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https://www.readbyqxmd.com/read/27895582/introduction-of-an-n-glycosylation-site-into-udp-glucuronosyltransferase-2b3-alters-its-sensitivity-to-cytochrome-p450-3a1-dependent-modulation
#1
Tatsuro Nakamura, Naho Yamaguchi, Yuu Miyauchi, Tomoki Takeda, Yasushi Yamazoe, Kiyoshi Nagata, Peter I Mackenzie, Hideyuki Yamada, Yuji Ishii
Our previous studies have demonstrated functional protein-protein interactions between cytochrome P450 (CYP) 3A and UDP-glucuronosyltransferase (UGT). However, the role of carbohydrate chains of UGTs in the interaction with CYP is not well understood. To address this issue, we examined whether CYP3A1 modulates the function of UGT2B3 which lacks potential glycosylation sites. We also examined whether the introduction of N-glycosylation to UGT2B3 affects CYP3A-dependent modulation of UGT function. To introduce a potential glycosylation site into UGT2B3, Ser 316 of UGT2B3 was substituted with Asn by site-directed mutagenesis...
2016: Frontiers in Pharmacology
https://www.readbyqxmd.com/read/27864798/pharmacokinetic-drug-interactions-with-panax-ginseng
#2
REVIEW
Meenakshi R Ramanathan, Scott R Penzak
Panax ginseng is widely used as an adaptogen throughout the world. The major active constituents of P. ginseng are ginsenosides. Most naturally occurring ginsenosides are deglycosylated by colonic bacteria to intestinal metabolites. Ginsenosides along with these metabolites are widely accepted as being responsible for the pharmacologic activity and drug interaction potential of ginseng. Numerous preclinical studies have assessed the influence of various ginseng components on cytochrome P450 (CYP), glucuronidation, and drug transport activity...
November 18, 2016: European Journal of Drug Metabolism and Pharmacokinetics
https://www.readbyqxmd.com/read/27861314/effect-of-the-direct-oral-anticoagulants-rivaroxaban-and-apixaban-on-the-disposition-of-calcineurin-inhibitors-in-transplant-recipients
#3
Thomas Vanhove, Isabel Spriet, Pieter Annaert, Johan Maertens, Johan Van Cleemput, Robin Vos, Dirk Kuypers
BACKGROUND: Calcineurin inhibitors (CNIs) and direct oral anticoagulants (DOACs) share certain metabolic pathways, but whether DOACs influence CNI exposure has not been assessed. METHODS: A single-center retrospective analysis was performed including 39 organ recipients treated with the combination of a CNI and rivaroxaban (n = 29) or apixaban (n = 10). Dose-corrected CNI trough concentrations (C0/D) during 200 days before and after DOAC initiation were recorded (n = 261), together with covariates known to influence CNI disposition such as steroid dose and hematocrit...
November 17, 2016: Therapeutic Drug Monitoring
https://www.readbyqxmd.com/read/27859472/effect-of-ketoconazole-a-strong-cyp3a-inhibitor-on-the-pharmacokinetics-of-venetoclax-a-bcl-2-inhibitor-in-patients-with-non-hodgkin-lymphoma
#4
Suresh K Agarwal, Ahmed Hamed Salem, Alexey V Danilov, Beibei Hu, Soham Puvvada, Martin Gutierrez, David Chien, Lionel D Lewis, Shekman L Wong
AIM: To examine the effect of a strong CYP3A inhibitor, ketoconazole, on the pharmacokinetics, safety, and tolerability of venetoclax. METHODS: Twelve patients with Non-Hodgkin lymphoma (NHL) were enrolled in this Phase 1, open-label, fixed-sequence study. Patients received a single 50 mg dose of venetoclax orally on Day 1 and Day 8, and a 400 mg once daily dose of ketoconazole on Days 5 through 11. Blood samples were collected predose and up to 96 hours after each venetoclax dose on Day 1 and Day 8...
November 2, 2016: British Journal of Clinical Pharmacology
https://www.readbyqxmd.com/read/27855510/uhplc-ms-ms-bioanalysis-of-urinary-dhea-cortisone-and-their-hydroxylated-metabolites-as-potential-biomarkers-for-cyp3a-mediated-drug-drug-interactions
#5
Naiyu Zheng, Lisa J Christopher, Xuewen Ma, Qin C Ji, Adela Buzescu, Hamza Kandoussi, Samira M Garonzik, Frank LaCreta, Anne-Francoise Aubry, Mark E Arnold, Jianing Zeng
AIM: A UHPLC-MS/MS assay was developed to quantify urinary dehydroepiandrosterone (DHEA), 7β-hydroxy-DHEA, cortisone and 6β-hydroxycortisone as potential biomarkers to predict CYP3A activity. RESULTS: A sensitive assay at LLOQ of 0.500 ng/ml with good accuracy and precision was developed for the four analytes in human urine. This UHPLC-MS/MS assay was optimized by eliminating nonspecific loss of the analytes in urine, ensuring complete hydrolysis of the conjugates to unconjugated forms and use of the product ions of [M+H-H2O](+) for multiple reaction monitoring detection of DHEA and 7β-hydroxy-DHEA...
