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CYP3A4/5

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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/27901175/adme-studies-and-preliminary-safety-pharmacology-of-ldt5-a-lead-compound-for-the-treatment-of-benign-prostatic-hyperplasia
#4
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/27872071/results-of-a-doravirine-atorvastatin-drug-drug-interaction-study
#5
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
#6
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/27862160/in-vitro-and-pbpk-based-assessment-of-drug-drug-interaction-potential-of-canagliflozin
#7
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
#8
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
https://www.readbyqxmd.com/read/27858915/genetic-polymorphisms-of-cyp3a4-among-chinese-patients-with-steroid-induced-osteonecrosis-of-the-femoral-head
#9
Yuan Wang, Xiuling Li, Yaoyu Gao, Zhi Li, Lidong Yu, Qingbo Meng, Li Sun, Jianzhong Wang
BACKGROUND: Steroid therapy has been an important reason of nontraumatic osteonecrosis of the femoral head (ONFH). Steroids are metabolized by hepatic cytochrome P4503A, a low endogenous activity of this enzyme can contribute to the pathogenesis of ONFH. The aim of this study was to investigate the associations of polymorphisms of cytochrome P4503A4 (CYP3A4) gene with steroid-induced ONFH in Chinese patients. METHODS: A total of 150 steroid-induced ONFH patients and 250 healthy controls were enrolled...
November 2016: Medicine (Baltimore)
https://www.readbyqxmd.com/read/27849442/to-genotype-or-phenotype-for-personalized-medicine-cyp450-drug-metabolizing-enzyme-genotype-phenotype-concordance-and-discordance-in-the-ecuadorian-population
#10
Fernando De Andrés, Santiago Terán, Francisco Hernández, Enrique Terán, Adrián LLerena
Genetic variations within the cytochrome P450 (CYP450) superfamily of drug metabolizing enzymes confer substantial person-to-person and between-population differences in pharmacokinetics, and by extension, highly variable clinical effects of medicines. In this context, "personalized medicine," "precision medicine," and "stratified medicine" are related concepts attributed to what is essentially targeted therapeutics and companion diagnostics, aimed at improving safety and effectiveness of health interventions...
November 16, 2016: Omics: a Journal of Integrative Biology
https://www.readbyqxmd.com/read/27834912/curcumin-prevents-aflatoxin-b%C3%A2-hepatoxicity-by-inhibition-of-cytochrome-p450-isozymes-in-chick-liver
#11
Ni-Ya Zhang, Ming Qi, Ling Zhao, Ming-Kun Zhu, Jiao Guo, Jie Liu, Chang-Qin Gu, Shahid Ali Rajput, Christopher Steven Krumm, De-Sheng Qi, Lv-Hui Sun
This study was designed to establish if Curcumin (CM) alleviates Aflatoxin B₁ (AFB₁)-induced hepatotoxic effects and to determine whether alteration of the expression of cytochrome P450 (CYP450) isozymes is involved in the regulation of these effects in chick liver. One-day-old male broilers (n = 120) were divided into four groups and used in a two by two factorial trial in which the main factors included supplementing AFB₁ (< 5 vs. 100 μg/kg) and CM (0 vs. 150 mg/kg) in a corn/soybean-based diet...
November 10, 2016: Toxins
https://www.readbyqxmd.com/read/27834819/synthesis-and-pharmacological-evaluation-of-novel-pleuromutilin-derivatives-with-substituted-benzimidazole-moieties
#12
Xin Ai, Xiuying Pu, Yunpeng Yi, Yu Liu, Shuijin Xu, Jianping Liang, Ruofeng Shang
A series of novel pleuromutilin derivatives with substituted benzimidazole moieties were designed and synthesized from pleuromutilin and 5-amino-2-mercaptobenzimidazole through sequential reactions. All the newly synthesized compounds were characterized by IR, NMR, and HRMS. Each of the derivatives was evaluated in vitro for their antibacterial activity against Escherichia coli (E. coli) and five Gram (+) inoculums. 14-O-((5-amino-benzimidazole-2-yl) thioacetyl) mutilin (3) was the most active compound and showed highest antibacterial activities...
