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https://www.readbyqxmd.com/read/27910729/identification-of-cytochrome-p450s-involved-in-the-metabolism-of-6-benzyl-1-benzyloxymethyl-5-iodouracil-w-1-using-human-recombinant-enzymes-and-rat-liver-microsomes-in-vitro
#1
Ying-Yuan Lu, Hai-Xu Cheng, Xin Wang, Xiao-Wei Wang, Jun-Yi Liu, Pu Li, Ya-Qing Lou, Jun Li, Chuang Lu, Guo-Liang Zhang
1. The aim of this study was to identify the hepatic metabolic enzymes, which involved in the biotransformation of 6-benzyl-1-benzyloxymethyl-5-iodouracil (W-1), a novel non-nucleoside reverse transcriptase inhibitor (NNRTIs) in rat and human in vitro. 2. The parent drug of W-1 was incubated with RLMs or recombinant CYPs (CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP2E1, CYP3A4 and CYP3A5, respectively) in the presence or absence of NADPH regenerating system. The metabolites of W-1 were analyzed with liquid chromatography-ion trap-time of flight-mass spectrometry (LC-IT-TOF-MS)...
December 2, 2016: Xenobiotica; the Fate of Foreign Compounds in Biological Systems
https://www.readbyqxmd.com/read/27909995/solithromycin-a-novel-fluoroketolide-for-the-treatment-of-community-acquired-bacterial-pneumonia
#2
REVIEW
George G Zhanel, Erika Hartel, Heather Adam, Sheryl Zelenitsky, Michael A Zhanel, Alyssa Golden, Frank Schweizer, Bala Gorityala, Philippe R S Lagacé-Wiens, Andrew J Walkty, Alfred S Gin, Daryl J Hoban, Joseph P Lynch, James A Karlowsky
Solithromycin is a novel fluoroketolide developed in both oral and intravenous formulations to address increasing macrolide resistance in pathogens causing community-acquired bacterial pneumonia (CABP). When compared with its macrolide and ketolide predecessors, solithromycin has several structural modifications which increase its ribosomal binding and reduce its propensity to known macrolide resistance mechanisms. Solithromycin, like telithromycin, affects 50S ribosomal subunit formation and function, as well as causing frame-shift errors during translation...
December 1, 2016: Drugs
https://www.readbyqxmd.com/read/27909741/the-role-of-epigenetic-modifiers-in-extended-cultures-of-functional-hepatocyte-like-cells-derived-from-human-neonatal-mesenchymal-stem-cells
#3
M Cipriano, J C Correia, S P Camões, N G Oliveira, P Cruz, H Cruz, M Castro, J L Ruas, J M Santos, J P Miranda
The development of predictive in vitro stem cell-derived hepatic models for toxicological drug screening is an increasingly important topic. Herein, umbilical cord tissue-derived mesenchymal stem cells (hnMSCs) underwent hepatic differentiation using an optimized three-step core protocol of 24 days that mimicked liver embryogenesis with further exposure to epigenetic markers, namely the histone deacetylase inhibitor trichostatin A (TSA), the cytidine analogue 5-azacytidine (5-AZA) and dimethyl sulfoxide (DMSO)...
December 1, 2016: Archives of Toxicology
https://www.readbyqxmd.com/read/27904973/platelet-reactivity-and-clinical-outcomes-in-patients-using-cyp3a4-metabolized-statins-with-clopidogrel-in-percutaneous-coronary-intervention
#4
Jin Sup Park, Kwang Soo Cha, Hye Won Lee, Jun-Hyok Oh, Jung Hyun Choi, Han Cheol Lee, Taek Jong Hong, Hyo Soo Kim
Statins are primarily metabolized by cytochrome P450 3A4 (CYP3A4), which reduces clopidogrel to its active metabolite. Recent studies suggest that CYP3A4-metabolized statins attenuate clopidogrel's anti-aggregatory effect on platelets. We aimed to assess the impact of concomitant CYP3A4-metabolized statin and clopidogrel use on antiplatelet activity and clinical outcomes in patients undergoing percutaneous coronary intervention (PCI). We enrolled 1187 patients from the HOST-ASSURE trial with platelet reactivity unit (PRU) values at both baseline and 1 month...