December 2016: Bioanalysis
https://www.readbyqxmd.com/read/27852117/pharmacokinetic-drug-evaluation-of-anacetrapib-for-the-treatment-of-dyslipidemia
#6
Claudio Borghi, Arrigo F G Cicero
While some cholesteryl ester transfer protein inhibitors have had their clinical study interrupted because of no or adverse effects on cardiovascular disease, anacetrapib (MK-0859) is being evaluated in Phase III cardiovascular outcomes trials. We review its pharmacokinetic properties. Areas covered: The apparent anacetrapib terminal elimination half-life after a single dose is 9-62 hours in the fasted state and 42-83 hours in the fed state. After repeat administrations, a biphasic elimination profile with a long terminal elimination phase (~60-80 h) was observed, although the effective half-life was ~20 h...
November 17, 2016: Expert Opinion on Drug Metabolism & Toxicology
https://www.readbyqxmd.com/read/27821435/what-can-be-learned-from-recent-new-drug-applications-a-systematic-review-of-drug-interaction-data-for-drugs-approved-by-the-u-s-fda-in-2015
#7
Jingjing Yu, Zhu Zhou, Katie H Owens, Tasha K Ritchie, Isabelle Ragueneau-Majlessi
As a follow-up to previous reviews, the aim of the present analysis was to systematically examine all drug metabolism, transport, PK, and DDI data available in the 33 NDAs and 12 BLAs approved by the FDA in 2015, using the University of Washington Drug Interaction Database©, and to highlight the significant findings. All of the NDAs were well-characterized with regard to drug metabolism, transport, and/or organ impairment, and were fully analyzed in this review. In vitro, a majority of the NMEs were found to be substrates or inhibitors/inducers of at least one DME or transporter...
November 7, 2016: Drug Metabolism and Disposition: the Biological Fate of Chemicals
https://www.readbyqxmd.com/read/27820970/pharmacovigilance-during-ibrutinib-therapy-for-chronic-lymphocytic-leukemia-cll-small-lymphocytic-lymphoma-sll-in-routine-clinical-practice
#8
Heidi D Finnes, Kari G Chaffee, Timothy G Call, Wei Ding, Saad S Kenderian, Deborah A Bowen, Michael Conte, Kristen B McCullough, Julianna A Merten, Gabriel T Bartoo, Matthew D Smith, Jose Leis, Asher Chanan-Khan, Susan M Schwager, Susan L Slager, Neil E Kay, Tait D Shanafelt, Sameer A Parikh
Due to Cytochrome P450 3A (CYP3A) metabolism, clinical trials of ibrutinib-treated chronic lymphocytic leukemia (CLL) patients prohibited concurrent medications metabolized by CYP3A. We evaluated concomitant medication use in 118 ibrutinib-treated CLL patients outside the context of clinical trials. Seventy-five (64%) patients were on medications that could increase ibrutinib toxicity and 4 (3%) were on drugs that could decrease ibrutinib efficacy. Nineteen (16%) patients were on concomitant CYP3A inhibitors (11 moderate, 8 strong), and 4 (3%) were on CYP3A inducers (two patients were on both CYP3A inhibitors and inducers)...
November 8, 2016: Leukemia & Lymphoma
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
#9
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 interindividual 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/27798496/how-recent-findings-on-the-pharmacokinetics-and-pharmacodynamics-of-integrase-inhibitors-can-inform-clinical-use
#10
Emilie Elliot, Mimie Chirwa, Marta Boffito
PURPOSE OF REVIEW: This review of recent published literature and data presented at scientific meetings on integrase stand transfer inhibitors (InSTIs) examines how these findings may impact on their future clinical use. RECENT FINDINGS: Elvitegravir (EVG), raltegravir (RAL) and dolutegravir (DTG) are InSTIs recommended as first-line options for treatment naive patients by the European AIDS Clinical Society, British HIV Association, International AIDS Society-USA and DHHS...
