclonal antibody against UGT1A10 to elucidate the tissue/cellular distribution and interindividual variability of UGT1A10 protein expression...
July 11, 2017: Drug Metabolism and Disposition: the Biological Fate of Chemicals
https://www.readbyqxmd.com/read/28698302/heme-modification-contributes-to-the-mechanism-based-inactivation-of-human-cytochrome-p450-2j2-by-two-terminal-acetylenic-compounds
#4
Hsia-Lien Lin, Haoming Zhang, Vyvyca J Walker, Jaime D'Agostino, Paul F Hollenberg
The mechanism-based inactivation of human CYP2J2 by three terminal acetylenic compounds: N-(methylsulfonyl)-6-(2-propargyloxyphenyl)hexanamide (MS), 17-octadecynoic acid (OD), and danazol (DZ) was investigated. The loss of hydroxyebastine (OHEB) carboxylation activity in a reconstituted system was time- and concentration-dependent and required NADPH for MS and OD, but not DZ. The kinetic constants for the mechanism-based inactivation of OHEB carboxylation activity were: KI of 6.1 µM and kinact of 0.22 min(-1) for MS and KI of 2...
July 11, 2017: Drug Metabolism and Disposition: the Biological Fate of Chemicals
https://www.readbyqxmd.com/read/28679672/the-impact-of-the-hepatocyte-to-plasma-ph-gradient-on-the-prediction-of-hepatic-clearance-and-drug-drug-interactions-for-cyp2c9-and-cyp3a4-substrates
#5
Luc Raymond Albert Rougee, Michael A Mohutsky, David W Bedwell, Kenneth J Ruterbories, Stephen D Hall
Surrogate assays for drug metabolism and inhibition are traditionally performed in buffer systems at pH 7.4, despite evidence that hepatocyte intracellular pH is 7.0. This pH gradient can result in a pKa-dependent change in intracellular/extracellular concentrations for ionizable drugs that could affect predictions of clearance and P450 inhibition. The effect of microsomal incubation pH on in vitro enzyme kinetic parameters for CYP2C9 (diclofenac, (S)-warfarin) and CYP3A4 (midazolam, dextromethorphan, testosterone) substrates, enzyme specific reversible inhibitors (amiodarone, desethylamiodarone, clozapine, nicardipine, fluconazole, fluvoxamine, itraconazole) and a mechanism-based inhibitor (amiodarone) was investigated...
July 5, 2017: Drug Metabolism and Disposition: the Biological Fate of Chemicals
https://www.readbyqxmd.com/read/28663285/inhibitory-effects-of-selected-antituberculosis-drugs-on-common-human-hepatic-cytochrome-p450-and-udp-glucuronosyltransferase-enzymes
#6
Lei Cao, David J Greenblatt, Awewura Kwara
The comorbidities of tuberculosis and diseases such as HIV require long-term treatment with multiple medications. Despite substantial in vitro and in vivo information on effects of rifampicin and isoniazid on human CYPs, there is limited published data regarding the inhibitory effects of other anti-TB drugs on human CYPs and UGTs. The inhibitory effects of 5 first-line anti-TB drugs (isoniazid, rifampicin, pyrazinamide, ethambutol, and rifabutin), and the newly approved bedaquiline, were evaluated for 6 common human hepatic UGT enzymes (UGT1A1, 1A4, 1A6, 1A9, 2B7 and 2B15) in vitro using HLMs...
June 29, 2017: Drug Metabolism and Disposition: the Biological Fate of Chemicals
https://www.readbyqxmd.com/read/28646080/considerations-from-the-iq-induction-working-group-in-response-to-drug-drug-interaction-guidances-from-regulatory-agencies-focus-on-down-regulation-cyp2c-induction-and-cyp2b6-positive-control
#7
Niresh Hariparsad, Diane Ramsden, Jairam Palamanda, Joshua G Dekeyser, Odette A Fahmi, Jane R Kenny, Heidi Einolf, Michael Mohutsky, Magalie Pardon, Amy Y Siu, Liangfu Chen, Michael Sinz, Barry Jones, Robert Walsky, Shannon Dallas, Suresh K Balani, George Zhang, David Buckley, Donald Tweedie
The European Medicines Agency (EMA), the Pharmaceutical and Medical Devices Agency and the Food and Drug Administration have issued guidances for the conduct of drug-drug interaction (DDI) studies. To examine the applicability of these regulatory recommendations specifically for induction, a group of scientists, under the auspices of the Drug Metabolism Leadership Group of the Innovation and Quality (IQ) Consortium, formed the Induction Working Group (WG). A team of 20 scientists, from 16 of the 39 pharmaceutical companies, which are members of the IQ Consortium, and three Contract Research Organizations, reviewed the recommendations, focusing initially on the current EMA guidance...
June 23, 2017: Drug Metabolism and Disposition: the Biological Fate of Chemicals
https://www.readbyqxmd.com/read/28646079/identification-of-flavin-containing-monooxygenase-5-fmo5-as-a-regulator-of-glucose-homeostasis-and-a-potential-sensor-of-gut-bacteria
#8
Flora Scott, Sandra G Gonzalez Malagon, Brett A O'Brien, Diede Fennema, Sunil Veeravalli, Clarissa R Coveney, Ian R Phillips, Elizabeth A Shephard
We have previously identified flavin-containing monooxygenase 5 (FMO5) as a regulator of metabolic ageing. The aim of the present study was to investigate the role of FMO5 in glucose homeostasis and the impact of diet and gut flora on the phenotype of mice in which the Fmo5 gene has been disrupted (Fmo5(-/-) mice). In comparison with wild-type (WT) counterparts, Fmo5(-/-) mice are resistant to age-related changes in glucose homeostasis and maintain the higher glucose tolerance and insulin sensitivity characteristic of young animals...
June 23, 2017: Drug Metabolism and Disposition: the Biological Fate of Chemicals
https://www.readbyqxmd.com/read/28646078/stereospecific-metabolism-of-r-and-s-warfarin-by-human-hepatic-cytosolic-reductases
#9
Dustyn A Barnette, Bryce Johnson, Dakota L Pouncey, Robert Nshimiyimana, Linda Desrochers, Thomas E Goodwin, Grover Paul Miller
Coumadin (rac-warfarin) is the most commonly used anticoagulant in the world, yet its clinical use is often challenging due to a narrow therapeutic range and inter-individual variations in response. A critical contributor to the uncertainty is variability in warfarin metabolism, which includes mostly oxidative but also reductive pathways. Reduction of each warfarin enantiomer yields two warfarin alcohol isomers, and the corresponding four alcohols retain varying levels of anticoagulant activity. Studies on the kinetics of warfarin reduction have often lacked resolution of parent drug enantiomers and suffered from co-elution of pairs of alcohol metabolites; thus, those studies fail to establish the importance of individual, stereospecific reductive pathways...
June 23, 2017: Drug Metabolism and Disposition: the Biological Fate of Chemicals
https://www.readbyqxmd.com/read/28607029/age-dependent-protein-abundance-of-cytosolic-alcohol-and-aldehyde-dehydrogenases-in-human-liver
#10
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/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
#11
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
#12
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
#13
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
#14
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
#15
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
#16
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/28526768/direct-comparison-of-the-enzymatic-characteristics-and-superoxide-production-of-the-four-aldehyde-oxidase-enzymes-present-in-mouse
#17
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
#18
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
#19
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/28442499/absorption-distribution-metabolism-and-excretion-of-the-oral-prostaglandin-d2-receptor-2-dp2-antagonist-fevipiprant-qaw039-in-healthy-volunteers-and-in-vitro
#20
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
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