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CYP3A4/5

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https://www.readbyqxmd.com/read/28087064/effect-of-cyp2d6-polymorphisms-on-the-pharmacokinetics-of-propafenone-and-its-two-main-metabolites
#1
Mohammad-Reza Rouini, Minoo Afshar
AIM OF THE STUDY: Propafenone (PPF) is an antiarrhythmic drug, metabolized mainly by CYP2D6 to 5-hydroxypropafenone (5OH-PPF) and by CYP3A4 to norpropafenone (NOR-PPF). CYP2D6 shows a high degree of genetic polymorphism which is associated with diminished antiarrhythmic efficacy or cardiac seizures/cardiotoxicity. This study aimed to investigate the effect of the CYP2D6 polymorphism on the pharmacokinetics of PPF and its two main metabolites. The usefulness of PPF/5OH-PPF ratio for CYP2D6 phenotyping in healthy adults was also evaluated...
December 19, 2016: Thérapie
https://www.readbyqxmd.com/read/28074333/rosiglitazone-metabolism-in-human-liver-microsomes-using-a-substrate-depletion-method
#2
Maryam Bazargan, David J R Foster, Andrew K Davey, Beverly S Muhlhausler
BACKGROUND: Elimination of rosiglitazone in humans is via hepatic metabolism. The existing studies suggest that CYP2C8 is the major enzyme responsible, with a minor contribution from CYP2C9; however, other studies suggest the involvement of additional cytochrome P450 enzymes and metabolic pathways. Thus a full picture of rosiglitazone metabolism is unclear. OBJECTIVE: This study aimed to improve the current understanding of potential drug-drug interactions and implications for therapy by evaluating the kinetics of rosiglitazone metabolism and examining the impact of specific inhibitors on its metabolism using the substrate depletion method...
January 10, 2017: Drugs in R&D
https://www.readbyqxmd.com/read/28073119/in-vitro-inhibition-of-human-cyp450s-1a2-2c9-3a4-5-2d6-and-2e1-by-grandisin
#3
Maísa Daniela Habenschus, Fernanda de Lima Moreira, Norberto Peporine Lopes, Anderson R M de Oliveira
Grandisin, a lignan isolated from many species of plants, such as Virola surinamensis, is a potential drug candidate due to its biological properties, highlighted by its antitumor and trypanocidal activities. In this study, the inhibitory effects of grandisin on the activities of human cytochrome P450 enzymes were investigated by using human liver microsomes. Results showed that grandisin is a competitive inhibitor of CYP2C9 and a competitive and mechanism-based inhibitor of CYP3A4/5. The apparent Ki value for CYP2C9 was 50...
January 10, 2017: Planta Medica
https://www.readbyqxmd.com/read/28050888/a-new-cyp3a5-3-and-cyp3a4-22-cluster-influencing-tacrolimus-target-concentrations-a-population-approach
#4
Franc Andreu, Helena Colom, Laure Elens, Teun van Gelder, Ronald H N van Schaik, Dennis A Hesselink, Oriol Bestard, Joan Torras, Josep M Cruzado, Josep M Grinyó, Nuria Lloberas
BACKGROUND: Single nucleotide polymorphisms (SNPs) in the CYP3A5 and CYP3A4 genes have been reported to be an important cause of variability in the pharmacokinetics of tacrolimus in renal transplant patients. The aim of this study was to merge all of the new genetic information available with tacrolimus pharmacokinetics to generate a more robust population model with data from renal transplant recipients. METHODS: Tacrolimus exposure data from 304 renal transplant recipients were collected throughout the first year after transplantation and were simultaneously analyzed with a population pharmacokinetic approach using NONMEM(®) version 7...
