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Drug Metabolism Letters

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https://www.readbyqxmd.com/read/29676238/effect-of-cyp2d6-poor-metabolizer-phenotype-on-stereoselective-nebivolol-pharmacokinetics
#1
Carolina P Vieira, Daniel V Neves, Eduardo B Coelho, Vera Lucia Lanchote
BACKGROUND: Nebivolol is a drug available as a racemate of d-nebivolol (SRRR) and l-nebivolol (RSSS). In human liver microsomes CYP2D6 mainly catalyses the metabolism of l-nebivolol, while CYP2C19 catalyses the metabolism of d-nebivolol. Nebivolol stereoselective pharmacokinetics has been described only for extensive metabolizers (EM). OBJECTIVE: To describe the stereoseletive nebivolol pharmacokinetics in CYP2D6 poor metabolizers (PM) and to assess whether the phenotype has an impact on nebivolol pharmacokinetics ...
April 19, 2018: Drug Metabolism Letters
https://www.readbyqxmd.com/read/29669508/in-vitro-drug-metabolism-investigation-of-7-ethoxycoumarin-in-human-monkey-dog-and-rat-hepatocytes-by-high-resolution-lc-ms-ms
#2
Wan-Yong Feng, Jenny Wen, Kathe Stauber
Recently, it has been an increasing concern on the bioactivation and adverse reactions associated with consumption of herbal and nature products such as coumarin family. 7-ethoxycoumarin is one of coumarin family compounds, but little information is available regarding its potential reactive metabolites. In this study, we investigated its metabolism in cryopreserved male/female mixed human, male Cynomolgus monkey, male Beagle dog and male Sprague Dawley rat hepatocytes. Following the incubation of 7-ethoxylcoumarin in the hepatocytes for 2 hr, 28 metabolites were detected and identified using high resolution LC-Q-Exactive system in the positive ion and negative ion modes...
April 18, 2018: Drug Metabolism Letters
https://www.readbyqxmd.com/read/29658443/evaluation-of-the-effect-of-uremic-serum-on-hepatic-reductase-functional-expression
#3
Osama Y Alshogran, Esra A F Al-Obaidi, Belal A Al-Husein, Ashraf O Oweis
BACKGROUND: The nonrenal clearance of drugs mediated by hepatic reduction is selectively altered by kidney disease. This study evaluated the influence of uremic serum on the expression and activity of reductase enzymes. METHODS: Human hepatocellular carcinoma cells (HepG2) were incubated with 5% pooled serum collected from patients with hemodialysis (pre- and post-dialysis session) or control subjects. The mRNA expression of various aldo-keto (AKR1C) and carbonyl (CBR) reductases were measured...
April 16, 2018: Drug Metabolism Letters
https://www.readbyqxmd.com/read/29595119/cytochrome-p450-3a4-induction-lumacaftor-versus-ivacaftor-potentially-resulting-in-significantly-reduced-plasma-concentration-of-ivacaftor
#4
Elena K Schneider
Since release of ivacaftor-lumacaftor several red-flags have been raised that highlight the clinical efficacy of this combination strategy may be be limited due to antagonistic drug-drug interactions. </p><p> Method: The effect of ivacaftor, its major metabolites M1 and M6, lumacaftor and the novel cystic fibrosis transmembrane conductance regulator (CFTR) modulator tezacaftor at 10 µg/mL on the enzymatic activity of the major xenobiotic metabolizing enzymes CYP1A2 and CYP3A4 as well as the minor enzymes CYP2B6 and CYP2C9 was assayed...
March 27, 2018: Drug Metabolism Letters
https://www.readbyqxmd.com/read/29577869/characterization-of-liver-and-cancer-type-organic-anion-transporting-polypeptide-oatp-1b3-messenger-rna-expression-in-normal-and-cancerous-human-tissues
#5
Khondoker Alam, Taleah Farasyn, Kai Ding, Wei Yue
BACKGROUND: Membrane transport protein organic anion transporting polypeptide (OATP) 1B3 mediates cellular uptake of many drugs including anti-cancer drugs (e.g. paclitaxel). In addition to the well-recognized hepatic expression and function of OATP1B3 [named as liver-type (Lt) OATP1B3], OATP1B3 also expresses in cancers and has been postulated to play a role in cancer therapy presumably by facilitating influx of anticancer drugs. Recently, a cancer type (Ct)-OATP1B3 mRNA variant was identified in colon and lung cancer tissues, which encodes truncated Ct-OATP1B3 with negligible transport activity...
