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https://www.readbyqxmd.com/read/28335376/genetic-polymorphisms-contribute-to-the-individual-variations-of-imatinib-mesylate-plasma-levels-and-adverse-reactions-in-chinese-gist-patients
#1
Jing Liu, Zhiyu Chen, Hanmei Chen, Yingyong Hou, Weiqi Lu, Junyi He, Hanxing Tong, Yuhong Zhou, Weimin Cai
Imatinib mesylate (IM) has dramatically improved the outcomes of gastrointestinal stromal tumor (GIST) patients. However, the clinical responses of IM may considerably vary among single individuals. This study aimed to investigate the influences of genetic polymorphisms of drug-metabolizing enzyme (CYP3A4), transporters (ABCB1, ABCG2), and nuclear receptor (Pregnane X Receptor (PXR, encoded by NR1I2)) on IM plasma levels and related adverse reactions in Chinese GIST patients. A total of 68 Chinese GIST patients who have received IM 300-600 mg/day were genotyped for six single nucleotide polymorphisms (SNPs) (CYP3A4 rs2242480; ABCB1 rs1045642; ABCG2 rs2231137; NRI12 rs3814055, rs6785049, rs2276706), and the steady-state IM trough plasma concentrations were measured by a validated HPLC method...
March 13, 2017: International Journal of Molecular Sciences
https://www.readbyqxmd.com/read/28324649/sulfonamides-as-selective-nav1-7-inhibitors-optimizing-potency-pharmacokinetics-and-metabolic-properties-to-obtain-atropisomeric-quinolinone-am-0466-that-affords-robust-in-vivo-activity
#2
Russell F Graceffa, Alessandro A Boezio, Jessica Able, Steven Altmann, Loren M Berry, Christiane M Boezio, John R Butler, Margaret Y Chu-Moyer, Melanie Cooke, Erin F DiMauro, Thomas A Dineen, Elma Feric Bojic, Robert S Foti, Robert T Fremeau, Angel Guzman-Perez, Hua Gao, Hakan Gunaydin, Hongbing Huang, Liyue Huang, Christopher Ilch, Michael Jarosh, Thomas Kornecook, Charles R Kreiman, Daniel S La, Joseph Ligutti, Benjamin Charles Milgram, Min-Hwa Jasmine Lin, Isaac E Marx, Hanh Nho Nguyen, Emily A Peterson, Gwen Rescourio, John Roberts, Laurie B Schenkel, Roman Shimanovich, Brian Andrew Sparling, John Stellwagen, Kristin Taborn, Karina R Vaida, Jean Wang, John T S Yeoman, Violeta L Yu, Dawn Zhu, Bryan D Moyer, Matthew M Weiss
Due to its strong genetic validation, NaV1.7 has attracted significant interest as a target for the treatment of pain. We have previously reported on a number of structurally distinct bicyclic heteroarylsulfonamides as NaV1.7 inhibitors that demonstrate high levels of selectivity over other NaV isoforms. Herein, we report the discovery and optimization of a novel series of atropisomeric quinolinone sulfonamide inhibitors of NaV1.7, which demonstrate nanomolar inhibition of NaV1.7 and exhibit high levels of selectivity over other sodium channel isoforms...
March 21, 2017: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28324001/cyp3a4-induction-by-rifampin-an-alternative-pathway-for-vitamin-d-inactivation-in-patients-with-cyp24a1-mutations
#3
Colin Patrick Hawkes, Dong Li, Hakon Hakonarson, Kevin E Meyers, Kenneth Thummel, Michael A Levine
Context: The P450 enzyme CYP24A1 is the principal inactivator of vitamin D metabolites. Biallelic loss-of-function mutations in CYP24A1 are associated with elevated serum levels of 1,25-dihydroxyvitamin D3 with consequent hypercalcemia and hypercalciuria, and represent the most common form of idiopathic infantile hypercalcemia (IIH). Current management strategies for this condition include a low calcium diet, reduced dietary vitamin D intake and limited sunlight exposure. CYP3A4 is a P450 enzyme that inactivates many drugs and xenobiotics and may represent an alternative pathway for inactivation of vitamin D metabolites...