January 3, 2017: Clinical Pharmacokinetics
https://www.readbyqxmd.com/read/28049954/no-effect-of-slco1b1-and-cyp3a4-5-polymorphisms-on-the-pharmacokinetics-and-pharmacodynamics-of-ticagrelor-in-healthy-chinese-male-subjects
#5
Mupeng Li, Yaodong Hu, Huilan Li, Zhipeng Wen, Xiaolei Hu, Daoyu Zhang, Yanjiao Zhang, Jian Xiao, Jie Tang, Xiaoping Chen
Ticagrelor is a direct-acting P2Y12 receptor antagonist. It is rapidly absorbed and partly metabolized to the active metabolite AR-C124910XX by CYP3A4 and CYP3A5. Three genetic loci (SLCO1B1, CYP3A4, and UGT2B7) were reported to affect ticagrelor pharmacokinetics. This study aimed to investigate the possible effects of SLCO1B1 and CYP3A4/5 genetic polymorphisms on the pharmacokinetics and pharmacodynamics of ticagrelor in healthy Chinese male volunteers. Eighteen healthy male volunteers who participated in pharmacogenetics study of ticagrelor were genotyped for SLCO1B1 rs113681054, SLCO1B1*5 (rs4149056), CYP3A4*1G (rs2242480), and CYP3A5*3 (rs776746)...
2017: Biological & Pharmaceutical Bulletin
https://www.readbyqxmd.com/read/28044353/donor-cyp3a5-genotype-influences-tacrolimus-disposition-on-the-first-day-after-paediatric-liver-transplantation
#6
Pier Luigi Calvo, Loredana Serpe, Andrea Brunati, Antonello Nonnato, Daniela Bongioanni, Dominic Dell Olio, Michele Pinon, Carlo Ferretti, Francesco Tandoi, Giulia Carbonaro, Mauro Salizzoni, Antonio Amoroso, Renato Romagnoli, Roberto Canaparo
AIM: The aim of our study was to investigate the influence of the CYP3A4/5 genotype in paediatric liver transplant recipients and donors and what contribution age and gender make to tacrolimus disposition on the first day after transplantation. METHODS: The contribution of the CYP3A4/5 genotype in paediatric liver transplant recipients and donors to the tacrolimus blood trough concentrations (C0 ) and tacrolimus concentration/weight-adjusted dose ratio on day one was evaluated in 67 liver transplanted children: 33 boys and 34 girls, mean age 4...
January 3, 2017: British Journal of Clinical Pharmacology
https://www.readbyqxmd.com/read/28042936/effect-of-type-2-diabetes-mellitus-on-the-pharmacokinetics-and-transplacental-transfer-of-nifedipine-in-hypertensive-pregnant-women
#7
Gabriela Campos de Oliveira Filgueira, Osmany Alberto Silva Filgueira, Daniela Miarelli Carvalho, Maria Paula Marques, Elaine Christine Dantas Moisés, Geraldo Duarte, Vera Lucia Lanchote, Ricardo Carvalho Cavalli
AIMS: Diabetes mellitus can inhibit CYP3A4, an enzyme responsible for the metabolism of nifedipine, used for the treatment of hypertension in pregnant women. We aimed to assess the effect of type 2 diabetes mellitus (T2DM) on the pharmacokinetics, placental transfer and distribution of nifedipine in amniotic fluid in hypertensive pregnant women. METHODS: The study was conducted on 12 hypertensive pregnant women (control group - CG) and 10 hypertensive pregnant women with T2DM taking slow-release nifedipine (20 mg, 12/12 hours)...
January 2, 2017: British Journal of Clinical Pharmacology
https://www.readbyqxmd.com/read/27995989/pharmacogenetic-variants-associated-with-outcome-in-patients-with-advanced-gastric-cancer-treated-with-fluoropyrimidine-and-platinum-based-triplet-combinations-a-pooled-analysis-of-three-prospective-studies
#8
D Meulendijks, E A Rozeman, A Cats, K Sikorska, M Joerger, M J Deenen, J H Beijnen, J H M Schellens
The main treatment for advanced gastric cancer is fluoropyrimidine and platinum-based chemotherapy. We investigated the clinical validitiy of 19 candidate pharmacogenetic variants in ENOSF1 (enolase superfamily member 1), TYMS, CDA, MTHFR, TYMP, DPYD, ERCC1, ERCC2, GSTP1, GSTT1, GSTM1, CYP3A4 and CYP3A5 in relation to overall survival (OS), progression-free survival, objective response rate (ORR) and toxicity in 185 patients receiving triplet chemotherapy. The formal significance threshold was P<0.0026. TYMS VNTR (variable number of 28-bp tandem repeats) 3 R/3 R genotype was formally associated with inferior ORR (odds ratio (OR) 0...
