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CYP3A4/5

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https://www.readbyqxmd.com/read/29043584/determination-of-the-human-cytochrome-p450-monooxygenase-catalyzing-the-enantioselective-oxidation-of-2-2-3-5-6-pentachlorobiphenyl-pcb-95-and-2-2-3-4-4-5-6-heptachlorobiphenyl-pcb-183
#1
Haruna Nagayoshi, Kensaku Kakimoto, Yoshimasa Konishi, Keiji Kajimura, Takeshi Nakano
2,2',3,5',6-Pentachlorobiphenyl (PCB 95) and 2,2',3,4,4',5',6-heptachlorobiphenyl (PCB 183) possess axial chirality and form the aS and aR enantiomers. The enantiomers of these congeners have been reported to accumulate in the human body enantioselectively via unknown mechanisms. In this study, we determined the cytochrome P450 (CYP) monooxygenase responsible for the enantioselective oxidization of PCB 95 and PCB 183, using a recombinant human CYP monooxygenase. We evaluated 13 CYP monooxygenases, namely CYP1A1, CYP1A2, CYP1B1, CYP2A6, CYP2B6, CYP2C8, CYP2C19, CYP2E1, CYP2J2, CYP3A4, CYP3A5, CYP4F2, and aromatase (CYP19), and revealed that CYP2A6 preferably oxidizes aS-PCB 95 enantioselectively; however, it did not oxidize PCB 183...
October 17, 2017: Environmental Science and Pollution Research International
https://www.readbyqxmd.com/read/29043387/cyp3a-genotypes-of-donors-but-not-those-of-the-patients-increase-the-risk-of-acute-rejection-in-renal-transplant-recipients-on-calcineurin-inhibitors-a-pilot-study
#2
Guillermo Gervasini, Guadalupe García-Pino, Esther Vergara, Sonia Mota-Zamorano, Montserrat García-Cerrada, Enrique Luna
PURPOSE: We aimed to determine whether polymorphisms in CYP3A genes may affect the risk of acute rejection episodes (ARE) in renal transplant recipients treated with calcineurin inhibitors (CNIs). METHODS: One hundred and thirty seven patients and their respective donors were screened, by RT-PCR techniques, for three polymorphisms previously related with CNI pharmacokinetics and pharmacodynamics (CYP3A4*1B, CYP3A4*22 and CYP3A5*3). Genotypes of donors and recipients were associated by logistic regression models with ARE risk and exposure to CNIs...
October 18, 2017: European Journal of Clinical Pharmacology
https://www.readbyqxmd.com/read/29038231/evaluation-of-clinical-drug-interaction-potential-of-clofazimine-using-static-and-dynamic-modeling-approaches
#3
Ramachandra Sangana, Helen Gu, Dung Yu Chun, Heidi J Einolf
The 2016 World Health Organization treatment recommendations for drug-resistant tuberculosis (DR-TB) positioned clofazimine as a core second-line drug. Being identified as a cytochrome P450 (CYP) inhibitor in vitro, a CYP-mediated drug interaction may be likely when clofazimine is co-administered with substrates of these enzymes. The CYP-mediated drug interaction potential of clofazimine was evaluated using both static (estimation of "R1" and area under the plasma concentration-time curve ratio [AUCR] values) and dynamic (physiologically based pharmacokinetic [PBPK]) modeling approaches...
October 16, 2017: Drug Metabolism and Disposition: the Biological Fate of Chemicals
https://www.readbyqxmd.com/read/29027194/predictive-performance-of-physiologically-based-pharmacokinetic-pbpk-modeling-of-drugs-extensively-metabolized-by-major-cytochrome-p450s-in-children
#4
Wangda Zhou, Trevor N Johnson, Khanh H Bui, S Y Amy Cheung, Jianguo Li, Hongmei Xu, Nidal Al-Huniti, Diansong Zhou
The accuracy of physiologically-based pharmacokinetic (PBPK) model prediction in children, especially those younger than 2 years old has not been systematically evaluated. The aim of this study was to characterize the pediatric predictive performance of the PBPK approach for ten drugs extensively metabolized by CYP1A2 (theophylline), CYP2C8 (desloratidine, montelukast), CYP2C9 (diclofenac), CYP2C19 (esomeprazole, lansoprazole), CYP2D6 (tramadol) and CYP3A4 (itraconazole, ondansetron, sufentanil). Model performance in children was evaluated by comparing simulated plasma concentration-time profiles with observed clinical results for each drug and age group...
