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Drug Metabolism and Disposition: the Biological Fate of Chemicals

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https://www.readbyqxmd.com/read/28536098/rosuvastatin-and-atorvastatin-are-ligands-of-the-human-car-rxr%C3%AE-complex
#1
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
#2
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
#3
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
#4
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
#5
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/28483778/mechanisms-and-predictions-of-drug-drug-interactions-of-the-hepatitis-c-virus-3-direct-acting-antiviral-3d-regimen-paritaprevir-ritonavir-ombitasvir-and-dasabuvir
#6
Mohamad Shebley, Jinrong Liu, Olga Kavetskaia, Jens Sydor, Sonia M de Morais, Volker Fischer, Marjoleen Jma Nijsen, Daniel Aj Bow
To assess drug-drug interaction (DDI) potential for the 3 direct-acting antiviral (3D) regimen of ombitasvir, dasabuvir and paritaprevir, in vitro studies profiled drug metabolizing enzyme and transporter interactions. Using mechanistic static and dynamic models, DDI potential was predicted for CYP3A, CYP2C8, UGT1A1, OATP1B1/1B3, BCRP and P-gp. Perpetrator static model DDI predictions for metabolizing enzymes were within 2-fold of the clinical observations but for drug transporters, additional PBPK modeling was necessary to achieve the same...
May 8, 2017: Drug Metabolism and Disposition: the Biological Fate of Chemicals
https://www.readbyqxmd.com/read/28468837/crypt-organoids-culture-as-an-in-vitro-model-in-drug-metabolism-and-cytotoxicity-studies
#7
Wenqi Lu, Eva Rettenmeier, Miles Paszek, Mei-Fei Yueh, Robert H Tukey, Jocelyn Trottier, Olivier Barbier, Shujuan Chen
The gastrointestinal tract is enriched with xenobiotic processing proteins that play important roles in xenobiotic bioactivation, metabolism, and detoxification. The application of genetically modified mouse models has been instrumental in characterizing the function of xenobiotic processing genes (XPG) and their proteins in drug metabolism. Here, we report the utilization of 3D crypt organoid cultures from these animal models to study intestinal drug metabolism and toxicity. With the successful culturing of crypt organoids, we profiled the abundance of Phase I and Phase II XPG expression, drug transporter gene expression and xenobiotic nuclear receptor (XNR) gene expression...
May 3, 2017: Drug Metabolism and Disposition: the Biological Fate of Chemicals
https://www.readbyqxmd.com/read/28468836/comparison-of-methods-for-estimating-unbound-intracellular-to-medium-concentration-ratios-in-rat-and-human-hepatocytes-using-statins
#8
Takashi Yoshikado, Kota Toshimoto, Tomohisa Nakada, Kazuaki Ikejiri, Hiroyuki Kusuhara, Kazuya Maeda, Yuichi Sugiyama
It is essential to estimate concentrations of unbound drugs inside the hepatocytes to predict hepatic clearance, efficacy, and toxicity of the drugs. The present study was undertaken to compare predictability of the unbound hepatocyte-to-medium concentration ratios (Kp,uu) by two methods based on the steady-state cell-to-medium total concentration ratios at 37°C and on ice (Kp,uu,ss) and based on their initial uptake rates (Kp,uu,V0). Poorly metabolized statins were used as test drugs because of their concentrative uptake via organic anion transporting polypeptides (OATPs)...
May 3, 2017: Drug Metabolism and Disposition: the Biological Fate of Chemicals
https://www.readbyqxmd.com/read/28461575/lky-047-first-selective-inhibitor-of-cytochrome-p450-2j2
#9
Nguyen Minh Phuc, Zhexue Wu, Yuseok O, Jee-Hyun Lee, Sangtaek Oh, Gyu Yong Song, Kwang-Hyeon Liu
Highly selective cytochrome P450 CYP2J2 (CYP2J2) inhibitors suitable for reaction phenotyping are currently not available. (7S)-(+)-(4-Nitro-phenyl)-acrylic acid, 8,8-dimethyl-2-oxo-6,7-dihydro-2H,8H-pyrano[3,2-g]chromen-7-yl-ester (LKY-047), a decursin derivative, was synthesized, and its inhibitor potencies towards CYP2J2 as well as other cytochrome P450 (P450) enzymes in human liver microsomes (HLM) were evaluated. LKY-047 was demonstrated to be a strong competitive inhibitor of CYP2J2-mediated astemizole O-demethylase and terfenadine hydroxylase, with Ki values of 0...