November 8, 2016: Molecules: a Journal of Synthetic Chemistry and Natural Product Chemistry
https://www.readbyqxmd.com/read/27822600/clarithromycin-midazolam-and-digoxin-application-of-pbpk-modeling-to-gain-new-insights-into-drug-drug-interactions-and-co-medication-regimens
#13
Daniel Moj, Nina Hanke, Hannah Britz, Sebastian Frechen, Tobias Kanacher, Thomas Wendl, Walter Emil Haefeli, Thorsten Lehr
Clarithromycin is a substrate and mechanism-based inhibitor of cytochrome P450 (CYP) 3A4 as well as a substrate and competitive inhibitor of P-glycoprotein (P-gp) and organic anion-transporting polypeptides (OATP) 1B1 and 1B3. Administered concomitantly, clarithromycin causes drug-drug interactions (DDI) with the victim drugs midazolam (CYP3A4 substrate) and digoxin (P-gp substrate). The objective of the presented study was to build a physiologically based pharmacokinetic (PBPK) DDI model for clarithromycin, midazolam, and digoxin and to exemplify dosing adjustments under clarithromycin co-treatment...
November 7, 2016: AAPS Journal
https://www.readbyqxmd.com/read/27821711/low-potential-of-basimglurant-to-be-involved-in-drug-drug-interactions-influence-of-non-michaelis-menten-cyp-kinetics-on-fraction-metabolized
#14
Stephen M Fowler, Elena Guerini, NaHong Qiu, Yumi Cleary, Neil J Parrott, Gerard Greig, Navita L Mallalieu
Basimglurant, a novel mGlu5 negative allosteric modulator under development for the treatment of major depressive disorder, is cleared via cytochrome P450 (CYP) mediated oxidative metabolism. Initial enzyme phenotyping studies indicated that CYP3A4/5 dominated basimglurant metabolism and highlighted a risk for drug-drug interactions when comedicated with strong CYP3A4/5 inhibitors or inactivators. However, a clinical drug-drug interaction (DDI) study using the potent and selective CYP3A4/5 inhibitor ketoconazole resulted in an AUCi/AUC ratio of only 1...
November 7, 2016: Journal of Pharmacology and Experimental Therapeutics
https://www.readbyqxmd.com/read/27821437/curcumin-piperine-and-capsaicin-a-comparative-study-of-spice-mediated-inhibition-of-human-cytochrome-p450-isozyme-activities
#15
Suhaili Shamsi, Huong Tran, Renee Siok Jin Tan, Zee Jian Tan, Lee Yong Lim
Inhibition of the cytochrome P450 (CYP) enzymes has been shown to enhance the metabolism of drugs that are CYP substrates, and to consequently alter their pharmacokinetic profiles. Curcumin (CUR), piperine (PIP) and capsaicin (CAP) are spice components (SC) that inhibit the activities of a range of CYP enzymes, but the selection of which SC to be prioritised for further development as adjuvant will depend on the ranking order of inhibitory potential of the SCs on specific CYP isozymes. This paper aimed to utilise common human recombinant enzyme platforms to provide a comparative evaluation of the inhibitory activities of CUR, PIP and CAP on the principal drug-metabolising CYP enzymes...
November 7, 2016: Drug Metabolism and Disposition: the Biological Fate of Chemicals
https://www.readbyqxmd.com/read/27819189/inhibitory-effects-of-curculigoside-on-human-liver-cytochrome-p450-enzymes
#16
Jixiao Lang, Wei Li, Jingming Zhao, Kaiyou Wang, Dexi Chen
1. Curculigoside possesses numerous pharmacological activities, and however, little data available for the effects of curculigoside on the activity of human liver cytochrome P450 (CYP) enzymes. 2. This study investigates the inhibitory effects of curculigoside on the main human liver CYP isoforms. In this study, the inhibitory effects of curculigoside on the eight human liver CYP isoforms 1A2, 2A6, 2E1, 2D6, 2C9, 2C19, 2C8, and 3A4 were investigated in human liver microsomes. 3. The results indicated that curculigoside could inhibit the activity of CYP1A2, CYP2C8, and CYP3A4, with IC50 values of 15...
