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https://www.readbyqxmd.com/read/29160300/genome-wide-association-study-identifies-the-common-variants-in-cyp3a4-and-cyp3a5-responsible-for-variation-in-tacrolimus-trough-concentration-in-caucasian-kidney-transplant-recipients
#1
W S Oetting, B Wu, D P Schladt, W Guan, R P Remmel, R B Mannon, A J Matas, A K Israni, P A Jacobson
The immunosuppressant tacrolimus (TAC) is metabolized by both cytochrome P450 3A4 (CYP3A4) and CYP3A5 enzymes. It is common for European Americans (EA) to carry two CYP3A5 loss-of-function (LoF) variants that profoundly reduces TAC metabolism. Despite having two LoF alleles, there is still considerable variability in TAC troughs and identifying additional variants in genes outside of the CYP3A5 gene could provide insight into this variability. We analyzed TAC trough concentrations in 1345 adult EA recipients with two CYP3A5 LoF alleles in a genome-wide association study...
November 21, 2017: Pharmacogenomics Journal
https://www.readbyqxmd.com/read/29157826/modulation-of-pregnane-x-receptor-pxr-and-constitutive-androstane-receptor-car-activation-by-ursolic-acid-ua-attenuates-rifampin-isoniazid-cytotoxicity
#2
Hsiao-Yun Chang, Chao-Jung Chen, Wei-Chih Ma, Wai-Kok Cheng, Yen-Ning Lin, Ying-Ray Lee, Jih-Jung Chen, Yun-Ping Lim
BACKGROUND: Interactions between transcriptional inducers of cytochrome P450 (CYP450) enzymes and therapeutic drugs may be prevented by antagonizing the activation of a nuclear receptor (NR), pregnane X receptor (PXR, NR1I2), thus improving therapeutic efficacy. PURPOSE: In the present study, we aim to identify that ursolic acid (UA), a widely distributed pentacyclic triterpene, may act as an effective antagonist of PXR and its sister NR receptor, constitutive androstane receptor (CAR, NR1I3)...
December 1, 2017: Phytomedicine: International Journal of Phytotherapy and Phytopharmacology
https://www.readbyqxmd.com/read/29155491/variation-in-the-response-of-clozapine-biotransformation-pathways-in-human-hepatic-microsomes-to-cyp1a2-and-cyp3a4-selective-inhibitors
#3
Michael Murray, Wei V Zhang, Robert J Edwards
The atypical antipsychotic agent clozapine (CLZ) is effective in many patients who are resistant to conventional antipsychotic drugs. Cytochromes P450 (CYPs) 1A2 and 3A4 oxidise CLZ to norCLZ and CLZ N-oxide in human liver. Concurrent treatment with inducers and inhibitors of CYP1A2 modulates CLZ elimination that disrupts therapy. Drug-drug interactions involving CYP3A4 are also significant but less predictable. To further characterise the factors underlying these interactions, we used samples from a cohort of human livers to assess variation in CLZ oxidation pathways in relation to intrinsic CYP3A4 and CYP1A2 activities and the effects of the corresponding selective inhibitors ketoconazole (0...
November 20, 2017: Basic & Clinical Pharmacology & Toxicology
https://www.readbyqxmd.com/read/29153269/vitamin-d-pathway-gene-polymorphisms-influenced-vitamin-d-level-among-pregnant-women
#4
Bule Shao, Shuying Jiang, Xiamusiye Muyiduli, Shuojia Wang, Minjia Mo, Minchao Li, Zhaopin Wang, Yunxian Yu
AIMS: To explore the relationship between vitamin D pathway genes, gene-environment interactions and vitamin D level among southeast Chinese pregnant women. METHODS: 759 participants from Zhoushan Pregnant Women Cohort (ZPWC) study, were enrolled from August 2011 to April 2014 in China. Plasma 25(OH)D levels and genetic variants in vitamin D pathway (NADSYN1/DHCR7, GC, CYP3A4, CYP2R1, CYP27A1, CYP27B1, VDR, CYP24A1, and LRP2) were measured using the blood sample collected at the first trimester...
