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Drug Metabolism Letters

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https://www.readbyqxmd.com/read/28403803/metabolic-profile-of-flunitrazepam-clinical-and-forensic-toxicological-aspects
#1
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
#2
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
#3
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
#4
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
#5
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
https://www.readbyqxmd.com/read/28137210/the-metabolism-of-methazolamide-in-immortalized-human-keratinocytes-hacat-cells
#6
Tetsuo Sasabe, Shinichiro Maeda, Kenichi Kishida, Mariko Yamano, Yoshihiro Miwa, Toshihiro Sugiyama
OBJECTIVE: Drug therapy is occasionally accompanied by an idiosyncratic severe toxicity, which occurs very rarely, but can lead to patient mortality. Methazolamide, an anti-glaucomatous agent, could cause severe skin eruptions called Stevens-Johnson syndrome/toxic epidermal necrolyis (SJS/TEN). Its precise etiology is still uncertain. In this study, the metabolism of methazolamide was investigated in immortalized human keratinocytes to reveal the possible mechanism which causes SJS/TEN...
January 27, 2017: Drug Metabolism Letters
https://www.readbyqxmd.com/read/28103788/pharmacokinetics-metabolism-and-disposition-of-14c-xq-1h-after-intravenous-administration-to-male-rats
#7
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
https://www.readbyqxmd.com/read/28093968/quantification-of-etodolac-in-human-plasma-for-pharmacokinetics-and-bioequivalence-studies-in-27-korean-subjects
#8
Il-Dong Song, Je-Seop Kang, Hyun-Jin Kim, Se-Mi Kim, Dong-Xu Zhao, Shin-Hee Kim, Min-Young Chun, Kyuhyun Lee
We developed a simple and validated liquid chromatography tandem mass spectrometry(LC-MS/MS) for quantification of etodolac using pioglitazone as an internal standard (IS) to assess pharmacokinetics and to appraise bioequivalence of two formulations of etodolac (reference and tested) in 27 healthy Korean subjects. Isocratic mobile phase consisted of 10 mM ammonium formate and acetonitrile were used to separate the analytes on a Gemini C18 column. Also, analytes were analyzed by MS/MS in multiple reaction monitoring (MRM) mode using the transitions of (M+H)+ ions, m/z 288...
January 16, 2017: Drug Metabolism Letters
https://www.readbyqxmd.com/read/28029084/variability-of-zaleplon-5-oxidase-activity-in-mice-and-humans-and-inhibition-by-raloxifene
#9
Chiaki Tanoue, Kazumi Sugihara, Yoshitaka Tayama, Naoto Uramaru, Yoko Watanabe, Shigeru Ohta, Shigeyuki Kitamura
Zaleplon (ZAL) is a sedative-hypnotic agent, which is mainly metabolized to inactive 5-oxidized zaleplon (5-oxo-ZAL) and N-des-ethylated ZAL (des-ethyl-ZAL) in mice and humans. The former reaction is considered to be catalyzed by aldehyde oxidase present in liver cytosol. Here, we examined sex and strain differences of ZAL metabolism to 5-oxo-ZAL among four strains of mice, as well as the inter-individual variation in humans, in order to evaluate the variability of 5-oxo-ZAL-forming activity and its relationship with aldehyde oxidase activity...
December 27, 2016: Drug Metabolism Letters
https://www.readbyqxmd.com/read/28000546/ortho-methylarylamines-as-time-dependent-inhibitors-of-cytochrome-p450-1a1-enzyme
#10
Jayalakshmi Sridhar, Jiawang Liu, Rajesh Komati, Richard Schroeder, Quan Jiang, Phan Tram, Kevin Riley, Maryam Foroozesh
Members of the cytochrome P450 1A family metabolize many procarcinogens such as polycyclic aromatic hydrocarbons and heterocyclic amines. Inactivation of these enzymes is prerequisite for cancer prevention and treatment in certain cases. Mechanism-based inhibition (time and co-factor dependent) is an effective method for the inactivation of these enzymes. Our recent study on emodin analogs revealed an anthraquinone with ortho-methylarylamine moiety that exhibited time-dependent inhibition of P450 enzymes 1A1 and 1A2...
December 20, 2016: Drug Metabolism Letters
https://www.readbyqxmd.com/read/27908259/a-novel-liquid-chromatography-tandem-mass-spectrometry-method-for-the-estimation-of-bilirubin-glucuronides-and-its-application-to-in-vitro-enzyme-assays
#11
Siva Prasad Putluru, Murali Krishna Matta, Deepak Ahire, Murali Subramanian, Michael Sinz, Sandhya Mandlekar
Bilirubin is a toxic waste product of metabolism, eliminated mainly through UGT1A1 mediated conjugation to mono- and di-glucuronides. Due to the potentially low Km value of bilirubin glucuronidation, the quantitative sensitivity obtained with most UV/visible light detection methods are not sufficient to accurately calculate UGT1A1 enzyme kinetics and inhibition properties of new chemical entities at low bilirubin concentrations. In addition, bilirubin, as well as its metabolites, are unstable during sample preparation and bioanalysis...