October 27, 2016: Current Opinion in Infectious Diseases
https://www.readbyqxmd.com/read/27798211/daclatasvir-30-mg-day-is-the-correct-dose-for-patients-taking-atazanavir-cobicistat
#11
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/27792868/phase-i-studies-of-acebilustat-pharmacokinetics-pharmacodynamics-food-effect-and-cyp3a-induction
#12
J S Elborn, L Bhatt, R Grosswald, S Ahuja, E B Springman
Acebilustat is a new once-daily oral antiinflammatory drug in development for treatment of cystic fibrosis (CF) and other diseases. It is an inhibitor of leukotriene A4 hydrolase; therefore, production of leukotriene B4 (LTB4) in biological fluids provides a direct measure of the pharmacodynamic (PD) response to acebilustat treatment. Here we compare the pharmacokinetics (PK) and PD between CF patients and healthy volunteers, and investigate the food effect and CYP3A4 induction in healthy volunteers. No significant differences between study populations were observed for peak plasma level (Cmax ) or exposure (AUC)...
October 28, 2016: Clinical and Translational Science
https://www.readbyqxmd.com/read/27788452/effects-of-alkylphenols-on-the-biotransformation-of-diuron-and-enzymes-involved-in-the-synthesis-and-clearance-of-sex-steroids-in-juvenile-male-tilapia-oreochromus-mossambica
#13
Andréia A Felício, Jordan Crago, Lindley A Maryoung, Eduardo A Almeida, Daniel Schlenk
Previous studies using in vivo bioassay guided fractionation indicated that the herbicide diuron (3-(3,4-dichlorophenyl)-1,1-dimethylurea) and alkylphenol (AP)-containing surfactants were detected in fractions of extracts that induced the estrogenic biomarker, vitellogenin in fish exposed to surface water extracts from the United States. However, when the compounds were evaluated individually using in vivo estrogenic assays or in vitro estrogen receptor assays, estrogenic activity was not observed. Since APs have been shown to alter activity and content of cytochrome P450s (CYP) which convert diuron to potential estrogenic metabolites, the hepatic biotransformation of diuron was measured with and without a 7day pretreatment of p-Octylphenol (OP) and p-Nonylphenol (NP) at low (OP 13ng/L+NP 91ng/L), and high concentrations (OP 65ng/L+NP 455ng/L) in juvenile male Nile tilapia (Oreochromus niloticus)...
October 22, 2016: Aquatic Toxicology
https://www.readbyqxmd.com/read/27777246/managing-the-risk-of-cyp3a-induction-in-drug-development-a-strategic-approach
#14
Barry C Jones, Helen Rollison, Susanne A Johansson, Kajsa P Kanebratt, Craig Lambert, Karthick Vishwanathan, Tommy B Andersson
Induction of cytochrome P450 (CYP) can impact the efficacy and safety of a drug molecule upon multiple dosing of co-administered drugs. This strategy is focused on CYP3A since the majority of clinically relevant cases of CYP induction are related to this enzyme. However, the in vitro evaluation of induction is applicable to other CYP enzymes but the in vivo relevance cannot be assessed because the scarcity of relevant clinical data. In the pre-clinical phase, compounds are screened using PXR reporter gene assay and, if necessary, structure-activity relationships (SAR) are developed...
October 24, 2016: Drug Metabolism and Disposition: the Biological Fate of Chemicals
https://www.readbyqxmd.com/read/27761990/effects-of-renal-impairment-on-the-pharmacokinetics-and-pharmacodynamics-of-a-novel-dpp-iv-inhibitor-evogliptin-da-1229
#15
Jaeseong Oh, Andrew HyoungJin Kim, SeungHwan Lee, Hyunjeong Cho, Yon Su Kim, Mi Young Bahng, Seo Hyun Yoon, Joo-Youn Cho, In-Jin Jang, Kyung-Sang Yu
Evogliptin is a novel potent and selective dipeptidyl peptidase-IV (DPP-IV) inhibitor. This study aimed to evaluate the pharmacokinetic and pharmacodynamic characteristics of evogliptin in renal impairment (RI) subjects. An open-label, parallel-group clinical study was conducted on mild, moderate, and severe RI subjects and matched normal renal function (NRF) subjects. A single oral 5 mg dose of evogliptin was administered and serial blood and urine samples were obtained to assess the pharmacokinetic and pharmacodynamic characteristics of evogliptin...