March 3, 2017: Journal of Clinical Endocrinology and Metabolism
https://www.readbyqxmd.com/read/28322152/serotonin-receptor-binding-characteristics-of-geissoschizine-methyl-ether-an-indole-alkaloid-in-uncaria-hook
#4
Yasushi Ikarashi, Kyoji Sekiguchi, Kazushige Mizoguchi
Geissoschizine methyl ether (GM) is one of the indole alkaloids in Uncaria hook, and an active ingredient of yokukansan (YKS) that improves behavioral and psychological symptoms of dementia (BPSD) in patients with several types of dementia. The pharmacological action of GM has been related to various serotonin (5-HT) receptor subtypes. Here we describe previous findings and our own data to review the binding characteristics of GM to the 5-HT receptor subtypes. Competitive receptor-binding assays showed that GM bound the following 5-HT receptor subtypes: 5-HT1A, 5-HT1B, 5-HT2A, 5-HT2B, 5-HT2C, 5-HT4, 5-HT5A, 5-HT6, and 5-HT7...
March 20, 2017: Current Medicinal Chemistry
https://www.readbyqxmd.com/read/28303724/non-alcoholic-fatty-liver-disease-nafld-pathogenesis-classification-and-effect-on-drug-metabolizing-enzymes-and-transporters
#5
Enoch Cobbina, Fatemeh Akhlaghi
Non-alcoholic fatty liver disease (NAFLD) is a spectrum of liver disorders. It is defined by the presence of steatosis in more than 5% of hepatocytes with little or no alcohol consumption. Insulin resistance, the metabolic syndrome or type 2 diabetes and genetic variants of PNPLA3 or TM6SF2 seem to play a role in the pathogenesis of NAFLD. The pathological progression of NAFLD follows tentatively a "three-hit" process namely steatosis, lipotoxicity and inflammation. The presence of steatosis, oxidative stress and inflammatory mediators like TNF-α and IL-6 has been implicated in the alterations of nuclear factors such as CAR, PXR, PPAR-α in NAFLD...
March 17, 2017: Drug Metabolism Reviews
https://www.readbyqxmd.com/read/28301431/cyp3a4-activity-is-markedly-lower-in-patients-with-crohn-s-disease
#6
Aze Wilson, Rommel G Tirona, Richard B Kim
BACKGROUND: Disease-dependent changes in the activity of drug metabolizing enzymes and transporters, such as Cytochrome P450 (CYP) 3A4 and P-glycoprotein (P-gp), are thought to have a major influence on the disposition of shared substrates. However, little is known regarding the in vivo relevance of these 2 proteins during drug therapy for gastrointestinal diseases. Our aim was to elucidate the activity of CYP3A4 and P-gp in subjects with Crohn's disease (CD) and to evaluate their influence on budesonide pharmacokinetics...
March 15, 2017: Inflammatory Bowel Diseases
https://www.readbyqxmd.com/read/28301155/exploration-of-2-pyridin-4-ylmethyl-amino-nicotinamide-derivatives-as-potent-reversal-agents-against-p-glycoprotein-mediated-multidrug-resistance
#7
Qianqian Qiu, Wei Shi, Zheng Li, Bo Zhang, Miaobo Pan, Jian Cui, Yuxuan Dai, Wenlong Huang, Hai Qian
Overexpression of the ATP-binding cassette (ABC) transport proteins, like ABCB1, commonly referred to as P-glycoprotein (P-gp), initiates active efflux of a broad spectrum of unrelated chemotherapeutic drugs in structure and function, leading to chemotherapy failure. A series of 2-((pyridin-4-ylmethyl)amino)nicotinamide derivatives as potent reversal agents against P-glycoprotein-mediated multidrug resistance (MDR) were designed and synthesized. The majority of target compounds displayed great reversal potency, especially 9n...