November 24, 2016: Drug Metabolism Letters
https://www.readbyqxmd.com/read/27842485/cytochrome-p450-2a6-phenotyping-using-dietary-caffeine-salivary-metabolite-ratios-and-genotyping-using-blood-on-storage-cards-in-non-smoking-japanese-volunteers
#12
Norie Murayama, Makiko Shimizu, Kenta KObayashi, Izumi KIshimoto, Hiroshi Yamazaki
BACKGROUND: A simple method of genotyping and phenotyping cytochrome P450 2A6 (CYP2A6) was previously reported using individual blood samples and urinary caffeine metabolite ratios of 1,7-dimethyluric acid (17U) to 1-methylxanthine (1X). OBJECTIVE: Blood spotted onto storage cards and salivary caffeine metabolites were analyzed in 27 healthy non-smoking Japanese volunteers with no prior abstention from dietary caffeine intake. METHODS: 1,7-Dimethylxanthine (17X), 17U, 1X, and caffeine levels in spot saliva samples were determined in Japanese non-smokers by high-performance liquid chromatography under normal dietary caffeine consumption...
November 14, 2016: Drug Metabolism Letters
https://www.readbyqxmd.com/read/27842484/strong-induction-of-cytochrome-p450-1a-3a-but-not-p450-2b-in-cultured-hepatocytes-from-common-marmosets-and-cynomolgus-monkeys-by-typical-human-p450-inducing-agents
#13
Shotaro Uehara, Yasuhiro Uno, Takako Suzuki, Takashi Inoue, Masahiro Utoh, Erika Sasaki, Hiroshi Yamazaki
BACKGROUND: Common marmosets (Callithrix jacchus) and cynomolgus monkeys (Macaca fascicularis) are used as non-human primate models in preclinical studies for drug development. OBJECTIVE: The assessment of P450 induction in hepatocytes from marmosets and cynomolgus monkeys was performed using typical P450 inducers. METHODS: Induction of cytochrome P450 1-4 family enzymes was analyzed in two lots of cultured hepatocytes from common marmosets and cynomolgus monkeys after 24-h treatment with typical human P450 inducing agents by real-time reverse transcription-polymerase chain reaction...
November 14, 2016: Drug Metabolism Letters
https://www.readbyqxmd.com/read/27774888/genipin-inhibits-the-induction-of-inducible-nitric-oxide-synthase-through-the-inhibition-of-nf-%C3%AE%C2%BAb-activation-in-rat-hepatocytes
#14
Richi Nakatake, Takumi Tsuda, Takashi Matsuura, Hirokazu Miki, Hideki Hishikawa, Hideyuki Matsushima, Morihiko Ishizaki, Kosuke Matsui, Masaki Kaibori, Mikio Nishizawa, Tadayoshi Okumura, Masanori Kon
BACKGROUND/AIMS: Genipin is a component of Japanese traditional herbal medicine (Kampo), inchinkoto, and is used for the treatment of various liver injuries. However, there are few scientific evidence for its anti-inflammatory effects and mechanisms. In inflamed liver, proinflammatory cytokines including tumor necrosis factor (TNF)-α and interleukin (IL)-1β stimulate liver cells, followed by the expression of inducible nitric oxide synthase (iNOS). Excessive levels of NO produced by iNOS have been implicated as one of the factors in liver injury...
October 20, 2016: Drug Metabolism Letters
https://www.readbyqxmd.com/read/27449528/the-uremic-toxin-indoxyl-3-sulfate-induces-cyp1a2-in-primary-human-hepatocytes
#15
Rangaraj Narayanan, Lisa Liu, Matthew Hoffmann, Sekhar Surapaneni
Chronic kidney disease (CKD) generally impacts clearance of renally eliminated drugs but growing evidence shows that it can influence clearance of hepatically eliminated drugs and a complete mechanistic understanding of this phenomenon is still lacking. CKD leads to accumulation of uremic toxins, including indoxyl-3-sulfate (3-INDS) and indole-3-acetic acid (3-IAA). OBJECTIVE: In this study, we evaluated the potential of 3-INDS and 3-IAA (10, 30 and 100 μM) to induce liver cytochrome P450 (CYP) enzymes CYP1A2, 2B6 and 3A4/5 using cultured primary human hepatocytes following once daily treatment for 3 days...
