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https://www.readbyqxmd.com/read/29678659/association-of-cyp3a4-1b-genotype-with-cyclosporin-a-pharmacokinetics-in-renal-transplant-recipients-a-meta-analysis
#1
Cai-E Wang, Ke-Peng Lu, Zhao Chang, Meng-Li Guo, Hai-Ling Qiao
OBJECTIVE: Cyclosporine (CsA) is a substrate of cytochrome P450 (CYP) 3A4 with a narrow therapeutic index and large individual difference. CYP3A4*1B is reported to be associated with CsA pharmacokinetics parameters, but the relevance is still in dispute. Therefore, a meta-analysis was employed to evaluate the influence of CYP3A4*1B on CsA pharmacokinetics at different post-transplantation times in adult renal transplant recipients. METHODS: Studies on evaluating the CYP3A4*1B genotype and CsA pharmacokinetics were retrieved through a systematical search of relevant database including PubMed, Emabase, Web of science, the Cochrane Library, Clinical Trials...
April 17, 2018: Gene
https://www.readbyqxmd.com/read/29676195/in-vitro-inhibitory-effects-of-sophocarpine-on-human-liver-cytochrome-p450-enzymes
#2
Jingwei Zhang, Chuansheng Li, Jingfa Zhang, Fan Zhang
1. Sophocarpine is a biologically active component isolated from the foxtail-like sophora herb and seed that is often orally administered for the treatment of cancer and chronic bronchial asthma. However, whether sophocarpine affects the activity of human liver cytochrome P450 (CYP) enzymes remains unclear. 2. In this study, the inhibitory effects of sophocarpine on the eight human liver CYP isoforms (CYP1A2, 3A4, 2A6, 2E1, 2D6, 2C9, 2C19, and 2C8) were investigated in vitro using human liver microsomes (HLMs)...
April 20, 2018: Xenobiotica; the Fate of Foreign Compounds in Biological Systems
https://www.readbyqxmd.com/read/29672818/the-in-vitro-and-in-vivo-effects-of-hypoxis-hemerocallidea-on-indinavir-pharmacokinetics-modulation-of-efflux
#3
Kaylee Havenga, Efrem Abay, Lubbe Wiesner, Alvaro Viljoen, Dewald Steyn, Josias Hamman
Hypoxis hemerocallidea (African potato) is a popular medicinal plant that has been used traditionally for the treatment of various disorders. Some HIV/AIDS patients use this traditional medicine together with their antiretroviral therapy. This study aimed to determine the impact of selected H. hemerocallidea materials (i.e., a commercial product, an aqueous extract, and biomass reference plant material) on the bidirectional permeability of indinavir across Caco-2 cell monolayers as well as the bioavailability of indinavir during an acute, single administration study in Sprague-Dawley rats...
April 19, 2018: Planta Medica
https://www.readbyqxmd.com/read/29672606/a-practice-changing-culture-method-relying-on-shaking-substantially-increases-mitochondrial-energy-metabolism-and-functionality-of-human-liver-cell-lines
#4
Aziza A A Adam, Vincent A van der Mark, Joanne M Donkers, Manon E Wildenberg, Ronald P J Oude Elferink, Robert A F M Chamuleau, Ruurdtje Hoekstra
Practice-changing culturing techniques of hepatocytes are highly required to increase their differentiation. Previously, we found that human liver cell lines HepaRG and C3A acquire higher functionality and increased mitochondrial biogenesis when cultured in the AMC-Bioartificial liver (BAL). Dynamic medium flow (DMF) is one of the major contributors to this stimulatory effect. Recently, we found that DMF-culturing by shaking of HepaRG monolayers resulted in higher mitochondrial biogenesis. Here we further investigated the effect of DMF-culturing on energy metabolism and hepatic functionality of HepaRG and C3A monolayers...
2018: PloS One
https://www.readbyqxmd.com/read/29667811/in-vitro-and-in-vivo-studies-of-the-electrophilicity-of-physcion-and-its-oxidative-metabolites
#5
Xiaotong Qin, Ying Peng, Jiang Zheng
Physcion (1,8-dihydroxy-3-methoxy-6-methyl-9,10-anthracenedione) is a bioactive component found in Polygoni Multiflori Radix (PMR) which has been widely used as traditional Chinese medicine. Unfortunately, studies showed hepatotoxicity of PMR during its clinical use. The mechanisms of its toxic action remain unknown. The major objectives of this study were to characterize oxidative metabolites of physcion in vitro and in vivo and to determine the electrophilicity of the parent compound and its oxidative metabolites...