November 7, 2017: Clinical Nutrition: Official Journal of the European Society of Parenteral and Enteral Nutrition
https://www.readbyqxmd.com/read/29152762/optimizing-lonafarnib-treatment-for-the-management-of-chronic-delta-hepatitis-the-lowr-hdv-1-study
#5
Cihan Yurdaydin, Onur Keskin, Çağdaş Kalkan, Fatih Karakaya, Aysun Çalişkan, Ersin Karatayli, Senem Karatayli, A Mithat Bozdayi, Christopher Koh, Theo Heller, Ramazan Idilman, Jeffrey S Glenn
BACKGROUND AND RATIONALE: In a proof-of-concept (POC) study, the oral prenylation inhibitor lonafarnib (LNF) decreased HDV RNA during 4 weeks of treatment. Here we explored optimal LNF regimens. METHODS: 15 patients (5 groups; 3 per group) completed dosing as follows: 1) LNF 200 mg BID (12 weeks); 2) LNF 300 mg BID (12 weeks); 3) LNF 100 mg TID (5 weeks); 4) LNF 100 mg BID + pegylated interferon alfa (PEG-IFNα) 180 mcg QW (8 weeks); and 5) LNF 100 mg BID + ritonavir (RTV) 100 mg QD (8 weeks)...
November 20, 2017: Hepatology: Official Journal of the American Association for the Study of Liver Diseases
https://www.readbyqxmd.com/read/29150561/influence-of-enzalutamide-on-cabazitaxel-pharmacokinetics-a-drug-drug-interaction-study-in-metastatic-castration-resistant-prostate-cancer-mcrpc-patients
#6
Bodine P S Belderbos, Sander Bins, Roelof W F van Leeuwen, Esther Oomen-de Hoop, Nelly van der Meer, Peter de Bruijn, Paul Hamberg, Esther N M Overkleeft, Wendy M van der Deure, Martijn Lolkema, Ronald de Wit, Ron H J Mathijssen
PURPOSE: In ongoing clinical research on metastatic castration-resistant prostate cancer (mCRPC) treatment, the potential enhanced efficacy of the combination of taxanes with AR-targeted agents, i.e. enzalutamide and abiraterone, is currently being explored. Since enzalutamide induces the CYP3A4 enzyme and taxanes are metabolized by this enzyme, a potential drug-drug interaction needs to be investigated. DESIGN: Therefore, we performed a pharmacokinetic cross-over study in mCRPC patients who were scheduled for treatment with cabazitaxel Q3W (25 mg/m(2))...
November 17, 2017: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/29145924/pharmacokinetic-interaction-between-bedaquiline-and-clofazimine-in-patients-with-drug-resistant-tuberculosis
#7
G Maartens, M J E Brill, M Pandie, E M Svensson
<h2>BACKGROUND:</h2>Bedaquiline (BDQ) and clofazimine (CFZ) are both recommended for treating drug-resistant tuberculosis (DR-TB). As CFZ is an inhibitor of the cytochrome P450 isoenzyme 3A4 (CYP3A4) in vitro, and BDQ a substrate of CYP3A4, there is a potential for pharmacokinetic (PK) drug-drug interaction that may result in increased BDQ exposure when co-administered with CFZ, which could increase the toxicity of BDQ.<h2>METHODS:</h2>We assessed the effect of co-administered CFZ on BDQ bioavailability, or on clearance of BDQ and its N-monodesmethyl metabolite (M2), in patients with DR-TB using a population PK model developed from data of patients with DR-TB...
November 16, 2017: International Journal of Tuberculosis and Lung Disease
https://www.readbyqxmd.com/read/29144397/sulforaphane-alters-%C3%AE-naphthoflavone-induced-changes-in-activity-and-expression-of-drug-metabolizing-enzymes-in-rat-hepatocytes
#8
Kateřina Lněničková, Andrea Dymáková, Barbora Szotáková, Iva Boušová
Sulforaphane (SFN), an isothiocyanate found in cruciferous vegetables, exerts many beneficial effects on human health such as antioxidant, anti-inflammatory, and anticancer effects. The effect of SFN alone on drug-metabolizing enzymes (DMEs) has been investigated in numerous in vitro and in vivo models, but little is known about the effect of SFN in combination with cytochrome P450 (CYP) inducer. The aim of our study was to evaluate the effect of SFN on the activity and gene expression of selected DMEs in primary cultures of rat hepatocytes treated or non-treated with β-naphthoflavone (BNF), the model CYP1A inducer...