July 19, 2016: Drug Metabolism Letters
https://www.readbyqxmd.com/read/27604990/application-of-a-fit-for-purpose-pbpk-model-to-investigate-the-cyp3a4-induction-potential-of-enzalutamide
#16
Rangaraj Narayanan, Matthew Hoffmann, Gondi Kumar, Sekhar Surapaneni
BACKGROUND: Oncology therapy typically involves drug combinations since monotherapy seldom provides the desired outcome. But combination therapy presents the potential for drug-drug interactions (DDIs). Due to the narrow window between therapeutic concentrations and onset of toxicity often observed with oncology therapeutics, managing DDIs with combination therapy in cancer is critical. Physiologically based pharmacokinetic (PBPK) modeling can be effectively used for predicting DDIs and guiding dose-selection, but requires development of PBPK models of cancer drugs...
2016: Drug Metabolism Letters
https://www.readbyqxmd.com/read/27550199/new-screening-criteria-setting-on-evaluation-of-cytochrome-p450-induction-using-heparg-cells-with-multiplex-branched-dna-technologies-in-early-drug-discovery
#17
Akira Ogasawara, Nao Torimoto, Naoki Tsuda, Fumika Aohara, Rikiya Ohashi, Yasuhiro Yamada, Hideki Taniguchi
BACKGROUND: Cytochrome P450 (CYP) enzymes are induced by some therapeutic drugs, leading to interactions reducing drug plasma concentrations. Recently, an assessment of CYP induction using messenger RNA (mRNA) levels has shown advantages over measurement of enzymatic activity; it has a larger dynamic range of induction and enables us to measure the intrinsic induction potential of time-dependent CYP inhibitors. In order to minimize the late-stage attrition of new chemical entities (NCE), it is important to evaluate CYP induction potency at mRNA levels in the early stage of drug development...
2016: Drug Metabolism Letters
https://www.readbyqxmd.com/read/27515451/cyp2b6-and-oprm1-receptor-polymorphisms-at-methadone-clinics-and-novel-oprm1-haplotypes-a-cross-sectional-study
#18
Ahmad Abdulrahman AlMeman, Rusli Ismail, Markus Perola
INTRODUCTION: Methadone is accepted as an alternative therapy in opioid use disorders worldwide. Methadone responsiveness, however, is affected by a range of CYP450 enzymes and OPRM1 polymorphisms. OBJECTIVE: This study sought to detect CYP2B6 and OPRM1 variants and their genotypes, as major contributors to inter-variability in methadone responsiveness and methadone dose requirements. METHODS: We carried out a prospective experimental one-phase pharmacogenetic study in four addiction clinics in Malaysia...
2016: Drug Metabolism Letters
https://www.readbyqxmd.com/read/27456669/intracellular-retention-of-three-quinuclidine-derivatives-in-caco-2-permeation-experiments-mechanisms-and-impact-on-estimating-permeability-and-active-efflux-ratio
#19
Hong Jin, Sudarshan Kapadnis, Ting Chen, Dooyoung Lee, Andrew McRiner, Andrew Cook, Duane A Burnett, Gerhard Koenig, Cuyue Tang
BACKGROUND: Three quinuclidine derivatives (FRM-1, FRM-2 and FRM-3) were subject to significant mass loss to cellular retention in Caco-2 permeation experiments. The apparent permeability coefficient (Papp) calculated with either 'sink' (Papp,sink) or 'non-sink' (Papp,nonsink) method was significantly biased. As a result, a simplified 3-compartmental distribution model was applied in this study to derive the 'intrinsic' Papp (Papp,int) and to understand the impact of cellular retention on estimating Papp and active efflux ratio (ER) values...
2016: Drug Metabolism Letters
https://www.readbyqxmd.com/read/27456668/uhplc-quantitation-method-for-new-thiazolidinedione-lpsf-gq-02-and-in-vitro-in-vivo-kinetic-studies
#20
Carla Monalizi Vieira, Michel Leandro de Campos, Elias Carvalho Padilha, Marina Pitta, Ivan da Rocha Pitta, Maria do Carmo Alves de Lima, Rosângela Gonçalves Peccinini
BACKGROUND: LPSF/GQ-02 is a promising benzylidene thiazolidinedione that has demonstrated antidiabetic, antidyslipidemic, anti-atherosclerotic properties and can also treat non-alcoholic fatty liver disease. Despite all activity studies of the new compound, its pharmacokinetics are not yet described. OBJECTIVE: The aim of this study was to perform its first pharmacokinetic profile. METHODS: For this purpose a bioanalytical method for the quantitation of 5-(4- Chloro-benzylidene)-3-(4-methylbenzyl)-thiazolidine-2,4-dione (LPSF/GQ-02) was developed and validated...
2016: Drug Metabolism Letters
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