December 20, 2016: Pharmacogenomics Journal
https://www.readbyqxmd.com/read/27991741/4%C3%AE-hydroxycholesterol-level-in-patients-with-rheumatoid-arthritis-before-vs-after-initiation-of-bdmards-and-correlation-with-inflammatory-state
#9
B M Wollmann, S W Syversen, E Lie, C Gjestad, L L Mehus, I C Olsen, E Molden
Systemic inflammation has been linked to suppressed CYP3A(4) activity. We determined 4β-hydroxycholesterol (4βOHC), an endogenous CYP3A4 metabolite, in patients with rheumatoid arthritis (RA) before and after treatment with biological disease-modifying antirheumatic drugs (bDMARDs). The 4βOHC was compared in 41 patients before and 2-5 months after initiating TNFα inhibitors (n = 31), IL-6 inhibitors (n = 5), or B-cell inhibitors (n = 5). Correlations between 4βOHC and inflammatory markers (C-reactive protein (CRP) and erythrocyte sedimentation rate (ESR)) were also tested before and after bDMARDs...
November 5, 2016: Clinical and Translational Science
https://www.readbyqxmd.com/read/27988088/biotransformation-of-bromhexine-by-cunninghamella-elegans-c-echinulata-and-c-blakesleeana
#10
Aman K Dube, Maushmi S Kumar
Fungi is a well-known model used to study drug metabolism and its production in in vitro condition. We aim to screen the most efficient strain of Cunninghamella sp. among C. elegans, C. echinulata and C. blakesleeana for bromhexine metabolites production. We characterized the metabolites produced using various analytical tools and compared them with mammalian metabolites in Rat liver microsomes (RLM). The metabolites were collected by two-stage fermentation of bromhexine with different strains of Cunninghamella sp...
December 5, 2016: Brazilian Journal of Microbiology: [publication of the Brazilian Society for Microbiology]
https://www.readbyqxmd.com/read/27974381/difference-in-mechanism-based-inhibition-of-cytochrome-p450-3a4-and-3a5-by-a-series-of-fluoroquinolone-antibacterial-agents
#11
Akiko Watanabe, Hideo Takakusa, Takako Kimura, Shin-Ichi Inoue, Hiroyuki Kusuhara, Osamu Ando
A series of fluoroquinolone antibacterial compounds were found to be irreversible (compounds 1 - 5) and quasi-irreversible (compounds 6 - 9) inhibitors of cytochrome P450 3A4 (CYP3A4). The purpose of this study was to evaluate their mechanism-based inhibition (MBI) potency against CYP3A5. Compounds 1 - 5 were also irreversible inhibitors of CYP3A5, whereas compounds 6 - 9 showed neither irreversible nor quasi-irreversible inhibition of CYP3A5. Compounds 6 and 8 did not form a metabolite-intermediate (MI) complex with the heme of CYP3A5 during incubation...
December 14, 2016: Drug Metabolism and Disposition: the Biological Fate of Chemicals
https://www.readbyqxmd.com/read/27955884/pharmacogenetics-guided-analgesics-in-major-abdominal-surgery-further-benefits-within-an-enhanced-recovery-protocol
#12
Anthony J Senagore, Bradley J Champagne, Eslam Dosokey, Justin Brady, Scott R Steele, Harry L Reynolds, Sharon L Stein, Conor P Delaney
OBJECTIVE: Effective, narcotic sparing analgesia is a major component of Enhanced Recovery Protocols (ERP), however the risk of poor analgesia and opioid related side effects (ORADE) remains an issue related to poor outcomes and satisfaction, and is strongly related to the risk of narcotic dependence after surgery. A variety of genes can impact narcotic and non-steroidal (NSAID) drug efficacy including: the CYP family (drug metabolism-narcotics and NSAID), or COMT/ABCB1/OPRM1 (functional receptor and transport activity for analgesia vs side effects)...