November 30, 2016: Heart and Vessels
https://www.readbyqxmd.com/read/27904813/glycyrrhetinic-acid-might-increase-the-nephrotoxicity-of-bakuchiol-by-inhibiting-cytochrome-p450-isoenzymes
#5
Aifang Li, Nana Ma, Zijing Zhao, Mei Yuan, Hua Li, Qi Wang
BACKGROUND: Licorice, a popular traditional Chinese medicine (TCM), is widely used to moderate the effects (detoxification) of other herbs in TCM and often combined with Fructus Psoraleae. However, the classical TCM book states that Fructus Psoraleae is incompatible with licorice; the mechanism underlying this incompatibility has not been identified. Glycyrrhetinic acid (GA), the active metabolite of licorice, may increase the toxicity of bakuchiol (BAK), the main chemical ingredient in Psoralea corylifolia, by inhibiting its detoxification enzymes CYP450s...
2016: PeerJ
https://www.readbyqxmd.com/read/27901175/adme-studies-and-preliminary-safety-pharmacology-of-ldt5-a-lead-compound-for-the-treatment-of-benign-prostatic-hyperplasia
#6
F Noël, J B Nascimento-Viana, L A S Romeiro, R O Silva, L F N Lemes, A S Oliveira, T B S Giorno, P D Fernandes, C L M Silva
This study aimed to estimate the absorption, distribution, metabolism and excretion (ADME) properties and safety of LDT5, a lead compound for oral treatment of benign prostatic hyperplasia that has previously been characterized as a multi-target antagonist of α1A-, α1D-adrenoceptors and 5-HT1A receptors. The preclinical characterization of this compound comprised the evaluation of its in vitro properties, including plasma, microsomal and hepatocytes stability, cytochrome P450 metabolism and inhibition, plasma protein binding, and permeability using MDCK-MDR1 cells...
2016: Brazilian Journal of Medical and Biological Research, Revista Brasileira de Pesquisas Médicas e Biológicas
https://www.readbyqxmd.com/read/27896399/cytochrome-p450-mediated-metabolism-of-triclosan-attenuates-its-cytotoxicity-in-hepatic-cells
#7
Yuanfeng Wu, Priyanka Chitranshi, Lucie Loukotková, Gonçalo Gamboa da Costa, Frederick A Beland, Jie Zhang, Jia-Long Fang
Triclosan is a widely used broad-spectrum anti-bacterial agent. The objectives of this study were to identify which cytochrome P450 (CYP) isoforms metabolize triclosan and to examine the effects of CYP-mediated metabolism on triclosan-induced cytotoxicity. A panel of HepG2-derived cell lines was established, each of which overexpressed a single CYP isoform, including CYP1A1, CYP1A2, CYP1B1, CYP2A6, CYP2A7, CYP2A13, CYP2B6, CYP2C8, CYP2C9, CYP2C18, CYP2C19, CYP2D6, CYP2E1, CYP3A4, CYP3A5, CYP3A7, CYP4A11, and CYP4B1...
November 28, 2016: Archives of Toxicology
https://www.readbyqxmd.com/read/27893182/inter-individual-variability-in-dabigatran-and-rivaroxaban-exposure-contribution-of-abcb1-genetic-polymorphisms-and-interaction-with-clarithromycin
#8
I Gouin-Thibault, X Delavenne, A Blanchard, V Siguret, J E Salem, C Narjoz, P Gaussem, P Beaune, C Funck-Brentano, M Azizi, P Mismetti, M A Loriot
BACKGROUND: The direct oral anticoagulants (DOACs) dabigatran and rivaroxaban are both substrates of the P-glycoprotein (P-gp) transporter, encoded by the ABCB1 gene. Rivaroxaban is metabolized by CYP3A4. Inter-individual variability in DOAC exposure and frequent P-gp associated drug-drug interactions have been described in patients. OBJECTIVE: To assess the influence of ABCB1 polymorphisms on the pharmacokinetics (PK) of dabigatran and rivaroxaban, associated or not with clarithromycin, a P-gp and CYP3A4 inhibitor...