October 13, 2017: Clinical Pharmacology and Therapeutics
https://www.readbyqxmd.com/read/29022184/effects-of-ketoconazole-on-the-pharmacokinetics-of-mifepristone-a-competitive-glucocorticoid-receptor-antagonist-in-healthy-men
#5
Dat Nguyen, Sarah Mizne
INTRODUCTION: Mifepristone, a competitive glucocorticoid receptor antagonist approved for Cushing syndrome, and ketoconazole, an antifungal and steroidogenesis inhibitor, are both inhibitors of and substrates for cytochrome P450 (CYP3A4). This study evaluated the pharmacokinetic effects of concomitant ketoconazole, a strong CYP3A4 inhibitor, on mifepristone. METHODS: In an open-label, two-period, single-center study, healthy adult men received mifepristone 600 mg orally daily for 12 days (period 1) followed by mifepristone 600 mg daily plus ketoconazole 200 mg orally twice daily for 5 days (period 2)...
October 11, 2017: Advances in Therapy
https://www.readbyqxmd.com/read/28990182/effect-of-chronic-kidney-disease-on-nonrenal-elimination-pathways-a-systematic-assessment-of-cyp1a2-cyp2c8-cyp2c9-cyp2c19-and-oatp
#6
Ming-Liang Tan, Kenta Yoshida, Ping Zhao, Lei Zhang, Thomas D Nolin, Micheline Piquette-Miller, Aleksandra Galetin, Shiew-Mei Huang
Our recent studies have shown that chronic kidney disease (CKD) affects the pharmacokinetics (PKs) of cytochrome P450 (CYP)2D6-metabolized drugs, whereas effects were less evident on CYP3A4/5. Therefore, the effect of CKD on the disposition of CYP1A2-metabolized, CYP2C8-metabolized, CYP2C9-metabolized, CYP2C19-metabolized, and organic anion-transporting polypeptide (OATP)-transported drugs was investigated. We identified dedicated CKD studies with 6, 5, 6, 4, and 12 "model" substrates for CYP1A2, CYP2C8, CYP2C9, CYP2C19, and OATP, respectively...
October 9, 2017: Clinical Pharmacology and Therapeutics
https://www.readbyqxmd.com/read/28986474/digging-deeper-into-cyp3a-testosterone-metabolism-kinetic-regio-and-stereoselectivity-differences-between-cyp3a4-5-and-cyp3a7
#7
Sylvie E Kandel, Lyrialle W Han, Qingcheng Mao, Jed N Lampe
The metabolism of testosterone to 6β-hydroxytestosterone is a commonly used assay to evaluate human CYP3A enzyme activities. However, previous reports have indicated that CYP3A7 also produces 2α-hydroxytestosterone, and that a 2α-hydroxytestosterone:6β-hydroxytestosterone ratio may be a unique biomarker of the isozyme's activity. Until now, the full metabolite and kinetic profile for testosterone hydroxylation by CYP3A7 has not been fully examined. To this end, we performed a complete kinetic analysis of the 6β-hydroxytestosterone, 2α-hydroxytestosterone and 2β-hydroxytestosterone metabolites for recombinant SupersomeTM CYP3A4, 3A5, and 3A7 enzymes and monitored metabolism in fetal and adult human liver microsomes for comparison...