March 16, 2017: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28301096/effects-of-tenapanor-on-cytochrome-p450-mediated-drug-drug-interactions
#8
Susanne Johansson, David P Rosenbaum, Marie Ahlqvist, Helen Rollison, Mikael Knutsson, Bergur Stefansson, Marie Elebring
Tenapanor (RDX5791, AZD1722) is an inhibitor of sodium/hydrogen exchanger isoform 3 in development for the treatment of constipation-predominant irritable bowel syndrome and the treatment of hyperphosphatemia in patients with chronic kidney disease on dialysis. We aimed to investigate whether tenapanor inhibits or induces cytochrome P450s (CYPs). In vitro experiments assessing the potential of tenapanor to affect various CYPs indicated that it could inhibit CYP3A4/5 (IC50 0.4-0.7 μM). An open-label, phase 1 clinical study (NCT02140268) evaluated the pharmacokinetics of the CYP3A4 substrate midazolam when administered with and without tenapanor...
March 16, 2017: Clinical Pharmacology in Drug Development
https://www.readbyqxmd.com/read/28291036/potential-mechanisms-of-hematological-adverse-drug-reactions-in-patients-receiving-clozapine-in-combination-with-proton-pump-inhibitors
#9
Michał Wiciński, Mateusz M Węclewicz, Mateusz Miętkiewicz, Bartosz Malinowski, Elżbieta Grześk, Joanna Klonowska
Clozapine is a second-generation antipsychotic which has proven efficacy in treating the symptoms of schizophrenia. Although clozapine therapy is associated with a number of adverse drug reactions, it is frequently used. One of the most common adverse drug reactions is gastroesophageal reflux disease which is an indication for treatment with proton pump inhibitors (PPIs). Coadministration of clozapine and PPIs increases the risk of hematological adverse drug reactions, including neutropenia and agranulocytosis...
March 2017: Journal of Psychiatric Practice
https://www.readbyqxmd.com/read/28289823/human-pregnane-x-receptor-is-activated-by-dibenzazepine-carbamate-based-inhibitors-of-constitutive-androstane-receptor
#10
Judith Jeske, Björn Windshügel, Wolfgang E Thasler, Matthias Schwab, Oliver Burk
Unintentional activation of xenosensing nuclear receptors pregnane X receptor (PXR) and/or constitutive androstane receptor (CAR) by clinical drug use is known to produce severe side effects in patients, which may be overcome by co-administering antagonists. However, especially antagonizing CAR is hampered by the lack of specific inhibitors, which do not activate PXR. Recently, compounds based on a dibenzazepine carbamate scaffold were identified as potent CAR inhibitors. However, their potential to activate PXR was not thoroughly investigated, even if the lead compound was named "CAR inhibitor not PXR activator 1" (CINPA1)...
March 13, 2017: Archives of Toxicology
https://www.readbyqxmd.com/read/28289057/applying-stable-isotope-labeled-amino-acids-in-micropatterned-hepatocyte-co-culture-to-directly-determine-the-degradation-rate-constant-for-cyp3a4
#11
Ryan H Takahashi, Sheerin Shahidi-Latham, Susan Wong, Jae H Chang
The rate of enzyme degradation (kdeg) is an important input parameter for the prediction of clinical drug-drug-interactions (DDI) that result from mechanism-based inactivation or induction of cytochrome P450s. Currently, a large range of reported estimates for CYP3A4 enzyme degradation exists, and consequently, large uncertainty exists in steady-state predictions for DDI. In the current investigations, stable isotope labeled amino acids in culture (SILAC) was applied to a long-lived primary human hepatocyte culture, HepatoPac, to directly monitor the degradation of CYP3A4...
March 13, 2017: Drug Metabolism and Disposition: the Biological Fate of Chemicals
https://www.readbyqxmd.com/read/28288941/differential-activation-of-pregnane-x-receptor-by-carnosic-acid-carnosol-ursolic-acid-and-rosmarinic-acid
#12
Chun Ling Seow, Aik Jiang Lau
Pregnane X receptor (PXR) regulates the expression of many genes, including those involved in drug metabolism and transport, and has been linked to various diseases, including inflammatory bowel disease. In the present study, we determined whether carnosic acid and other chemicals in rosemary extract (carnosol, ursolic acid, and rosmarinic acid) are PXR activators. As assessed in dual-luciferase reporter gene assays, carnosic acid, carnosol, and ursolic acid, but not rosmarinic acid, activated human PXR (hPXR) and mouse PXR (mPXR), whereas carnosol and ursolic acid, but not carnosic acid or rosmarinic acid, activated rat PXR (rPXR)...