November 28, 2016: Journal of Thrombosis and Haemostasis: JTH
https://www.readbyqxmd.com/read/27891633/direct-inhibition-of-re-du-ning-injection-and-its-active-compounds-on-human-liver-cytochrome-p450-enzymes-by-a-cocktail-method
#9
Danyu Kang, Ting Geng, Yuanpei Lian, Yanjing Li, Gang Ding, Wenzhe Huang, Shiping Ma, Zhenzhong Wang, Zheng Ma, Wei Xiao
The aim of this study was to investigate the direct inhibitory effects of Re Du Ning Injection (RDN) and its active compounds on the major CYP isoforms (CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6 and CYP3A4) of human liver microsomes by "a cocktail method". The activity of each CYP isform was represented as the formation rate of the specific metabolite from relevant substrate. Then a sensitive and specific ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) method was developed and validated to simultaneously analyze the seven metabolites...
November 28, 2016: Biomedical Chromatography: BMC
https://www.readbyqxmd.com/read/27890698/clementine-juice-has-the-potential-for-drug-interactions-in-vitro-comparison-with-grapefruit-and-mandarin-juice
#10
Dirk Theile, Nicolas Hohmann, Dominik Kiemel, Giuseppe Gattuso, Davide Barreca, Gerd Mikus, Walter Emil Haefeli, Vedat Schwenger, Johanna Weiss
Adverse drug interactions due to grapefruit juice are well known prompting warnings even in drug labels. Similar issues have not been reported for clementines and available data is scarce, despite of genetic descent. We observed substantially increased tacrolimus trough concentrations in a renal transplant patient consuming high clementine amounts and, thus, scrutinised the effects of clementine juice on drug metabolism and drug transporters in vitro and compared it to the effects of mandarin and grapefruit juice...
November 24, 2016: European Journal of Pharmaceutical Sciences
https://www.readbyqxmd.com/read/27889832/effects-of-cytochrome-p450-cyp3a4-and-cyp2c19-inhibition-and-induction-on-the-exposure-of-selumetinib-a-mek1-2-inhibitor-in-healthy-subjects-results-from-two-clinical-trials
#11
Angela W Dymond, Karen So, Paul Martin, Yifan Huang, Paul Severin, David Mathews, Eleanor Lisbon, Gabriella Mariani
PURPOSE: Two phase I, open-label trials in healthy subjects assessed whether co-administration with CYP3A4/CYP2C19 inhibitors, itraconazole/fluconazole (study A), or CYP3A4 inducer, rifampicin (study B), affects the exposure, safety/tolerability and pharmacokinetics of selumetinib and its metabolite N-desmethyl selumetinib. METHODS: In study A (n = 26), subjects received a single dose of selumetinib 25 mg and, after 4 days of washout, were randomized to treatment 1 (itraconazole 200 mg twice daily on days 1-11) or treatment 2 (fluconazole 400 mg on day 1 then 200 mg/day on days 2-11) plus co-administration of single-dose selumetinib 25 mg on day 8 (selumetinib staggered 4 h after itraconazole/fluconazole dose); Twenty-one days after discharge/washout, subjects received the alternate treatment...
November 26, 2016: European Journal of Clinical Pharmacology
https://www.readbyqxmd.com/read/27885867/protein-corona-modulation-of-hepatocyte-uptake-and-molecular-mechanisms-of-gold-nanoparticle-toxicity
#12
Kyoungju Choi, Jim E Riviere, Nancy A Monteiro-Riviere
Protein corona formation over gold nanoparticles (AuNP) can modulate cellular responses by altering AuNP physicochemical properties. The liver plays an essential role in metabolism, detoxification and elimination of xenobiotics and drugs as well as circulating NP clearance. We investigated human hepatic uptake of 40 and 80nm AuNP with branched polyethylenimine (BPEI), lipoic acid (LA) and polyethylene glycol (PEG) coatings as well as human plasma protein (HP) and human serum albumin (HSA) coronas. AuNP-mediated cytotoxicity, reactive oxygen/reactive nitrogen species (ROS/RNS), and CYP activity in human hepatocytes as well as molecular mechanisms with 40nm bare and HP BPEI-AuNP were investigated...