April 18, 2018: Chemical Research in Toxicology
https://www.readbyqxmd.com/read/29659506/in-vitro-inhibitory-effects-of-synthetic-cannabinoid-eam-2201-on-cytochrome-p450-and-udp-glucuronosyltransferase-enzyme-activities-in-human-liver-microsomes
#6
Tae Yeon Kong, Soon-Sang Kwon, Jae Chul Cheong, Hee Seung Kim, Jin Young Kim, Hye Suk Lee
EAM-2201, a synthetic cannabinoid, is a potent agonist of the cannabinoid receptors that is widely abused as an illicit recreational drug in combination with other drugs. To evaluate the potential of EAM-2201 as a perpetrator of drug–drug interactions, the inhibitory effects of EAM-2201 on major drug-metabolizing enzymes, cytochrome P450s (CYPs) and uridine 5′-diphospho-glucuronosyltransferases (UGTs) were evaluated in pooled human liver microsomes using liquid chromatography–tandem mass spectrometry (LC-MS/MS)...
April 16, 2018: Molecules: a Journal of Synthetic Chemistry and Natural Product Chemistry
https://www.readbyqxmd.com/read/29649093/comparison-of-cyp3a4-inducing-capacity-of-enzyme-inducing-antiepileptic-drugs-using-4%C3%AE-hydroxycholesterol-as-biomarker
#7
Kristine Hole, Birgit M Wollmann, Camilla Nguyen, Tore Haslemo, Espen Molden
BACKGROUND: Enzyme-inducing antiepileptic drugs (EIAEDs) are among the clinically most important inducers of cytochrome P450 (CYP) 3A4, but there is limited evidence regarding the comparative potency of each EIAED in raising CYP3A4 activity. The aim of this study was to estimate CYP3A4-inductive potency of EIAEDs by comparing CYP3A4 activity in patients treated with carbamazepine, phenobarbital, or phenytoin. METHODS: Residual serum samples from patients treated with EIAEDs or levetiracetam were collected from a therapeutic drug monitoring service for analysis of 4β-hydroxycholesterol (4βOHC), which is an indicator of CYP3A4 activity...
April 11, 2018: Therapeutic Drug Monitoring
https://www.readbyqxmd.com/read/29648533/the-effect-of-fluconazole-on-the-pharmacokinetics-of-everolimus-and-tacrolimus-in-a-heart-transplant-recipient-a-case-report
#8
Kazuki Nakagita, Kyoichi Wada, Yuka Terada, Sachi Matsuda, Nobue Terakawa, Akira Oita, Mitsutaka Takada
OBJECTIVE: Everolimus is an inhibitor of the mammalian target of rapamycin (mTOR) and has been used in combination with calcineurin inhibitors (tacrolimus and cyclosporine) to prevent allograft rejection following organ transplantation. In heart transplant recipients, everolimus should be maintained at a target blood concentration of 3 - 8 ng/mL, in combination with reduced-dose calcineurin inhibitors and therefore, requires strict monitoring. Fluconazole, an azole antifungal agent, affects blood concentration of tacrolimus by inhibiting the cytochromes P450 (CYP) 3A4 and 3A5...
April 12, 2018: International Journal of Clinical Pharmacology and Therapeutics
https://www.readbyqxmd.com/read/29626440/in-vivo-and-in-vitro-diclofenac-5-hydroxylation-mediated-primarily-by-cytochrome-p450-3a-enzymes-in-common-marmoset-livers-genotyped-for-p450-2c19-variants
#9
Kazuyuki Nakanishi, Shotaro Uehara, Takashi Kusama, Takashi Inoue, Kanami Shimura, Yusuke Kamiya, Norie Murayama, Makiko Shimizu, Yasuhiro Uno, Erika Sasaki, Hiroshi Yamazaki
Common marmosets (Callithrix jacchus) are potentially useful nonhuman primate models for preclinical studies. An anti-inflammatory drug, diclofenac is reportedly metabolized mainly by human cytochrome P450 (P450) 2C9 to 4'-hydroxydiclofenac and minorly by P450 3A4 to 5-hydroxydiclofenac that leads to reactive intermediates. In this study, in vivo pharmacokinetics in six marmosets and in vitro metabolism in nine marmoset liver microsomes were analyzed using diclofenac to evaluate marmosets as preclinical drug metabolism models...