October 20, 2016: Diabetes, Obesity & Metabolism
https://www.readbyqxmd.com/read/27757267/evaluation-of-the-synergistic-effect-of-allium-sativum-eugenia-jambolana-momordica-charantia-ocimum-sanctum-and-psidium-guajava-on-hepatic-and-intestinal-drug-metabolizing-enzymes-in-rats
#16
Devendra Kumar, Neerja Trivedi, Rakesh K Dixit
AIMS/BACKGROUND: This study was to investigated the synergistic effect of polyherbal formulations (PHF) of Allium sativum L., Eugenia jambolana Lam., Momordica charantia L., Ocimum sanctum Linn., and Psidium guajava L. in the inhibition/induction of hepatic and intestinal cytochrome P450 (CYPs) and Phase-II conjugated drug metabolizing enzymes (DMEs). Consumption of these herbal remedy has been extensively documented for diabetes treatment in Ayurveda. METHODOLOGY: PHF of these five herbs was prepared, and different doses were orally administered to Sprague-Dawley rats of different groups except control group...
September 2016: Journal of Intercultural Ethnopharmacology
https://www.readbyqxmd.com/read/27718639/perspective-4%C3%AE-hydroxycholesterol-as-an-emerging-endogenous-biomarker-of-hepatic-cyp3a
#17
Jialin Mao, Iain Martin, James McLeod, Gail Nolan, Robert van Horn, Manoli Vourvahis, Yvonne S Lin
A key goal in the clinical development of a new molecular entity is to quickly identify whether it has the potential for drug-drug interactions. In particular, confirmation of in vitro data in the early stage of clinical development would facilitate the decision making and inform future clinical pharmacology study designs. Plasma 4β-hydroxycholesterol (4β-HC) is considered as an emerging endogenous biomarker for cytochrome P450 3A (CYP3A), one of the major drug metabolizing enzymes. Although there are increasing reports of the use of 4β-HC in academic- and industry-sponsored clinical studies, a thorough review, summary and consideration of the advantages and challenges of using 4β-HC to evaluate changes in CYP3A activity has not been attempted...
October 10, 2016: Drug Metabolism Reviews
https://www.readbyqxmd.com/read/27709656/predicting-clinical-relevance-of-grapefruit-drug-interactions-a-complicated-process
#18
D G Bailey
WHAT IS KNOWN AND OBJECTIVE: Grapefruit juice interacts with a number of drugs. This commentary provides feedback on a previously proposed approach for predicting clinically relevant interactions with grapefruit juice based on the average inherent oral bioavailability (F) and magnitude of increase in bioavailability with other CYP3A inhibitors of the drug. COMMENT: Additional factors such as variability of the magnitude of the pharmacokinetic interaction among individuals, product monograph cautionary statements and vulnerability of the patient population should be considered...
October 6, 2016: Journal of Clinical Pharmacy and Therapeutics
https://www.readbyqxmd.com/read/27694226/pharmacokinetics-and-differential-regulation-of-cytochrome-p450-enzymes-in-type-1-allergic-mice
#19
Tadatoshi Tanino, Akira Komada, Koji Ueda, Toru Bando, Yukie Nojiri, Yukari Ueda, Eiichi Sakurai
Type 1 allergic diseases are characterized by elevated production of specific immunoglobulin E (IgE) for each antigen and have become a significant health problem worldwide. This study investigated the effect of IgE-mediated allergy on drug pharmacokinetics. To further understand differential suppression of hepatic cytochrome P450 (CYP) activity, we examined the inhibitory effect of nitric oxide (NO), a marker of allergic conditions. Seven days after primary or secondary sensitization (PS7 and SS7, respectively), hepatic CYP1A2, CYP2C, CYP2E1 and CYP3A activities were decreased to 45%-75% of the corresponding control, however, CYP2D activity was not downregulated...
September 30, 2016: Drug Metabolism and Disposition: the Biological Fate of Chemicals
https://www.readbyqxmd.com/read/27666601/allosteric-activation-of-midazolam-cyp3a5-hydroxylase-activity-by-icotinib-enhancement-by-ketoconazole
#20
XiaoMei Zhuang, TianHong Zhang, SiJia Yue, Juan Wang, Huan Luo, YunXia Zhang, Zheng Li, JinJing Che, HaiYing Yang, Hua Li, MingShe Zhu, Chuang Lu
Icotinib (ICO), a novel small molecule and a tyrosine kinase inhibitor, was developed and approved recently in China for non-small cell lung cancer. During screening for CYP inhibition potential in human liver microsomes (HLM), heterotropic activation toward CYP3A5 was revealed. Activation by icotinib was observed with CYP3A-mediated midazolam hydroxylase activity in HLM (∼40% over the baseline) or recombinant human CYP3A5 (rhCYP3A5) (∼70% over the baseline), but not in the other major CYPs including rhCYP3A4...
September 22, 2016: Biochemical Pharmacology
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