March 25, 2018: Drug Metabolism Letters
https://www.readbyqxmd.com/read/29542427/evaluation-of-herb-drug-interaction-of-synacinntm-and-individual-biomarker-through-cytochrome-450-inhibition-assay
#6
Fadzilah Adibah Abd Majid, Nur Syukriah Ab Rahman, Effendy Abd Wahid, Ain Nabihah Zainudin, Siti Nurazwa Zainol, Hassan Fahmi Ismail, Tet Soon Wong, K Vijaya Bhargava, Nirbhay Kumar Tiwari, Sanjeev Giri
Drug interaction of SynacinnTM polyherbal with known diabetic drugs is unknown. SynacinnTM contains standardized extracts of five herbal against gallic acid, curcumin, rosmarinic acid, catechin and andrographolide. SynacinnTM and its five standard markers were analysed for its possible interaction with CYP450 enzymes assay. This study was conducted using liquid chromatography-tandem mass spectroscopy (LC-MS/MS) using probe substrates using human liver microsomes against CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP3A4(Midazolam) and CYP3A4 (Testosteron)...
March 13, 2018: Drug Metabolism Letters
https://www.readbyqxmd.com/read/29521215/lc-ms-ms-identification-and-structural-characterization-of-biodegradation-products-of-nitroproston-a-novel-prostaglandin-based-pharmaceutical-compound
#7
Natalia Vladimirovna Mesonzhnik, Natalia Moskaleva, Ksenia Shestakova, Ksenia Kurynina, Pavel Baranov, Natalia Gretskaya, Igor Serkov, Igor Lyubimov, Vladimir Bezuglov, Svetlana Appolonova
OBJECTIVE: Nitroproston is a novel prostaglandin-based compound modified by NO-donating groups with potential application in obstructive respiratory diseases such as asthma and obstructive bronchitis. Nitroproston have been extensively studied using various pharmacological models. Its biological stability is still uncertain. The main aim of the present study was to evaluate Nitroproston stability in vitro, as well as to identify and characterize its major biodegradation products. METHODS: The principal biodegradation products of Nitroproston were identified in vitro using liquid chromatography/ion trap - time-of-flight mass-spectrometry...
March 9, 2018: Drug Metabolism Letters
https://www.readbyqxmd.com/read/29357810/cytochrome-p450-1a2-messenger-rna-is-a-more-reliable-marker-than-cytochrome-p450-1a2-activity-phenacetin-o-deethylation-for-assessment-of-induction-potential-of-drug-metabolizing-enzymes-using-heparg-cells
#8
Akira Ogasawara, Nozomu Kato, Nao Torimoto, Fumika Aohara, Rikiya Ohashi, Yasuhiro Yamada, Hideki Taniguchi
BACKGROUND: The HepaRG cells have key drug metabolism functionalities comparable to those of primary human hepatocytes. Many studies have reported that this cell line can be used as a reliable in vitro model for human drug metabolism studies, including the assessment of cytochrome P450 (CYP) induction. OBJECTIVES: The objective of this study is to determine whether CYP mRNA level measurement is superior to the CYP enzyme activity measurement as a convenient high-throughput method for evaluating CYP induction potential using HepaRG cells...
January 18, 2018: 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
#9
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/29197321/preface
#10
Suresh K Balani
No abstract text is available yet for this article.
November 17, 2017: Drug Metabolism Letters
https://www.readbyqxmd.com/read/28762319/quantification-of-sulfotransferases-1a1-and-1a3-4-in-tissue-fractions-and-cell-lines-by-multiple-reaction-monitoring-mass-spectrometry
#11
Sho Yoshitake, Melissa McKay-Daily, Masaki Tanaka, Zeqi Huang
BACKGROUND: Within the sulfotransferase (SULT) superfamily of metabolic enzymes, SULT1A1 and 1A3/4 isoforms are of particular interest, due to their abilities to catalyze the sulfation of phenolic endobiotics and xenobiotics. Although the difference in their substrate specificity is well documented, an isoform-specific quantification method is still not available. OBJECTIVE: To detect and quantify SULT1A1 and 1A3/4 in S9 fractions and cell lines using targeted mass spectrometry-based proteomics...