April 4, 2018: Biochemical Pharmacology
https://www.readbyqxmd.com/read/29626326/development-of-a-physiologically-based-pharmacokinetic-model-for-sinogliatin-a-first-in-class-glucokinase-activator-by-integrating-allometric-scaling-in-vitro-to-in-vivo-exploration-and-steady-state-concentration-mean-residence-time-methods-mechanistic-understanding
#10
Ling Song, Yi Zhang, Ji Jiang, Shuang Ren, Li Chen, Dongyang Liu, Xijing Chen, Pei Hu
AIM: The objective of this study was to develop a physiologically based pharmacokinetic (PBPK) model for sinogliatin (HMS-5552, dorzagliatin) by integrating allometric scaling (AS), in vitro to in vivo exploration (IVIVE), and steady-state concentration-mean residence time (Css -MRT) methods and to provide mechanistic insight into its pharmacokinetic properties in humans. METHODS: Human major pharmacokinetic parameters were analyzed using AS, IVIVE, and Css -MRT methods with available preclinical in vitro and in vivo data to understand sinogliatin drug metabolism and pharmacokinetic (DMPK) characteristics and underlying mechanisms...
April 6, 2018: Clinical Pharmacokinetics
https://www.readbyqxmd.com/read/29618712/cytochrome-p450-dependent-drug-oxidation-activities-in-commercially-available-hepatocytes-derived-from-human-induced-pluripotent-stem-cells-cultured-for-3-weeks
#11
Norie Murayama, Hiroshi Yamazaki
Hepatocyte-like cells differentiated from human induced pluripotent stem (iPS) cells are of great interest for applications in pharmacological research. For drug metabolism testing, commercially available hepatocytes derived from human iPS cells are generally recommended to be used 1 week after seeding on plates. In this study, however, after 3-4 weeks of culture according to the manufacturer's instructions, human cytochrome P450 (P450) 2C9- and 2C19-dependent diclofenac 4'-hydroxylation and omeprazole 5-hydroxylation activities of the iPS-derived hepatocytes had significantly increased above the activities at 1 week and had reached levels similar to those in HepaRG cells, a human hepatocyte-like cell line...
2018: Journal of Toxicological Sciences
https://www.readbyqxmd.com/read/29616291/the-role-of-hepatic-cytochrome-p450s-in-the-cytotoxicity-of-dronedarone
#12
Si Chen, Qiangen Wu, Baitang Ning, Matthew Bryant, Lei Guo
Dronedarone is used to treat patients with cardiac arrhythmias and has been reported to be associated with liver injury. Our previous mechanistic work demonstrated that DNA damage-induced apoptosis contributes to the cytotoxicity of dronedarone. In this study, we examined further the underlying mechanisms and found that after a 24-h treatment of HepG2 cells, dronedarone caused cytotoxicity, G1-phase cell cycle arrest, suppression of topoisomerase II, and DNA damage in a concentration-dependent manner. We also investigated the role of cytochrome P450s (CYPs)-mediated metabolism in the dronedarone-induced toxicity using our previously established HepG2 cell lines expressing individually 14 human CYPs (1A1, 1A2, 1B1, 2A6, 2B6, 2C8, 2C9, 2C18, 2C19, 2D6, 2E1, 3A4, 3A5, and 3A7)...
April 3, 2018: Archives of Toxicology
https://www.readbyqxmd.com/read/29615438/generation-of-intestinal-organoids-suitable-for-pharmacokinetic-studies-from-human-induced-pluripotent-stem-cells
#13
Daichi Onozato, Misaki Yamashita, Anna Nakanishi, Takumi Akagawa, Yuriko Kida, Isamu Ogawa, Tadahiro Hashita, Takahiro Iwao, Tamihide Matsunaga
Intestinal organoids morphologically resemble intestinal tissues, and are expected to be used in both regenerative medicine and drug development studies, including pharmacokinetic studies. However, the pharmacokinetic properties of these organoids remain poorly characterized. In this study, we aimed to generate pharmacokinetically functional intestinal organoids from human induced pluripotent stem (iPS) cells. Human iPS cells were induced to differentiate into the hindgut and then seeded on EZSPHERE plates to generate uniform spheroids, and the floating spheroids were subsequently differentiated into intestinal organoids by using small-molecule compounds...