October 6, 2017: Drug Metabolism and Disposition: the Biological Fate of Chemicals
https://www.readbyqxmd.com/read/28975417/effects-of-food-and-grapefruit-juice-on-single-dose-pharmacokinetics-of-blonanserin-in-healthy-chinese-subjects
#8
De-Wei Shang, Zhan-Zhang Wang, Hai-Tang Hu, Yue-Feng Zhang, Xiao-Jia Ni, Hao-Yang Lu, Ming Zhang, Jin-Qing Hu, Chang Qiu, Huan Peng, Ling-Fang Shen, Yu-Guan Wen
PURPOSE: The purpose of this study was to investigate the potential effects of a meal and grapefruit juice on the pharmacokinetics of blonanserin and its metabolite N-desethyl blonanserin in healthy Chinese volunteers. METHODS: This was a single-centre, open-label, fixed-sequence study, where 12 healthy Chinese volunteers received a single dose of 8 mg blonanserin after an overnight fast in period 1 (reference), a high-fat meal during period 2 and with co-administration of 250 mL of grapefruit juice in period 3...
October 3, 2017: European Journal of Clinical Pharmacology
https://www.readbyqxmd.com/read/28971609/coffee-inhibition-of-cyp3a4-in%C3%A2-vitro-was-not-translated-to-a-grapefruit-like-pharmacokinetic-interaction-clinically
#9
George K Dresser, Brad L Urquhart, Julianne Proniuk, Alvin Tieu, David J Freeman, John Malcolm Arnold, David G Bailey
Grapefruit can augment oral medication bioavailability through irreversible (mechanism-based) inhibition of intestinal CYP3A4. Supplementary data from our recent coffee-drug interaction clinical study showed some subjects had higher area under the plasma drug concentration - time curve (AUC) and plasma peak drug concentration (Cmax) of the CYP3A4 probe felodipine compared to aqueous control. It was hypothesized that coffee might interact like grapefruit in responsive individuals. Beans from six geographical locations were consistently brewed into coffee that was separated chromatographically to a methanolic fraction for in vitro inhibition testing of CYP3A4 metabolism of felodipine at 1% coffee strength...
October 2017: Pharmacology Research & Perspectives
https://www.readbyqxmd.com/read/28967981/pharmacokinetic-drug-interactions-of-apatinib-with-rifampin-and-itraconazole
#10
Xiaoyun Liu, Yifan Zhang, Qian Chen, Yan Zhan, Quanren Wang, Chaoying Hu, Chen Yu, Zitao Guo, Xiaoyan Chen, Dafang Zhong
Apatinib is a small-molecule tyrosine kinase inhibitor that has been approved for the treatment of patients with advanced-stage gastric cancer or gastroesophageal junction cancer who have progressed or recurred after at least 2 kinds of systemic chemotherapy. In vitro data indicate that cytochrome P450 (CYP) 3A4 is the primary CYP isoenzyme involved in the metabolism of apatinib. Pharmacokinetic drug-drug interactions of apatinib and (1) a CYP3A4 inducer (rifampin) or (2) a CYP3A inhibitor (itraconazole) were clinically evaluated in healthy volunteers...
October 2, 2017: Journal of Clinical Pharmacology
https://www.readbyqxmd.com/read/28962866/in-vitro-metabolism-of-4-5-dimethoxycanthin-6-one-by-human-liver-microsomes-and-its-inhibition-on-human-cyp1a2
#11
Xiaolei Miao, Jiaojiao You, Junjun Wang, Yong Chen
AIMS: P. quassioides is a traditional Chinese medicine used for the treatment of gastroenteritis, snakebite, infection and hypertension in China. 4, 5-dimethoxycanthin-6-one is one of the main active canthinone alkaloid isolated from P. quassioides. The aim of this work was to identify the cytochrome P (CYP) 450 enzymes responsible for the metabolism of 4, 5-dimethoxycanthin-6-one (DCO) and to evaluate the inhibitory effect of DCO on CYP activity in human liver microsomes (HLM) in vitro...
September 26, 2017: Life Sciences
https://www.readbyqxmd.com/read/28962047/comparison-of-1%C3%A2-mg-versus-2%C3%A2-mg-dexamethasone-suppression-test-in-patients-with-obesity
#12
Sandrine Andrea Urwyler, Nina Cupa, Mirjam Christ-Crain
In this study, we compared the 2 mg dexamethasone suppression test (DST) with the gold-standard 1 mg DST in obese patients in order to reduce the false-positive rate for Cushing's syndrome (CS). The primary endpoint was the comparison of serum cortisol levels after 1 mg versus 2 mg DST in patients with a BMI >30 kg/m(2) and at least one additional feature of the metabolic syndrome. Secondary endpoints were comparison of salivary cortisol and ACTH levels, respectively. Fifty-four obese patients were included...