March 10, 2017: Pharmacological Research: the Official Journal of the Italian Pharmacological Society
https://www.readbyqxmd.com/read/28288489/impact-of-the-herbal-breviscapine-on-the-pharmacokinetics-of-simvastatin-in-rats-the-involvement-of-cyp3a4
#13
Aixia Ju, Yang Yang Li, Zhe Qu, Qiuhong Li
The effect of breviscapine injection on the pharmacokinetics of simvastatin and the mRNA expression of hepatic cytochrome P450 (CYP) enzyme was investigated with rats. The rats were pretreated for 8 consecutive days with breviscapine injection (20 mg/kg/day, i. v.), followed by administration of simvastatin through gavage (40 mg/kg). The control rats received the corresponding volume of saline solution for the pretreatment. Blood samples were collected at varied time points after simvastatin administration and the liver was harvested after the last collection of the blood sample for measurement of the CYP3A4 mRNA expression...
March 13, 2017: Drug Research
https://www.readbyqxmd.com/read/28287723/sulfonamides-as-selective-nav1-7-inhibitors-optimizing-potency-and-pharmacokinetics-while-mitigating-metabolic-liabilities
#14
Matthew M Weiss, Thomas A Dineen, Isaac E Marx, Steven Altmann, Alessandro A Boezio, Howard Bregman, Margaret Y Chu-Moyer, Erin F DiMauro, Elma Feric Bojic, Robert S Foti, Hua Gao, Russell F Graceffa, Hakan Gunaydin, Angel Guzman-Perez, Hongbing Huang, Liyue Huang, Michael Jarosh, Thomas Kornecook, Charles R Kreiman, Joseph Ligutti, Daniel S La, Min-Hwa Jasmine Lin, Dong Liu, Bryan D Moyer, Hanh Nho Nguyen, Emily A Peterson, Paul E Rose, Kristin Taborn, Beth D Youngblood, Violeta L Yu, Robert T Fremeau
Several reports have recently emerged regarding the identification of heteroarylsulfonamides as NaV1.7 inhibitors that demonstrate high levels of selectivity over other NaV isoforms. The optimization of a series of internal NaV1.7 leads that address a number of metabolic liabilities including bioactivation, PXR activation, as well as CYP3A4 induction and inhibition led to the identification of potent and selective inhibitors that demonstrated favorable pharmacokinetic profiles and were devoid of the aforementioned liabilities...
March 13, 2017: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28287454/am-2201-inhibits-multiple-cytochrome-p450-and-uridine-5-diphospho-glucuronosyltransferase-enzyme-activities-in-human-liver-microsomes
#15
Ju-Hyun Kim, Soon-Sang Kwon, Tae Yeon Kong, Jae Chul Cheong, Hee Seung Kim, Moon Kyo In, Hye Suk Lee
AM-2201 is a synthetic cannabinoid that acts as a potent agonist at cannabinoid receptors and its abuse has increased. However, there are no reports of the inhibitory effect of AM-2201 on human cytochrome P450 (CYP) or uridine 5'-diphospho-glucuronosyltransferase (UGT) enzymes. We evaluated the inhibitory effect of AM-2201 on the activities of eight major human CYPs (1A2, 2A6, 2B6, 2C8, 2C9, 2C19, 2D6, and 3A4) and six major human UGTs (1A1, 1A3, 1A4, 1A6, 1A9, and 2B7) enzymes in pooled human liver microsomes using liquid chromatography-tandem mass spectrometry to investigate drug interaction potentials of AM-2201...
March 10, 2017: Molecules: a Journal of Synthetic Chemistry and Natural Product Chemistry
https://www.readbyqxmd.com/read/28287022/metabolic-map-of-osthole-and-its-effect-on-lipids
#16
Qi Zhao, Xin-Mei Li, Hong-Ning Liu, Frank J Gonzalez, Fei Li
1. Osthole, a coumarin compound from plants, is a promising agent for the treatment of metabolic diseases, including hyperglycemia, fatty liver, and cancers. Studies indicate that the peroxisome proliferator-activated receptors (PPAR) α and γ are involved in the pharmacological effects of osthole. The in vitro and in vivo metabolism of osthole, and its biological activity are not completely understood. 2. In this study, UPLC-ESI-QTOFMS-based metabolomics was used to determine the metabolic pathway of osthole and its influence on the levels of endogenous metabolites...