November 5, 2016: Xenobiotica; the Fate of Foreign Compounds in Biological Systems
https://www.readbyqxmd.com/read/27809336/polymorphisms-in-cyp1a1-and-cyp3a5-genes-contribute-to-the-variability-in-granisetron-clearance-and-exposure-in-pregnant-women-with-nausea-and-vomiting
#17
Martha L Bustos, Yang Zhao, Huijun Chen, Steve N Caritis, Raman Venkataramanan
BACKGROUND: Nausea and vomiting affect up to 90% of pregnant women. Granisetron is a potent and highly selective serotonin receptor antagonist and is an effective antiemetic. Findings from a prior study in pregnant women demonstrated a large iner-individual variability in granisetron exposure. Granisetron is primarily metabolized by the cytochrome P450 (CYP) enzymes CYP1A1 and CYP3A and is likely a substrate of the ABCB1 transporter. Single-nucleotide polymorphisms (SNPs) in CYP3A, CYP1A1 and ABCB1 can alter drug metabolism...
November 3, 2016: Pharmacotherapy
https://www.readbyqxmd.com/read/27799217/population-pharmacokinetics-and-pharmacogenetics-analysis-of-rilpivirine-in-hiv-1-infected-individuals
#18
Manel Aouri, Catalina Barcelo, Monia Guidi, Margalida Rotger, Matthias Cavassini, Cédric Hizrel, Thierry Buclin, Laurent A Decosterd, Chantal Csajka
BACKGROUND: Rilpivirine (RPV), the latest non nucleoside reverse transcriptase inhibitor active against HIV-1, is prescribed in a standard dosage of 25 mg once a day in combination with emtricitabine (FTC) and tenofovir disoproxil fumarate (TDF). The aim of this observational study was to characterize RPV pharmacokinetic profile, to quantify interpatient variability and to identify potential factors that could influence drug exposure. METHODS: RPV concentrations data were collected from HIV patients as part of routine therapeutic drug monitoring performed in our centre...
October 31, 2016: Antimicrobial Agents and Chemotherapy
https://www.readbyqxmd.com/read/27798211/daclatasvir-30-mg-day-is-the-correct-dose-for-patients-taking-atazanavir-cobicistat
#19
E J Smolders, E P H Colbers, C T M M de Kanter, K Velthoven-Graafland, J P H Drenth, D M Burger
BACKGROUND: Atazanavir is boosted with the cytochrome P450 (CYP) 3A4 inhibitor ritonavir. When combined with the CYP3A4 substrate daclatasvir, the daclatasvir dosage should be reduced from 60 to 30 mg once daily. Recently, cobicistat was licensed as a CYP3A booster and used with atazanavir. OBJECTIVES: To determine whether the fixed-dose combination of atazanavir/cobicistat has an influence on daclatasvir pharmacokinetics comparable to that of the separate agents atazanavir and ritonavir...
October 20, 2016: Journal of Antimicrobial Chemotherapy
https://www.readbyqxmd.com/read/27789970/pharmacogenetic-polymorphism-as-an-independent-risk-factor-for-frequent-hospitalizations-in-older-adults-with-polypharmacy-a-pilot-study
#20
Joseph Finkelstein, Carol Friedman, George Hripcsak, Manuel Cabrera
Pharmacogenetic testing identifies genetic biomarkers that are predictive of individual sensitivity to particular drugs. A significant proportion of medications that are widely prescribed for older adults are metabolized by enzymes that are encoded by highly polymorphic genes. Pharmacogenetic testing is increasingly used to optimize the medication regimen; however, its potential in older adults with polypharmacy has not been systematically explored. Following the initial case-series study, this study hypothesized that frequently hospitalized older adults with polypharmacy have higher frequency of pharmacogenetic polymorphism as compared to older adults with polypharmacy who are rarely admitted to a hospital...
2016: Pharmacogenomics and Personalized Medicine
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