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Drug Metabolism Letters

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https://www.readbyqxmd.com/read/29283075/evaluation-of-farnesoid-x-receptor-target-gene-induction-in-human-hepatocytes-amino-acid-conjugation
#1
Jean Simmermacher, Michael Sinz
BACKGROUND: The nuclear hormone receptor, farnesoid X receptor (FXR) regulates the transcription of genes associated with bile acid metabolism and disposition. OBJECTIVE: This study investigates possible changes in the expression of target genes responsible for amino acid conjugation, i.e., bile acid-CoA synthetase (BACS) and bile acid-CoA: amino acid N-acetyltransferase (BAT). These genes have been shown to be inducible by FXR agonists in rat models, however, to date no studies have been conducted in a human hepatocyte model...
December 27, 2017: Drug Metabolism Letters
https://www.readbyqxmd.com/read/29237391/utility-of-pooled-cryopreserved-human-enterocytes-as-an-in-vitro-model-for-assessing-intestinal-clearance-and-drug-drug-interactions
#2
Zhengyin Yan, Susan Wong, Jane Kelly, Hoa Le, Ning Liu, Mika Kosaka, Suzanne Tey, Peter Vuong, Albert Li
A recent advancement in isolation and cryopreservation has resulted in commercially available primary human enterocytes that express various drug metabolizing enzymes (DMEs) and transporters. The main objective of this study was to further evaluate the utility of pooled cryopreserved enterocytes, specifically MetMax™ cryopreserved human enterocytes (In Vitro ADMET Laboratories), as an in vitro model for assessing intestinal clearance in comparison to hepatocytes. It was found that, for CYP3A4 substrates such as midazolam, amprenavir and loperamide, in vitro metabolic clearance is generally lower in enterocytes compared to that of hepatocytes, which is consistent with the relative abundance of the enzyme between the intestine and liver...
December 12, 2017: Drug Metabolism Letters
https://www.readbyqxmd.com/read/29219065/transactivation-assays-that-identify-indirect-and-direct-activators-of-human-pregnane-x-receptor-pxr-nr1i2-and-constitutive-androstane-receptor-car-nr1i3
#3
Marija Pinne, Elsa Ponce, Judy L Raucy
BACKGROUND: Nuclear receptors (NRs), including PXR and CAR, are presumed to be ligand-dependent transcription factors, but ligand binding is not an absolute requirement for activation. Indeed, many compounds activate PXR and CAR by indirect mechanisms. Detecting these indirect activators of specific nuclear receptors in vitro has been difficult. As NR activation of either or both PXR and CAR can lead to drug-drug interactions and adverse drug effects, false negatives obtained with screening tools incapable of detecting indirect activators could present liabilities...
December 6, 2017: Drug Metabolism Letters
https://www.readbyqxmd.com/read/29189189/selective-suppression-of-cyp3a4-mrna-and-enzyme-activity-by-epidermal-growth-factor-in-plated-human-hepatocytes
#4
George Zhang, Duan Wang, Thuy Ho, Robert J Clark, David M Stresser
BACKGROUND: Epidermal growth factor (EGF) is a well-known mitogen that has importance in cell proliferation and differentiation. These properties have led to the common use of EGF as an additive to some cell culture media. EGF has been previously shown to modulate constitutive cytochrome P450 (CYP) expression in vitro. OBJECTIVES: To assess the influence of EGF on the basal and induced expression of CYP3A4, CYP1A2 and CYP2B6 in plated human hepatocytes. METHODS: Human hepatocytes from 3 donors were treated with EGF with and without in the presence of positive control inducers...
November 28, 2017: Drug Metabolism Letters
https://www.readbyqxmd.com/read/29165101/therapeutic-potentials-and-cytochrome-p450-mediated-interactions-involving-herbal-products-indicated-for-diabetes-mellitus
#5
Cyprian Ogbonna Onyeji, Sharon I Igbinoba, Gbola Olayiwola
There has been an increase in the use of herbal products to complement conventional drugs in the treatment of various diseases especially in developing countries. This may be attributable to the relatively cost-effectiveness and ease of accessibility of these products as well as the perception of their safety profiles. However, there are numerous literature reports on herbs altering the pharmacokinetics and pharmacodynamics of other co-administered drugs thereby modulating the therapeutic outcomes. The prevalence of diabetes is on a steady increase worldwide and it is now identified as one of the main threats to human health...