November 16, 2017: Molecules: a Journal of Synthetic Chemistry and Natural Product Chemistry
https://www.readbyqxmd.com/read/29140712/high-expression-of-ugt1a1-1a6-in-monkey-small-intestine-comparison-of-protein-expression-levels-of-cytochromes-p450-udp-glucuronosyltransferases-and-transporters-in-small-intestine-of-cynomolgus-monkey-and-human
#9
Takanori Akazawa, Yasuo Uchida, Eisuke Miyauchi, Masanori Tachikawa, Sumio Ohtsuki, Tetsuya Terasaki
Cynomolgus monkeys have been widely used for the prediction of drug absorption in humans. The purpose of this study was to clarify the regional protein expression levels of cytochromes P450 (CYPs), UDP-glucuronosyltransferases (UGTs), and transporters in small intestine of cynomolgus monkey using liquid chromatography-tandem mass spectrometry, and to compare them with the corresponding levels in human. UGT1A1 in jejunum and ileum were >4.57- and >3.11-fold, and UGT1A6 in jejunum and ileum were >16...
November 15, 2017: Molecular Pharmaceutics
https://www.readbyqxmd.com/read/29137842/comparison-of-pharmacokinetics-of-newly-discovered-aromatase-inhibitors-by-a-cassette-microdosing-approach-in-healthy-japanese-subjects
#10
Hiroyuki Kusuhara, Tadayuki Takashima, Hisako Fujii, Tsutomu Takashima, Masaaki Tanaka, Akira Ishii, Shusaku Tazawa, Kazuhiro Takahashi, Kayo Takahashi, Hidekichi Tokai, Tsuneo Yano, Makoto Kataoka, Akihiro Inano, Suguru Yoshida, Takamitsu Hosoya, Yuichi Sugiyama, Shinji Yamashita, Taisuke Hojo, Yasuyoshi Watanabe
The aim of the present study is to investigate the pharmacokinetics of our newly developed aromatase inhibitors (cetrozole and TMD-322) in healthy subjects by a cassette microdose strategy. A cocktail of cetrozole and TMD-322 was administered intravenously or orally (1.98 μg for each drug) to six healthy volunteers in a crossover fashion. Anastrozole (1.98 μg) was also included in the oral cocktail. Total body clearance and bioavailability were 12.1 ± 7.1 mL/min/kg and 34.9 ± 32.3% for cetrozole, and 16...
September 21, 2017: Drug Metabolism and Pharmacokinetics
https://www.readbyqxmd.com/read/29136555/non-targeted-metabolomics-guided-sildenafil-metabolism-study-in-human-liver-microsomes
#11
Ju-Hyun Kim, Jun Hyun Jo, Kyung-Ah Seo, Hayoung Hwang, Hye Suk Lee, Sangkyu Lee
Metabolomics combined with high-resolution mass spectrometry (HR-MS) and multivariate data analysis has broad applications in the study of xenobiotic metabolism. Although information about xenobiotic metabolism is essential to understand toxic mechanisms, pharmacokinetic parameters and excretion pathways, it is limited to predict all generated metabolites in biological fluids. Here, we revisited sildenafil metabolism in human liver microsomes using a metabolomics approach to achieve a global picture of sildenafil phase 1 metabolism...
November 7, 2017: Journal of Chromatography. B, Analytical Technologies in the Biomedical and Life Sciences
https://www.readbyqxmd.com/read/29135906/effect-of-age-and-allele-variants-of-cyp3a5-cyp3a4-and-por-genes-on-the-pharmacokinetics-of-cyclosporin-a-in-pediatric-renal-transplant-recipients-from-serbia
#12
Mirjana Cvetković, Maja Zivković, Maja Bundalo, Ivana Gojković, Brankica Spasojević-Dimitrijeva, Aleksandra Stanković, Mirjana Kostić
BACKGROUND: The interindividual variability of cyclosporin A (CsA) pharmacokinetics might be explained by heterogeneity in the cytochrome P450 3A (CYP3A) subfamily. Altered CYP3A enzyme activity was associated with variant allele of P450 oxidoreductase gene (POR*28). The aim of this study was to assess the impact of age, CYP3A5*3, CYP3A4*22, and POR*28 alleles on CsA pharmacokinetics in pediatric renal transplant recipients. METHODS: Renal transplant patients receiving CsA (n = 47) were genotyped for CYP3A5*3, CYP3A4*22, and POR*28...