March 13, 2017: Xenobiotica; the Fate of Foreign Compounds in Biological Systems
https://www.readbyqxmd.com/read/28283499/metabolite-identification-reaction-phenotyping-and-retrospective-drug-drug-interaction-predictions-of-17-deacetylnorgestimate-the-active-component-of-the-oral-contraceptive-norgestimate
#17
Deepak Ahire, Sarmistha Sinha, Barry Brock, Ramaswamy Iyer, Sandhya Mandlekar, Murali Subramanian
Ortho-Tri-Cyclen® (OTC), a two drug cocktail comprising of ethinylestradiol (EE) and norgestimate (13-ethyl-17-acetoxy-18, 19-dinor-17α-pregn-4-en-20yn-3 oxime), is commonly prescribed to avert unwanted pregnancies in women of reproductive age. In vivo, norgestimate undergoes extensive and rapid deacetylation to produce 17-deacetylnorgestimate (NGMN), an active circulating metabolite that likely contributes significantly to norgestimate efficacy. Despite being of primary significance, the metabolism and reaction phenotyping of NGMN have not been previously reported...
March 10, 2017: Drug Metabolism and Disposition: the Biological Fate of Chemicals
https://www.readbyqxmd.com/read/28280092/a-phase-i-ib-study-of-enzalutamide-alone-and-in-combination-with-endocrine-therapies-in-women-with-advanced-breast-cancer
#18
Lee S Schwartzberg, Denise Yardley, Anthony Elias, Manish Patel, Patricia M LoRusso, Howard A Burris, Ayca Gucalp, Amy Peterson, Martha Blaney, Joyce Steinberg, Jacqueline Gibbons, Tiffany A Traina
PURPOSE: Several lines of evidence support targeting the androgen signaling pathway in breast cancer. Enzalutamide is a potent inhibitor of androgen receptor signaling. Preclinical data in estrogen-expressing breast cancer models demonstrated activity of enzalutamide monotherapy and enhanced activity when combined with various endocrine therapies (ETs). Enzalutamide is a strong cytochrome P450 3A4 (CYP3A4) inducer, and ETs are commonly metabolized by CYP3A4. The pharmacokinetic (PK) interactions, safety, and tolerability of enzalutamide monotherapy and in combination with ETs were assessed in this phase I/Ib study...
March 9, 2017: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/28279567/optimizing-everolimus-exposure-when-combined-with-calcineurin-inhibitors-in-solid-organ-transplantation
#19
REVIEW
Teun van Gelder, Lutz Fischer, Fuad Shihab, Maria Shipkova
The mammalian target of rapamycin (mTOR) inhibitor everolimus is a narrow therapeutic index drug for which optimal exposure levels are essential. The consistent pharmacokinetic profile of everolimus allows trough concentration (C0) measurement to be an appropriate and reliable index for therapeutic drug monitoring (TDM). Exposure-response analyses of data from early fixed-dose trials demonstrated that rates of biopsy-proven acute rejection (BPAR) are significantly higher if everolimus C0 declines below 3 ng/mL, an observation confirmed in subsequent concentration-controlled trials...
February 27, 2017: Transplantation Reviews
https://www.readbyqxmd.com/read/28276728/determinants-of-high-on-treatment-platelet-reactivity-and-agreement-between-verifynow-and-multiplate-assays
#20
Dorota Danielak, Anna Komosa, Aleksandra Tomczak, Agnieszka Graczyk-Szuster, Maciej Lesiak, Franciszek Główka, Marta Karaźniewicz-Łada
Dual antiplatelet therapy with clopidogrel is a regimen used before and after drug-eluting stent (DES) implantation. Point-of-care platelet reactivity assays are easy-to-use methods to determine adequate response to the drug. The aim of this study was a comparison of the two platelet reactivity assays: Multiplate(®) and VerifyNow(®) and an identification of factors potentially influencing the results of these tests, including common genetic polymorphisms. The study included 39 patients receiving 75 mg clopidogrel daily before angioplasty with DES implantation...
May 2017: Scandinavian Journal of Clinical and Laboratory Investigation
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