November 20, 2017: Drug Metabolism Letters
https://www.readbyqxmd.com/read/29141576/analysis-of-elevated-levels-of-nandrolone-decanoate-induced-cytochrome-p450-alterations-in-mice
#6
Parmita Chowdhury, Rita Mahantab
BACKGROUND: Frequent non-medicated use of anabolic androgenic steroids (AAS) is an instance of substance abuse which mimics the status of a natural hormone and upon prolonged exposure may lead to adverse drug reactions. These adverse drug reactions proceed in a manner so as to alter the normal metabolism of an enzyme mediated pathway such as the cytochrome P450 (CYP) family of enzymes. OBJECTIVE: The present study was conducted to investigate the impact of overuse of Nandrolone Decanoate (ND), an AAS, upon CYP enzyme activity and a CYP gene, belonging to CYP1 family...
November 14, 2017: Drug Metabolism Letters
https://www.readbyqxmd.com/read/29110630/genotoxicity-of-4-piperazin-1-yl-8-trifluoromethyl-pyrido-2-3-e-1-2-4-triazolo-4-3-a-pyrazine-a-potent-h4-receptor-antagonist-for-the-treatment-of-allergy-evidence-of-glyoxal-intermediate-involvement
#7
Mithat Gunduz, Amanda L Cirello, Peter Klimko, Jennifer L Dumouchel, Upendra A Argikar
BACKGROUND: 4-(piperazin-1-yl)-8-(trifluoromethyl)pyrido[2,3-e][1,2,4]triazolo[4,3-a]pyrazine (1) is small-molecule which demonstrated a sub-nM inhibitory potency toward the histamine H4 receptor (H4R). However, it was found to be mutagenic an in vitro Ames assay. Metabolic bioactivation of 1 could potentially arise from the piperazine moiety by forming reactive intermediates such as glyoxal, aldehyde-imine and/or iminium ion, which could all lead to genotoxicity. The aim was to investigate bioactivation of 1 to determine the potential causes of the genotoxicity and mitigate liabilities in this scaffold...
November 6, 2017: Drug Metabolism Letters
https://www.readbyqxmd.com/read/29197321/preface
#8
Suresh K Balani
No abstract text is available yet for this article.
November 17, 2017: Drug Metabolism Letters
https://www.readbyqxmd.com/read/29032766/the-effects-of-drug-metabolizing-enzyme-inhibitors-on-hepatic-efflux-and-uptake-transporters
#9
Jonathan Cheong, Jason S Halladay, Jasleen K Sodhi, Emile Plise, Laurent Salphati
BACKGROUND: Non-selective chemical inhibitors of phase I and phase II enzymes are commonly used in in vitro metabolic studies to elucidate the biotransformation pathways of drugs. However, the inhibition of the inhibitors on efflux and uptake transporters is not well investigated, potentially leading to unexpected and ambiguous results in these studies. OBJECTIVE: The commonly used metabolizing enzyme inhibitors, 1-aminobenzotriazole (ABT), SKF-525A, pargyline, allopurinol, menadione, methimazole, piperine and raloxifene, were examined for their potential inhibition of the major hepatic ABC (ATP binding cassette) and SLC (solute carrier) transporters...
October 10, 2017: Drug Metabolism Letters
https://www.readbyqxmd.com/read/28891437/investigation-of-ocular-bioactivation-potential-and-the-role-of-cytochrome-p450-2d-enzymes-in-rat
#10
Jennifer L Dumouchel, Upendra A Argikar, Jaimie Spear, Ann Brown, Christine E Dunne, Valerie M Kramlinger, Amanda L Cirello, Mithat Gunduz
BACKGROUND: Timolol is clinically administered topically (ocular) to reduce intraocular pressure and treat open-angle glaucoma. Ocular administration of timolol in low doses (0.5% w/v in the form of eye drops) has led to challenges for in vivo metabolite identification. An understanding of drug metabolism in the eye is important for clinical ocular therapeutics and potential drug candidates. METHODS: We aimed to investigate the metabolism of timolol in rat ocular and liver S9 fractions, as well as rat ocular tissue and plasma following a 0...