November 17, 2017: Drug Metabolism Letters
https://www.readbyqxmd.com/read/28699487/mixed-matrix-method-provides-a-reliable-metabolite-exposure-comparison-for-assessment-of-metabolites-in-safety-testing-mist
#12
Ryan H Takahashi, Cyrus Khojasteh, Matthew Wright, Cornelis E C A Hop, Shuguang Ma
BACKGROUND: 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 major 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...
November 17, 2017: Drug Metabolism Letters
https://www.readbyqxmd.com/read/28606035/potential-minor-haplotypes-of-cyp2d6-in-the-japanese-population
#13
Masatoshi Masuda, Tsutomu Fujiwara, Masayuki Matsunaga, Takehisa Matsumaru
BACKGROUND: CYP2D6 is one of the most significant polymorphic genes of drugmetabolizing 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...
November 17, 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
#14
Valentina M Fokina, Svetlana L Patrikeeva, Cheryl Oncken, Gary D V Hankins, Mahmoud S Ahmed, Tatiana 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...
November 17, 2017: Drug Metabolism Letters
https://www.readbyqxmd.com/read/28403803/metabolic-profile-of-flunitrazepam-clinical-and-forensic-toxicological-aspects
#15
Ricardo Jorge Dinis-Oliveira
BACKGROUND: Flunitrazepam (FNZ) 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 led to important clinical and forensic concerns. OBJECTIVE: In this work the metabolism of FNZ, and pharmacological- and toxicological-related effects, were fully reviewed. METHODS: FNZ and related known metabolizing enzymes and metabolites were searched in books and in PubMed (U...
November 17, 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
#16
LETTER
Rebecca Kent, Hyunyoung Jeong
BACKGROUND: 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 the mouse liver. The objective of this study was to determine whether fenofibrate decreases CYP2D6 expression via upregulating SHP expression...
November 17, 2017: Drug Metabolism Letters
https://www.readbyqxmd.com/read/28393714/gender-difference-of-hepatic-and-intestinal-cyp3a4-in-cyp3ahumanized-mice-generated-by-a-human-chromosome-engineering-technique
#17
LETTER
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 (CYP3AHAC) mice have essential regulatory regions, including promoters and enhancers, and unknown elements affecting the expression of CYP3A4...
November 17, 2017: Drug Metabolism Letters
https://www.readbyqxmd.com/read/28332451/inhibitory-effect-of-fruit-juices-on-the-doxorubicin-metabolizing-activity-of-carbonyl-reductase-1
#18
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 of doxorubicinol production...
November 17, 2017: Drug Metabolism Letters
https://www.readbyqxmd.com/read/28260523/obesity-and-inflammation-and-altered-clopidogrel-pharmacokinetics-and-pharmacodynamics
#19
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 of 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...
November 17, 2017: Drug Metabolism Letters
https://www.readbyqxmd.com/read/28103788/pharmacokinetics-metabolism-and-disposition-of-14c-xq-1h-after-intravenous-administration-to-male-rats
#20
Yinlin Qin, Tao Chen, Qiu Jin, Kai Guo, Hao Feng, Dennis Heller, Zheming Gu
This study describes the in vivo pharmacokinetics and metabolism of [14C]labeled XQ-1H in male rats. XQ-1H is a methanesulfonate of XQ, 10-O-(N,N-dimethylaminoethyl)-ginkgolide B is a derivative of ginkgolide B (GB) with enhanced water solubility. Since it is very difficult to synthesize radiolabeled GB, the results obtained in this study may provide helpful insight to further ADME investigation of GB and its analogue compounds. After an i.v. administration of [14C]XQ-1H to male rats, XQ (the freebase form of XQ-1H) was extensively hydrolyzed, moderately metabolized, and mainly excreted in feces (71...
January 18, 2017: Drug Metabolism Letters
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