September 29, 2017: Hormone and Metabolic Research, Hormon- und Stoffwechselforschung, Hormones et Métabolisme
https://www.readbyqxmd.com/read/28958437/a-thorough-qt-qtc-study-of-clobazam-in-healthy-volunteers
#13
Dwain Tolbert, Judy Gordon, Stuart Harris, Mark Walzer, Ihor Bekersky, Susan Reid
PURPOSE: A thorough QT study was conducted to assess the proarrhythmic potential of clobazam and its active metabolite, N-desmethylclobazam (N-CLB). METHODS: In this Phase I, single-site, randomized, double-blind, double-dummy, parallel-group study, healthy participants were randomized to 1 of 4 treatment groups: clobazam 40 mg/d (maximum therapeutic dosage), clobazam 160 mg/d (supratherapeutic dosage), placebo, or moxifloxacin 400 mg (active control). FINDINGS: Of 280 enrolled participants (n = 70 per treatment arm), 250 (92%) completed the study; 194 were included in the pharmacokinetics population (clobazam 40 mg/d, n = 66; clobazam 160 mg/d, n = 62; and moxifloxacin, n = 66)...
September 25, 2017: Clinical Therapeutics
https://www.readbyqxmd.com/read/28945481/long-term-influence-of-cyp3a5-cyp3a4-abcb1-and-nr1i2-polymorphisms-on-tacrolimus-concentration-in-chinese-renal-transplant-recipients
#14
Fei Liu, Yang-Meng Ou, Ai-Rong Yu, Lei Xiong, Hua-Wen Xin
BACKGROUND: The highly pharmacokinetic variability of tacrolimus makes it difficult to adjust the dose. In the current study, we investigated the influence of gene polymorphisms and other clinical factors on long-term tacrolimus dosing in Chinese renal transplant recipients. METHODS: A total of 276 renal transplant recipients were enrolled. The tacrolimus trough concentration and other clinical variables were recorded for 5 years following transplantation. Eight single nucleotide polymorphisms in four genes (CYP3A5, CYP3A4, ABCB1, and NR1I2) were genotyped using polymerase chain reaction-restriction fragment length polymorphism analysis and sequencing...
September 25, 2017: Genetic Testing and Molecular Biomarkers
https://www.readbyqxmd.com/read/28945011/prediction-of-drug-drug-interaction-between-tacrolimus-and-principal-ingredients-of-wuzhi-capsule-in-chinese-healthy-volunteers-using-physiologically-based-pharmacokinetic-modelling
#15
Hongyan Zhang, Fengjiao Bu, Lei Li, Zheng Jiao, Guo Ma, Weimin Cai, Xiaomei Zhuang, Hai-Shu Lin, Jae-Gook Shin, Xiaoqiang Xiang
Schisantherin A and schisandrin A, the most abundant active ingredients of Wuzhi capsule, are known to inhibit tacrolimus metabolism by inhibiting CYP3A4/5. We aimed to predict the contribution of schisantherin A and schisandrin A to drug-drug interaction (DDI) between Wuzhi capsule and tacrolimus using physiologically-based pharmacokinetic (PBPK) modelling. Firstly, the inhibition mechanism of schisantherin A and schisandrin A on CYP3A4/5 were investigated. Thereafter, PBPK models of schisantherin A, schisandrin A and tacrolimus were established...
September 25, 2017: Basic & Clinical Pharmacology & Toxicology
https://www.readbyqxmd.com/read/28929404/rolapitant-a-review-in-chemotherapy-induced-nausea-and-vomiting
#16
Young-A Heo, Emma D Deeks
Oral rolapitant (Varubi™; Varuby(®)), a long-acting neurokinin-1 (NK1) receptor antagonist (RA), is indicated in the USA and EU as part of an antiemetic regimen to prevent delayed chemotherapy-induced nausea and vomiting (CINV) in adults receiving highly or moderately emetogenic chemotherapy (HEC or MEC). In randomized, phase III trials, a single oral dose of rolapitant 180 mg was effective in preventing delayed CINV compared with placebo, when each was used in combination with a 5-HT3 RA plus dexamethasone, in adults receiving their first course of HEC or MEC...