November 22, 2016: American Journal of Surgery
https://www.readbyqxmd.com/read/27942916/synergistic-disruption-of-er%C3%AE-her2-crosstalk-by-endoxifen-and-lapatinib-in-breast-cancer-cells
#13
James Chun Yip Chan, Pei Shi Ong, Peirong Lim, Preben Xiang Long Teng, Eric Chun Yong Chan
BACKGROUND: Despite decades of clinical success, tamoxifen therapy is complicated by inter-individual variability due to CYP450 polymorphism and resistance attributed to ERα/HER2 crosstalk. Direct administration of endoxifen shows promise in circumventing obligatory CYP450 bioactivation while maintaining efficacy. Separately, disruption of the crosstalk using probe antagonists against ERα (tamoxifen) and HER2 (e.g., lapatinib) has been explored clinically. However, the efficacy of this combination may be confounded by lapatinib, a potent inactivator of CYP3A4/5 which could negate the bioactivation of tamoxifen to the active metabolite endoxifen...
January 2017: Cancer Chemotherapy and Pharmacology
https://www.readbyqxmd.com/read/27935260/in-vitro-studies-on-flubromazolam-metabolism-and-detection-of-its-metabolites-in-authentic-forensic-samples
#14
Carolina Noble, Marie Mardal, Niels Bjerre Holm, Sys Stybe Johansen, Kristian Linnet
Flubromazolam is a triazole benzodiazepine with high potency and long-lasting central nervous system depressant effects; however, limited data about its pharmacokinetics are available. Here, we report in vitro studies of the human flubromazolam metabolism analyzed by liquid chromatography high-resolution mass spectrometry (LC-HRMS). In vitro investigations were carried out in pooled human liver microsomes (pHLM) and recombinant cytochrome P450 (CYP)-enzymes. To confirm those metabolites detected in vitro, authentic samples obtained from two forensic cases were also analyzed by LC-HRMS...
December 9, 2016: Drug Testing and Analysis
https://www.readbyqxmd.com/read/27933361/biotransformation-and-detectability-of-the-new-psychoactive-substances-n-n-diallyltryptamine-dalt-derivatives-5-fluoro-dalt-7-methyl-dalt-and-5-6-methylenedioxy-dalt-in-urine-using-gc-ms-lc-ms-n-and-lc-hr-ms-ms
#15
Julian A Michely, Simon D Brandt, Markus R Meyer, Hans H Maurer
Derivatives of N,N-diallyltryptamine (DALT) can be classified as new psychoactive substances. Biotransformation and detectability of 5-fluoro-DALT (5-F-DALT), 7-methyl-DALT (7-Me-DALT), and 5,6-methylenedioxy-DALT (5,6-MD-DALT) are described here. Their metabolites detected in rat urine and pooled human liver microsomes were identified by liquid chromatography (LC)-high resolution (HR)-tandem mass spectrometry (MS/MS). In addition, the human cytochrome-P450 (CYP) isoenzymes involved in the main metabolic steps were identified and detectability tested in urine by the authors' urine screening approaches using GC-MS, LC-MS(n), or LC-HR-MS/MS...
December 8, 2016: Analytical and Bioanalytical Chemistry
https://www.readbyqxmd.com/read/27928738/effect-of-multiple-oral-doses-of-the-potent-cyp3a4-inhibitor-clarithromycin-on-the-pharmacokinetics-of-a-single-oral-dose-of-vonoprazan-a-phase-i-open-label-sequential-design-study
#16
Helen Jenkins, Richard Jenkins, Alain Patat
BACKGROUND AND OBJECTIVES: This phase I, open-label, sequential design study assessed the effect of multiple oral doses of the potent cytochrome P450 (CYP) 3A4 inhibitor clarithromycin on the pharmacokinetics of a single oral dose of vonoprazan. METHODS: During the 10-day treatment period, 16 healthy male subjects received vonoprazan 40 mg on days 1 and 8, and clarithromycin 1000 mg on days 3-9, with the pharmacokinetics of both examined. Primary endpoints included the maximum observed plasma concentration (C max) and area under the plasma concentration-time curve (AUC) of vonoprazan and its major metabolites (M-I, M-II, M-III, and M-IV-Sul)...