September 11, 2017: Drug Metabolism Letters
https://www.readbyqxmd.com/read/28814243/a-pharmacokinetic-pharmacodynamic-model-of-tamoxifen-and-endoxifen-to-predict-their-distribution-and-effects-on-inhibition-of-tumor-growth
#11
Shengyue Yuan, Qingrong Sun, Yao Chen, Jun Liao
BACKGROUND: Tamoxifen is widely used in the therapy for breast cancer and has three major metabolites, N-desmethyltamoxifen, 4-hydroxytamoxifen, and endoxifen. Endoxifen has played a major role in the inhibition of tumor growth of breast cancer and the tumor growth is related to endoxifen concentration. OBJECTIVES: The aim of this study was to develop a pharmacokinetic-pharmacodynamic model to predict the distribution of tamoxifen and endoxifen quantitatively, and to discover the anti-tumor effect patterns of tamoxifen and endoxifen...
August 15, 2017: Drug Metabolism Letters
https://www.readbyqxmd.com/read/28762319/quantification-of-sulfotransferase-1a-isoforms-in-human-tissue-fractions-and-cell-lines-by-multiple-reaction-monitoring-mass-spectrometry
#12
Sho Yoshitake, Melissa McKay-Daily, Masaki Tanaka, Zeqi Huang
BACKGROUND: Within the sulfotransferase (SULT) superfamily of metabolic enzymes, the SULT1A family of cytosolic sulfotransferases is of particular interest, due to its ability to catalyze the sulfation of phenolic substrates. In humans, there are three distinct SULT1A enzymes: SULT1A1, SULT1A2, and SULT1A3/4. OBJECTIVE: To detect and quantify these enzymes in S9 fractions and cell lines using targeted mass spectrometry-based proteomics. METHOD: Samples were tryptically digested, and signature peptides were quantified using liquid chromatography-multiple reaction monitoring mass spectrometry (LC-MRM/MS)...
July 31, 2017: Drug Metabolism Letters
https://www.readbyqxmd.com/read/28699487/mixed-matrix-method-provides-a-reliable-metabolite-exposure-comparison-for-assessment-of-metabolite-in-safety-testing-mist
#13
Ryan Takahashi, Cyrus Khojasteh, Matthew Wright, Cornelis Hop, Shuguang Ma
The regulatory guidances on metabolites in safety testing (MIST) by US Food and Drug Administration (FDA) and International Conference on Harmonisation (ICH) describe the necessity to assess exposures of circulating metabolites in humans at steady state relative to exposures achieved in nonclinical safety studies prior to the initiation of large scale clinical trials. This comparison can be accomplished by measuring metabolite concentrations in animals and humans with validated bioanalytical methods. However, bioanalysis of metabolites in multiple species and multiple studies is resource intensive and may impact the timelines of clinical studies...
July 10, 2017: Drug Metabolism Letters
https://www.readbyqxmd.com/read/28606035/potential-minor-haplotypes-of-cyp2d6-in-the-japanese-population
#14
Masatoshi Masuda, Tsutomu Fujiwara, Masayuki Matsunaga, Takehisa Matsumaru
BACKGROUND: CYP2D6 is one of the most significant polymorphic genes of drug-metabolizing enzymes due to its association with different metabolic activities and the pharmacokinetics of CYP2D6 substrates. OBJECTIVE: The objective of this study was to explore for a novel haplotype of CYP2D6 in the Japanese population by using a large database of previous clinical studies. METHODS: We analyzed CYP2D6 genotype data from a total of 723 Japanese individuals for 8 loci (100C>T, 1758G>A, 1846G>A, 2573 insertion of C, 2850C>T, 2988G>A, 4125 insertion of 9bp, and 4180G>C) and gene deletion...
June 12, 2017: Drug Metabolism Letters
https://www.readbyqxmd.com/read/28595558/the-role-of-placental-carbonyl-reducing-enzymes-in-biotransformation-of-bupropion-and-4-methylnitrosamino-1-3-pyridyl-1-butanone
#15
Valentina M Fokina, Svetlana L Patrikeeva, Cheryl Oncken, Gary Dv Hankins, Mahmoud S Ahmed, Tatiana N Nanovskaya
BACKGROUND: Bupropion (BUP) has a potential to be an effective pharmacotherapy for smoking cessation during pregnancy. Smoking during pregnancy stimulates placental carbonyl reductases that catalyze the biotransformation of BUP. 4-methylnitrosamino-1-(3-pyridyl)-1-butanone (NNK) is a potent carcinogen of cigarette smoke. Carbonyl reduction of NNK into 4-methylnitrosamino-1-(3-pyridyl)-1-butanol (NNAL) constitutes a major step in NNK detoxification. Thus, placentas of pregnant smokers on BUP therapy can become a site of drug-drug interaction...