December 2017: Therapeutic Drug Monitoring
https://www.readbyqxmd.com/read/29134945/drug-drug-interaction-potential-of-the-hepatitis-b-and-hepatitis-d-virus-entry-inhibitor-myrcludex-b-assessed-in-vitro
#13
Antje Blank, Katrin Meier, Stephan Urban, Walter Emil Haefeli, Johanna Weiss
BACKGROUND: Myrcludex B is a first-in-class virus entry inhibitor for patients with chronic hepatitis B or B/D infections. In patients it will be co-administered with drugs needed for the disease or comorbidities. We aimed to define the risk of drug-drug interactions by characterizing the influence of myrcludex B on relevant drug transporting and metabolizing enzymes in vitro. METHODS: Inhibition of P-glycoprotein (P-gp, ABCB1), breast cancer resistance protein (BCRP/ABCG2), and the organic anion transporting polypeptides 1B1 and 1B3 (OATP1B1/SLCO1B1 and OATP1B3/SLCO1B3) was measured in cells over-expressing the respective transporter using fluorogenic substrates...
November 14, 2017: Antiviral Therapy
https://www.readbyqxmd.com/read/29129847/effects-of-ketoconazole-on-cyclophosphamide-metabolism-evaluation-of-cyp3a4-inhibition-effect-using-the-in-vitro-and-in-vivo-models
#14
Le Yang, Chenyang Yan, Feng Zhang, Bo Jiang, Shouhong Gao, Youtian Liang, Lifeng Huang, Wansheng Chen
Cyclophosphamide (CP) is widely used in anticancer therapy regimens and 2-dechloroethylcyclophosphamide (DECP) is its side-chain dechloroethylated metabolite. N-dechloroethylation of CP mediated by the enzyme CYP3A4 yields nephrotoxic and neurotoxic chloroacetaldehyde (CAA) in equimolar amount to DECP. This study aimed to evaluate the inhibitory effect of ketoconazole (KTZ) on CP metabolism through in vitro and in vivo drug-drug interaction (DDI) research. Long-term treatment of KTZ induces hepatic injury; thus single doses of KTZ at low, middle, and high levels (10, 20, and 40 mg/kg) were investigated for pharmacokinetic DDI with CP...
November 13, 2017: Experimental Animals
https://www.readbyqxmd.com/read/29123154/modification-of-single-nucleotide-polymorphism-in-a-fully-humanized-cyp3a-mouse-by-genome-editing-technology
#15
Satoshi Abe, Kaoru Kobayashi, Asami Oji, Tetsushi Sakuma, Kanako Kazuki, Shoko Takehara, Kazuomi Nakamura, Azusa Okada, Yasuko Tsukazaki, Naoto Senda, Kazuhisa Honma, Takashi Yamamoto, Masahito Ikawa, Kan Chiba, Mitsuo Oshimura, Yasuhiro Kazuki
Cytochrome P450, family 3, subfamily A (CYP3A) enzymes metabolize approximately 50% of commercially available drugs. Recently, we developed fully humanized transchromosomic (Tc) CYP3A mice with the CYP3A cluster including CYP3A4, CYP3A5, CYP3A7, and CYP3A43. Our humanized CYP3A mice have the CYP3A5*3 (g.6986G) allele, resulting in the almost absence of CYP3A5 protein expression in the liver and intestine. To produce model mice for predicting CYP3A5's contribution to pharmacokinetics, we performed a single-nucleotide polymorphism (SNP) modification of CYP3A5 (g...
November 9, 2017: Scientific Reports
https://www.readbyqxmd.com/read/29118935/a-systems-biology-analysis-protein-protein-interaction-of-nash-and-ibd-based-on-comprehensive-gene-information
#16
Reza Karbalaei, Mehran Piran, Mostafa Rezaei-Tavirani, Hamid Asadzadeh-Aghdaei, Mohammad Hossein Heidari
Aim: Analysis reconstruction networks from two diseases, IBD and NASH and their relationship, based on systems biology methods. Background: IBD and NASH are two complex diseases, with progressive prevalence and high cost for countries. There are some reports on co-existence of these two diseases. In addition, they have some similar risk factors such as age, obesity, and insulin resistance. Therefore, systems biology approach can help to discover their relationship...