September 20, 2017: Drugs
https://www.readbyqxmd.com/read/28915658/oxidative-stress-mediates-an-increased-formation-of-vascular-endothelial-growth-factor-in-human-hepatocarcinoma-cells-exposed-to-erlotinib
#17
Nataliya Rohr-Udilova, Florian Klinglmüller, Martha Seif, Hubert Hayden, Martin Bilban, Matthias Pinter, Klaus Stolze, Wolfgang Sieghart, Markus Peck-Radosavljevic, Michael Trauner
The tyrosine kinase inhibitor erlotinib targets the receptor of epidermal growth factor (EGFR) involved in development of hepatocellular carcinoma (HCC). Although inefficient in established HCC, erlotinib has been recently proposed for HCC chemoprevention. Since Cyp3A4 and Cyp1A2 enzymes metabolize erlotinib in the liver, the insights into the mechanisms of erlotinib effects on liver cells with maintained drug metabolizing activity are needed. We applied erlotinib to both commercially available (SNU398, Huh7) and established in Austria HCC cell lines (HCC-1...
August 22, 2017: Oncotarget
https://www.readbyqxmd.com/read/28914344/influence-of-genetic-co-factors-on-the-population-pharmacokinetic-model-for-clopidogrel-and-its-active-thiol-metabolite
#18
Dorota Danielak, Marta Karaźniewicz-Łada, Anna Komosa, Paweł Burchardt, Maciej Lesiak, Łukasz Kruszyna, Agnieszka Graczyk-Szuster, Franciszek Główka
PURPOSE: A high interindividual variability is observed in the pharmacokinetics of clopidogrel, a widely used antiplatelet drug. In the present study, a joint parent-metabolite population pharmacokinetic model was developed to adequately describe observed concentrations of clopidogrel and its active thiol metabolite (H4). METHODS: The study included 63 patients undergoing elective coronarography or percutaneous coronary intervention. The population pharmacokinetic model was developed in the NONMEM 7...
September 15, 2017: European Journal of Clinical Pharmacology
https://www.readbyqxmd.com/read/28912253/physiologically-based-pharmacokinetic-model-predictions-of-panobinostat-lbh589-as-a-victim-and-perpetrator-of-drug-drug-interactions
#19
Heidi J Einolf, Wen Lin, Christina S Won, Lai Wang, Helen Gu, Dung Yu Chun, Handan He, James B Mangold
Panobinostat (Farydak®) is an orally active hydroxamic acid derived histone deacetylase inhibitor for the treatment of relapsed/refractory multiple myeloma. Based upon recombinant cytochrome P450 (CYP) kinetic analyses in vitro, panobinostat oxidative metabolism in human liver microsomes was found to be primarily mediated by CYP3A4 with lower contributions by CYP2D6 and CYP2C19. Panobinostat was also shown to be an in vitro reversible and time-dependent inhibitor of CYP3A4/5, and a reversible inhibitor of CYP2D6 and CYP2C19...
September 14, 2017: Drug Metabolism and Disposition: the Biological Fate of Chemicals
https://www.readbyqxmd.com/read/28900995/-association-between-genetic-polymorphisms-and-variation-of-imatinib-pharmacokinetics-in-gastrointestinal-stromal-tumors
#20
Haibo Qiu, Wei Zhuang, Xueding Wang, Min Huang, Zhiwei Zhou
OBJECTIVE: To investigate the influence of metabolic enzymes polymorphisms on variations of imatinib (IM) pharmacokinetics in gastrointestinal stromal tumors (GIST) patients. METHODS: Clinical data of 118 Chinese GIST patients receiving 400 mg/d IM at Sun Yat-sen University Cancer Center between 2014 and 2016 were retrospectively analyzed. The plasma concentration of imatinib mesylate(IM) and its main metabolic N-demethyl imatinib (NDI) were determined by LC-MS/MS...
September 25, 2017: Zhonghua Wei Chang Wai Ke za Zhi, Chinese Journal of Gastrointestinal Surgery
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