May 1, 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
#10
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/28450578/integrated-assessment-of-diclofenac-biotransformation-pharmacokinetics-and-omics-based-toxicity-in-a-3d-human-liver-immunocompetent-co-culture-system
#11
Ujjal Sarkar, Kodihalli C Ravindra, Emma Large, Carissa L Young, Dinelia Rivera-Burgos, Jiajie Yu, Murat Cirit, David J Hughes, John S Wishnok, Douglas A Lauffenburger, Linda G Griffith, Steven R Tannenbaum
In vitro hepatocyte culture systems have inherent limitations in capturing known human drug toxicities that arise from complex immune responses. Therefore, we established and characterized a liver immuno-competent co-culture model and evaluated diclofenac (DCF) metabolic profiles, in vitro-in vivo clearance correlations, toxicological responses, and acute phase responses using liquid chromatography tandem mass spectrometry. DCF biotransformation was assessed after 48 h of culture, and the major phase I and II metabolites were similar to the in vivo DCF metabolism profile in humans...
April 27, 2017: Drug Metabolism and Disposition: the Biological Fate of Chemicals
https://www.readbyqxmd.com/read/28446509/inhibition-of-the-all-trans-retinoic-acid-hydroxylases-cyp26a1-and-cyp26b1-results-in-dynamic-tissue-specific-changes-in-endogenous-atra-signaling
#12
Faith Stevison, Cathryn Hogarth, Sasmita Tripathy, Travis Kent, Nina Isoherranen
all-trans-retinoic acid (atRA), the active metabolite of vitamin A, is a ligand for several nuclear receptors and acts as a critical regulator of many physiological processes. The cytochrome P450 family 26 (CYP26) enzymes are responsible for atRA clearance, and are potential drug targets to increase concentrations of endogenous atRA in a tissue-specific manner. Talarozole is a potent inhibitor of CYP26A1 and CYP26B1, and has shown some success in clinical trials. Yet, it is not known what magnitude of change is needed in tissue atRA concentrations to promote atRA signaling changes...
April 26, 2017: Drug Metabolism and Disposition: the Biological Fate of Chemicals
https://www.readbyqxmd.com/read/28442500/high-fat-diet-feeding-alters-expression-of-hepatic-drug-metabolizing-enzymes-in-mice
#13
Miaoran Ning, Hyunyoung Jeong
Medical conditions accompanying obesity often require drug therapy, but whether and how obesity alters the expression of drug-metabolizing enzymes and thus drug pharmacokinetics is poorly defined. Previous studies have shown that high fat diet (HFD) feeding and subsequent obesity in mice lead to altered expression of transcriptional regulators for cytochrome P450 (CYP) 2D6, including hepatocyte nuclear factor 4α (HNF4α, a transcriptional activator of CYP2D6) and small heterodimer partner (SHP, a transcriptional repressor of CYP2D6)...
April 25, 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/28438781/transporter-mediated-disposition-clinical-pharmacokinetics-and-cholestatic-potential-of-glyburide-and-its-primary-active-metabolites
#15
Rui Li, Yi-An Bi, Anna Vildhede, Renato J Scialis, Sumathy Mathialagan, Xin Yang, Lisa D Marroquin, Jian Lin, Manthena V S Varma
Glyburide is widely used for the treatment of type 2 diabetes mellitus. We studied the mechanisms involved in the disposition of glyburide and its pharmacologically active hydroxy metabolites, M1 and M2b; and evaluated their clinical pharmacokinetics and the potential role in glyburide-induced cholestasis employing physiologically based pharmacokinetic (PBPK) modeling. Transport studies of parent and metabolites in human hepatocytes and transfected cell systems imply hepatic uptake mediated by organic anion transporting polypeptides...
April 24, 2017: Drug Metabolism and Disposition: the Biological Fate of Chemicals
https://www.readbyqxmd.com/read/28438780/penetration-route-of-the-selective-glucocorticoid-receptor-agonist-sa22465-and-betamethasone-into-rabbit-meibomian-gland-based-on-pharmacokinetics-and-autoradiography
#16
Nagayoshi Asano, Kenji Ueda, Kouichi Kawazu
Meibomian glands are tiny sebaceous glands embedded within specific types of dense connective tissues. This study investigated drug penetration into meibomian glands following a single topical administration in rabbits. We measured time-course concentrations of the selective glucocorticoid receptor agonist (SEGRA) SA22465 and betamethasone in lid margins, palpebral conjunctival epithelium, and meibomian glands following a single instillation using a newly established collection method. We also visualized the distribution of (14)C-SA22465 in eyelid tissue sections using micro-autoradiography...