December 7, 2016: Clinical Drug Investigation
https://www.readbyqxmd.com/read/27924364/metabolic-characterization-of-1-5-fluoropentyl-1h-indol-3-yl-4-methyl-1-naphthalenyl-methanone-mam-2201-using-human-liver-microsomes-and-cdna-overexpressed-cytochrome-p450-enzymes
#17
Tae Yeon Kong, Ju-Hyun Kim, Won Gu Choi, Joo Young Lee, Hee Seung Kim, Jin Young Kim, Moon Kyo In, Hye Suk Lee
MAM-2201 is a synthetic cannabinoid that is increasingly found in recreational drug abusers and cases of severe intoxication. Thus, characterization of the metabolic pathways of MAM-2201 is necessary to predict individual pharmacokinetics and toxicity differences, and to avoid toxic drug-drug interactions. Collectively, 19 phase 1 metabolites of MAM-2201 were identified using liquid chromatography-Orbitrap mass spectrometry following human liver microsomal incubations in the presence of NADPH: 7 hydroxy-MAM-2201 (M1-M7), 4 dihydroxy-MAM-2201 (M8-M11), dihydrodiol-MAM-2201 (M12), N-(5-hydroxypentyl)-MAM-2201 (M13), hydroxy-M13 (M14), N-dealkyl-MAM-2201 (M15), 2 hydroxy-M15 (M16, M17), MAM-2201 N-pentanoic acid (M18), and hydroxy-M18 (M19)...
December 6, 2016: Analytical and Bioanalytical Chemistry
https://www.readbyqxmd.com/read/27919007/challenges-in-assignment-of-allosteric-effects-in-cytochrome-p450-catalyzed-substrate-oxidations-to-structural-dynamics-in-the-hemoprotein-architecture
#18
Peter Hlavica
Cytochrome P450s (CYP) represent a superfamily of b-type hemoproteins catalyzing NAD(P)H-dependent oxidative biotransformation of a vast array of natural and xenobiotic compounds. Many eu- and prokaryotic members of this class of monooxygenases display complex non-Michaelis-Menten saturation kinetics, suggestive of homo-/heterotropic cooperativity arising from substrate-/effector-induced allosteric interactions. Here, the paradigm of multiple-ligand occupancy of the catalytic pocket in combination with enzyme oligomerization provides the most favored explanations for the atypical kinetic patterns...
February 2017: Journal of Inorganic Biochemistry
https://www.readbyqxmd.com/read/27915193/metabolic-fate-and-detectability-of-the-new-psychoactive-substances-2-4-bromo-2-5-dimethoxyphenyl-n-2-methoxyphenyl-methyl-ethanamine-25b-nbome-and-2-4-chloro-2-5-dimethoxyphenyl-n-2-methoxyphenyl-methyl-ethanamine-25c-nbome-in-human-and-rat-urine-by-gc-ms
#19
Achim T Caspar, Simon D Brandt, Andreas E Stoever, Markus R Meyer, Hans H Maurer
25B-NBOMe and 25C-NBOMe are potent 5-HT2A receptor agonists that have been associated with inducing hallucinogenic effects in drug users and severe intoxications. This paper describes the identification of their metabolites in rat and human urine by liquid chromatography (LC)-high resolution (HR)-MS/MS, the comparison of metabolite formation in vitro and in vivo and in different species, the general involvement of human cytochrome-P450 (CYP) isoenzymes on their metabolism steps, and their detectability by standard urine screening approaches (SUSAs) using GC-MS, LC-MS(n), or LC-HR-MS/MS...
February 5, 2017: Journal of Pharmaceutical and Biomedical Analysis
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
#20
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
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