June 6, 2017: Drug Metabolism Letters
https://www.readbyqxmd.com/read/28403803/metabolic-profile-of-flunitrazepam-clinical-and-forensic-toxicological-aspects
#16
Ricardo Jorge Dinis-Oliveira
BACKGROUND: Flunitrazepam is a potent hypnotic, sedative, and amnestic drug used to treat insomnia and as a pre-anesthetic agent. The illicit practice in drug-facilitated sexual assault has been implicating important clinical and forensic issues. OBJECTIVE: In this work the metabolism of flunitrazepam was fully reviewed. METHODS: Flunitrazepam and related known metabolizing enzymes and metabolites were searched in books and in PubMed (U.S...
April 7, 2017: Drug Metabolism Letters
https://www.readbyqxmd.com/read/28403802/effects-of-fenofibrate-on-the-expression-of-small-heterodimer-partner-shp-and-cytochrome-p450-cyp-2d6
#17
Rebecca Kent, Hyunyoung Jeong
Cytochrome P450 (CYP) 2D6 is a major drug-metabolizing enzyme, responsible for eliminating 25% of marketed drugs. We recently identified SHP as a negative regulator of CYP2D6 expression and showed that factors that alter SHP expression influence CYP2D6 expression. Fenofibrate, an agonist of peroxisome proliferator-activated receptor α (PPARα), has been previously reported to upregulate SHP expression in mouse liver [1]. The objective of this study was to determine whether fenofibrate decreases CYP2D6 expression via upregulating SHP expression...
April 7, 2017: Drug Metabolism Letters
https://www.readbyqxmd.com/read/28393714/gender-difference-of-hepatic-and-intestinal-cyp3a4-in-cyp3a-humanized-mice-generated-by-a-human-chromosome-engineering-technique
#18
Kaoru Kobayashi, Chihiro Abe, Mika Endo, Yasuhiro Kazuki, Mitsuo Oshimura, Kan Chiba
BACKGROUND: Cytochrome P450 3A4 (CYP3A4) is an important drug-metabolizing enzyme that is expressed in the liver and small intestine of humans. Various factors influence the expression of CYP3A4, but gender difference in CYP3A4 expression remains debatable. OBJECTIVE: To clarify gender difference of hepatic and intestinal CYP3A4 in CYP3A-humanized mice generated by a human artificial chromosome (HAC) vector system. The CYP3A-humanized (CYP3A-HAC) mice have essential regulatory regions, including promoters and enhancers, and unknown elements affecting the expression of CYP3A4...
April 4, 2017: Drug Metabolism Letters
https://www.readbyqxmd.com/read/28332451/inhibitory-effect-of-fruit-juices-on-the-doxorubicin-metabolizing-activity-of-carbonyl-reductase-1
#19
Takeshi Miura, Katsutoshi Nagai, Shingo Kaneshiro, Ayako Taketomi, Toshikatsu Nakabayashi, Hiroki Konishi, Toru Nishinaka, Tomoyuki Terada
BACKGROUND AND OBJECTIVE: Doxorubicin, an anthracycline anti-cancer drug, is effective for breast cancer and childhood lymphoma. Chronic cardiotoxicity has been known as a critical adverse effect of doxorubicin and is attributed to its metabolite doxorubicinol produced by carbonyl reductase 1 (CBR1, SDR21C1). Some flavonoids have been reported to act as inhibitors for CBR1, therefore, commercially available juices containing flavonoids are likely to be applicable as a prophylactic treatment against doxorubicin-induced cardiotoxicity by suppression doxorubicinol production...
March 9, 2017: Drug Metabolism Letters
https://www.readbyqxmd.com/read/28260523/obesity-and-inflammation-and-altered-clopidogrel-pharmacokinetics-and-pharmacodynamics
#20
Nicholas B Norgard, Scott V Monte
BACKGROUND: Clopidogrel is a key antiplatelet drug that has substantial interpatient variability in pharmacodynamic response. Patients with lesser degrees of platelet inhibition in response to clopidogrel appear to be at increased risk for cardiovascular events. Obesity is an independent risk factor for cardiovascular morbidity and mortality due to atherothrombotic events and represents a group of patients who are in need of optimized antithrombotic therapy. Central to the obesity-related risk of atherothrombosis is a pro-thrombotic state characterized by increased levels of coagulation factors, impaired fibrinolysis and platelet hyper-reactivity, which results from the interaction among the features clustering in obesity: insulin resistance, inflammation, oxidative stress, and endothelial dysfunction...
March 1, 2017: Drug Metabolism Letters
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