2017: Gastroenterology and Hepatology From Bed to Bench
https://www.readbyqxmd.com/read/29117990/simultaneous-physiologically-based-pharmacokinetic-pbpk-modeling-of-parent-and-active-metabolites-to-investigate-complex-cyp3a4-drug-drug-interaction-potential-a-case-example-of-midostaurin
#17
Helen Gu, Catherine Dutreix, Sam Rebello, Taoufik Ouatas, Lai Wang, Dung Yu Chun, Heidi J Einolf, Handan He
Midostaurin (PKC412) is being investigated for the treatment of acute myeloid leukemia (AML) and advanced systemic mastocytosis (advSM). It is extensively metabolized by cytochrome P450 (CYP) 3A4 to form 2 major active metabolites, CGP52421 and CGP62221. In vitro and clinical drug-drug interaction (DDI) studies indicated that midostaurin and its metabolites are substrates, reversible and time-dependent inhibitors, and inducers of CYP3A4. A simultaneous pharmacokinetic model of parent and active metabolites was initially developed by incorporating data from in vitro, preclinical, and clinical pharmacokinetic studies in healthy volunteers and in patients with AML or advSM...
November 8, 2017: Drug Metabolism and Disposition: the Biological Fate of Chemicals
https://www.readbyqxmd.com/read/29117640/functional-characterization-of-22-cyp3a4-protein-variants-to-metabolize-ibrutinib-in-vitro
#18
Ren-Ai Xu, Jian Wen, Pengfei Tang, Chenchen Wang, Saili Xie, Bo-Wen Zhang, Quan Zhou, Jian-Ping Cai, Guo-Xin Hu
Cytochrome P450 3A4 (CYP3A4) is quantitatively the most important P450 enzyme in adults. It is suggested that CYP3A4 genetic polymorphisms may influence the rate of the metabolism and elimination of CYP3A4 substrates in humans. Ibrutinib is an anti-cancer drug and primarily metabolized by CYP3A4. The aim of this study was to systematically investigate the effects of 22 CYP3A4 protein variants on the metabolism of ibrutinib in vitro. When compared with wild-type CYP3A4.1, two variants (CYP3A4.17 and CYP3A4.24) had no detectable enzyme activity; five variants (CYP3A4...
November 8, 2017: Basic & Clinical Pharmacology & Toxicology
https://www.readbyqxmd.com/read/29115994/exploring-venlafaxine-pharmacokinetic-variability-with-a-phenotyping-approach-a-multicentric-french-swiss-study-marvel-study
#19
Célia Lloret-Linares, Youssef Daali, Sylvie Chevret, Isabelle Nieto, Fanny Molière, Philippe Courtet, Florence Galtier, Raphaëlle-Marie Richieri, Sophie Morange, Pierre-Michel Llorca, Wissam El-Hage, Thomas Desmidt, Frédéric Haesebaert, Philippe Vignaud, Jerôme Holtzmann, Jean-Luc Cracowski, Marion Leboyer, Antoine Yrondi, Fabienne Calvas, Liova Yon, Philippe Le Corvoisier, Olivier Doumy, Kyle Heron, Damien Montange, Siamak Davani, Julien Déglon, Marie Besson, Jules Desmeules, Emmanuel Haffen, Frank Bellivier
BACKGROUND: It is well known that the standard doses of a given drug may not have equivalent effects in all patients. To date, the management of depression remains mainly empirical and often poorly evaluated. The development of a personalized medicine in psychiatry may reduce treatment failure, intolerance or resistance, and hence the burden and costs of mood depressive disorders. The Geneva Cocktail Phenotypic approach presents several advantages including the "in vivo" measure of different cytochromes and transporter P-gp activities, their simultaneous determination in a single test, avoiding the influence of variability over time on phenotyping results, the administration of low dose substrates, a limited sampling strategy with an analytical method developed on DBS analysis...
November 7, 2017: BMC Pharmacology & Toxicology
https://www.readbyqxmd.com/read/29110626/the-rationale-for-repurposing-sildenafil-as-an-adjuvant-to-lung-cancer-treatment
#20
Theodore Keats, Rhonda J Rosengren, John C Ashton
There is now a considerable body of evidence for sildenafil possessing anticancer properties. In this article we argue the case for testing sildenafil as a lung cancer therapy chemoadjuvant. Currently, lung cancer is a disease with insufficient treatment options, with only 20% of patients responding to systemic chemotherapy, and even incremental potential improvements should be explored. We review the literature concerning the biochemical, physiological and metabolic effects on cancer cells by sildenafil alone, and when combined with chemotherapeutic agents...
November 2, 2017: Anti-cancer Agents in Medicinal Chemistry
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