November 25, 2016: Nanotoxicology
https://www.readbyqxmd.com/read/27882460/development-of-a-specific-substrate-inhibitor-panel-liver-on-a-chip-for-evaluation-of-cytochrome-p450-activity
#13
A A Zakhariants, O A Burmistrova, M Y Shkurnikov, A A Poloznikov, D A Sakharov
We developed a cytochrome P450 substrate-inhibitor panel for preclinical in vitro evaluation of drugs in a 3D histotypical microfluidic cell model of human liver (liver-on-a-chip technology). The concentrations of substrates and inhibitors were optimized to ensure reliable detection of the principal metabolites by HPLC-mass-spectroscopy. The selected specific substrate-inhibitor pairs, namely bupropion/2-phenyl-2-(1-piperidinyl)propane) for evaluation of CYP2B6B activity, tolbutamide/sulfaphenazole for CYP2C9, omeprazole/(+)-N-benzylnirvanol for CYP2C19, and testosterone/ketoconazole for CYP3A4, enable reliable evaluation of the drug metabolism pathway...
November 23, 2016: Bulletin of Experimental Biology and Medicine
https://www.readbyqxmd.com/read/27876007/effect-of-pregnane-x-receptor-1b-genetic-polymorphisms-on-postoperative-analgesia-with-fentanyl-in-chinese-patients-undergoing-gynecological-surgery
#14
Jing-Jing Yuan, Xiao-Jing Ma, Zhi-Song Li, Yan-Zi Chang, Wei Zhang, Quan-Cheng Kan, Jun-Kai Hou, Li-Rong Zhang
BACKGROUND: The purpose of the study was to investigate the effects of the pregnane X receptor (PXR)*1B polymorphisms on CYP3A4 enzyme activity and postoperative fentanyl consumption in Chinese patients undergoing gynecological surgery. METHODS: A total of 287 females of Han ethnicity, aged 20 to 50 years old, ASA I or II, scheduled to abdominal total hysterectomy or myomectomy under general anesthesia were enrolled. The analgesic model used was fentanyl consumption via patient-controlled intravenous analgesia (PCIA) in the post-operative period...
November 23, 2016: BMC Medical Genetics
https://www.readbyqxmd.com/read/27872071/results-of-a-doravirine-atorvastatin-drug-drug-interaction-study
#15
Sauzanne Khalilieh, Ka Lai Yee, Rosa I Sanchez, Ilias Triantafyllou, Li Fan, Noha Maklad, Heather Jordan, Maureen Martell, Marian Iwamoto
Doravirine is a novel, highly potent, once-daily non-nucleoside reverse transcriptase inhibitor in development for HIV-1 infection treatment. In vitro and clinical data suggest doravirine is unlikely to cause significant drug-drug interactions via major drug metabolizing enzymes or transporters. As a common HIV-1 infection comorbidity, hypercholesterolemia is often treated with statins, including the commonly prescribed atorvastatin. Atorvastatin is subject to drug-drug interactions with CYP3A4 inhibitors. Increased exposure due to CYP3A4 inhibition may lead to serious adverse events (AEs), including rhabdomyolysis...
November 21, 2016: Antimicrobial Agents and Chemotherapy
https://www.readbyqxmd.com/read/27872069/an-evaluation-of-doravirine-pharmacokinetics-when-switching-from-efavirenz-to-doravirine-in-healthy-subjects
#16
Ka Lai Yee, Rosa I Sanchez, Patrice Auger, Rachael Liu, Li Fan, Ilias Triantafyllou, Ming-Tain Lai, Mike Di Spirito, Marian Iwamoto, Sauzanne G Khalilieh
Doravirine is a novel, potent, human immunodeficiency virus-1 (HIV-1) non-nucleoside reverse transcriptase inhibitor (NNRTI) demonstrating a high genetic barrier to resistance and is well tolerated in studies to date. Doravirine is a candidate for patients switching from less-tolerated NNRTIs, such as efavirenz. While doravirine is a CYP3A4 substrate, efavirenz induces CYP3A4; therefore, the pharmacokinetics of both drugs following switching from efavirenz to doravirine were assessed.This was a 3-period, fixed-sequence, open-label study...