April 24, 2017: Drug Metabolism and Disposition: the Biological Fate of Chemicals
https://www.readbyqxmd.com/read/28428366/in-vitro-metabolism-of-oprozomib-an-oral-proteasome-inhibitor-role-of-epoxide-hydrolases-and-cytochrome-p450s
#17
Zhican Wang, Ying Fang, Juli Teague, Hansen Wong, Christophe Morisseau, Bruce D Hammock, Dan A Rock, Zhengping Wang
Oprozomib is an oral proteasome inhibitor currently under investigation in patients with hematologic malignancies or solid tumors. Oprozomib elicits potent pharmacological actions by forming a covalent bond with the active site N-terminal threonine of the 20S proteasome. Oprozomib has a short half-life across preclinical species and in patients due to systemic clearance via metabolism. Potential for drug-drug interactions (DDIs) could alter the exposure of this potent therapeutic therefore a thorough investigation of pathways responsible for metabolism is required...
April 20, 2017: Drug Metabolism and Disposition: the Biological Fate of Chemicals
https://www.readbyqxmd.com/read/28428365/interaction-and-transport-of-methamphetamine-and-its-primary-metabolites-by-organic-cation-and-multidrug-and-toxin-extrusion-transporters
#18
David J Wagner, Jennifer E Sager, Haichuan Duan, Nina Isoherranen, Joanne Wang
Methamphetamine is one of the most abused illicit drugs with roughly 1.2 million users in the United States alone. A large portion of methamphetamine and its metabolites is eliminated by the kidney with renal clearance larger than glomerular filtration clearance. Yet the mechanism of active renal secretion is poorly understood. The goals of this study were to characterize the interaction of methamphetamine and its major metabolites with organic cation transporters (OCT) and multidrug and toxin extrusion (MATE) transporters and to identify the major transporters involved in the disposition of methamphetamine and its major metabolites, amphetamine and p-hydroxymethamphetamine (p-OHMA)...
April 20, 2017: Drug Metabolism and Disposition: the Biological Fate of Chemicals
https://www.readbyqxmd.com/read/28416614/modeling-combined-immunosuppressive-and-anti-inflammatory-effects-of-dexamethasone-and-naproxen-in-rats-predicts-the-steroid-sparing-potential-of-naproxen
#19
Xiaonan Li, Debra C DuBois, Dawei Song, Richard R Almon, William J Jusko, Xijing Chen
Dexamethasone (DEX), a widely prescribed corticosteroid (CS), has long been the cornerstone for the treatment of inflammation and immunological dysfunctions in Rheumatoid Arthritis (RA). The CS are frequently used in combination with other anti-rheumatic agents such as nonsteroidal anti-inflammatory drugs (NSAIDs) and disease-modifying anti-rheumatic drugs (DMARDs) to mitigate disease symptoms and minimize unwanted effects. The steroid dose-sparing potential of the NSAID naproxen (NPX) was explored with in vitro and in vivo studies...
April 17, 2017: Drug Metabolism and Disposition: the Biological Fate of Chemicals
https://www.readbyqxmd.com/read/28411281/long-term-stability-of-cryopreserved-human-hepatocytes-evaluation-of-phase-i-and-ii-drug-metabolizing-enzyme-activities-and-cyp3a4-5-induction-for-more-than-a-decade
#20
Miyako Sudo, Mitsuhiro Nishihara, Junzo Takahashi, Satoru Asahi
We evaluated the long term stability of hepatocytes stored in vapor phase of liquid nitrogen for their viability, cytochrome P450 (CYP) 1A2 activity, CYP3A4/5 activity, uridine diphosphate-glucuronosyl transferase (UGT) activity, sulfotransferase (SULT) activity, and CYP3A4/5 induction during 14 years of preservation. No substantial degradation of viability, CYP1A2 activity, UGT activity, or CYP3A4/5 induction was observed. CYP3A4/5 activity showed a slight decrease after 7 years of storage, and SULT activity gradually decreased during storage, although substantial activities remained even after 14 years...
April 14, 2017: Drug Metabolism and Disposition: the Biological Fate of Chemicals
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