November 21, 2016: Antimicrobial Agents and Chemotherapy
https://www.readbyqxmd.com/read/27871908/acetylated-deoxycholic-dca-and-cholic-ca-acids-are-potent-ligands-of-pregnane-x-pxr-receptor
#17
Alejandro Carazo, Lucie Hyrsova, Jan Dusek, Hana Chodounska, Alzbeta Horvatova, Karel Berka, Vaclav Bazgier, Hongying Gan-Schreier, Waleé Chamulitrat, Eva Kudova, Petr Pavek
The Pregnane X (PXR), Vitamin D (VDR) and Farnesoid X (FXR) nuclear receptors have been shown to be receptors of bile acids controlling their detoxification or synthesis. Chenodeoxycholic (CDCA) and lithocholic (LCA) acids are ligands of FXR and VDR, respectively, whereas 3-keto and acetylated derivates of LCA have been described as ligands for all three receptors. In this study, we hypothesized that oxidation or acetylation at position 3, 7 and 12 of bile acids DCA (deoxycholic acid), LCA, CA (cholic acid), and CDCA by detoxification enzymes or microbiome may have an effect on the interactions with bile acid nuclear receptors...
November 18, 2016: Toxicology Letters
https://www.readbyqxmd.com/read/27867264/traditional-herbal-formulas-to-as-treatments-for-musculoskeletal-disorders-their-inhibitory-effects-on-the-activities-of-human-microsomal-cytochrome-p450s-and-udp-glucuronosyltransferases
#18
Seong Eun Jin, Chang-Seob Seo, Hyeun-Kyoo Shin, Hyekyung Ha
OBJECTIVE: The aim of this study was to assess the influence of traditional herbal formulas, including Bangpungtongseong-san (BPTSS; Fangfengtongsheng-san, Bofu-tsusho-san), Ojeok-san (OJS; Wuji-san, Goshaku-san), and Oyaksungi-san (OYSGS; Wuyaoshungi-san, Uyakujyunki-san), on the activities of the human cytochrome P450s (CYP450s) and UDP-glucuronosyltransferases (UGTs), which are drug-metabolizing enzymes. MATERIALS AND METHODS: The activities of the major human CYP450 isozymes (CYP1A2, CYP3A4, CYP2B6, CYP2C9, CYP2C19, CYP2D6, and CYP2E1) and UGTs (UGT1A1, UGT1A4, and UGT2B7) were investigated using in vitro fluorescence-based and luminescence-based enzyme assays, respectively...
October 2016: Pharmacognosy Magazine
https://www.readbyqxmd.com/read/27862160/in-vitro-and-pbpk-based-assessment-of-drug-drug-interaction-potential-of-canagliflozin
#19
Rao N V S Mamidi, Shannon Dallas, Carlo Sensenhauser, Heng Keang Lim, Ellen Scheers, Peter Verboven, Filip Cuyckens, Laurent Leclercq, David C Evans, Michael F Kelley, Mark D Johnson, Jan Snoeys
AIMS: Canagliflozin is a recently approved drug for use in the treatment of type 2 diabetes. The potential for canagliflozin to cause clinical drug-drug interactions (DDIs) was assessed. METHODS: DDI potential of canagliflozin was investigated using in vitro test systems containing drug metabolizing enzymes or transporters. Basic predictive approaches were applied to determine potential interaction in vivo. A physiologically-based pharmacokinetic (PBPK) model was developed and clinical DDI simulations were performed to determine the likelihood of CYP inhibition by canagliflozin...
November 11, 2016: British Journal of Clinical Pharmacology
https://www.readbyqxmd.com/read/27861439/trends-in-tramadol-pharmacology-metabolism-and-misuse
#20
Karen Miotto, Arthur K Cho, Mohamed A Khalil, Kirsten Blanco, Jun D Sasaki, Richard Rawson
Tramadol is a unique analgesic medication, available in variety of formulations, with both monoaminergic reuptake inhibitory and opioid receptor agonist activity increasingly prescribed worldwide as an alternative for high-affinity opioid medication in the treatment of acute and chronic pain. It is a prodrug that is metabolized by cytochrome P450 (CYP) enzymes CYP2D6 and CYP3A4 to its more potent opioid analgesic metabolites, particularly the O-demethylation product M1. The opioid analgesic potency of a given dose of tramadol is influenced by an individual's CYP genetics, with poor metabolizers experiencing little conversion to the active M1 opioid metabolite and individuals with a high metabolic profile, or ultra-metabolizers, experiencing the greatest opioid analgesic effects...
November 17, 2016: Anesthesia and Analgesia
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