April 3, 2018: Drug Metabolism and Disposition: the Biological Fate of Chemicals
https://www.readbyqxmd.com/read/29603629/cyp3a5-3-and-abcb1-61a-g-significantly-influence-dose-adjusted-trough-blood-tacrolimus-concentrations-in-the-first-three-months-post-kidney-transplantation
#14
Rong Hu, Daniel T Barratt, Janet K Coller, Benedetta C Sallustio, Andrew A Somogyi
Tacrolimus (TAC) is a first-line immunosuppressant used to prevent organ rejection after kidney transplantation. There is large inter-individual variability in its pharmacokinetics. Single nucleotide polymorphisms (SNPs) in genes encoding TAC metabolising enzymes cytochromes P450 3A4/5 (CYP3A4/5), P-glycoprotein efflux transporter (ABCB1), their expression regulator pregnane X receptor (NR1I2), and CYP3A co-factor cytochrome P450 reductase (POR), have been studied for their effects on tacrolimus disposition...
March 30, 2018: Basic & Clinical Pharmacology & Toxicology
https://www.readbyqxmd.com/read/29601950/association-between-mdr-1-cyp3a4-oprm-1-gene-polymorphisms-and-the-post-caesarean-fentanyl-analgesic-effect-on-chinese-women
#15
Jingliang Zhang, Li Zhang, Xia Zhao, Sheliang Shen, Xiaopan Luo, Yunlong Zhang
OBJECTIVE: Our study aimed to evaluate the association between the multidrug resistance 1 (MDR1 )/cytochrome P450 3A4 (CYP3A4)/μ-opioid receptor (OPRM1 ) gene polymorphisms and the post-caesarean analgesic effect of fentanyl on Chinese women. METHODS: We recruited 240 patients who received lower segment caesarean section surgeries. Sanger sequencing was used to analyze the MDR1 1236C > T/CYP3A4*1G/OPRM1 A118G polymorphisms. We evaluated post-operative fentanyl consumption and the effect of intravenous analgesia in patients with different genotypes...
March 27, 2018: Gene
https://www.readbyqxmd.com/read/29595119/cytochrome-p450-3a4-induction-lumacaftor-versus-ivacaftor-potentially-resulting-in-significantly-reduced-plasma-concentration-of-ivacaftor
#16
Elena K Schneider
Since release of ivacaftor-lumacaftor several red-flags have been raised that highlight the clinical efficacy of this combination strategy may be be limited due to antagonistic drug-drug interactions. </p><p> Method: The effect of ivacaftor, its major metabolites M1 and M6, lumacaftor and the novel cystic fibrosis transmembrane conductance regulator (CFTR) modulator tezacaftor at 10 µg/mL on the enzymatic activity of the major xenobiotic metabolizing enzymes CYP1A2 and CYP3A4 as well as the minor enzymes CYP2B6 and CYP2C9 was assayed...
March 27, 2018: Drug Metabolism Letters
https://www.readbyqxmd.com/read/29593874/statin-induced-rhabdomyolysis-a-complication-of-a-commonly-overlooked-drug-interaction
#17
Saad Ezad, Hooria Cheema, Nicholas Collins
Rhabdomyolysis is a well-documented side effect of statin therapy. This risk is increased with concurrent use of medications that inhibit cytochrome p450-3A4 (CYP3A4), such as macrolide antibiotics. We present the case of a 67-year-old patient who was commenced on clarithromycin on a background of simvastatin therapy, resulting in rhabdomyolysis. This case highlights the need for awareness of common drug interactions associated with statins. It also emphasizes the significance of commencing statins at a lower dose in new patients, and lastly, the importance of early recognition and management of rhabdomyolysis to prevent the development of complications...
March 2018: Oxford Medical Case Reports
https://www.readbyqxmd.com/read/29589331/population-pharmacokinetic-analysis-of-asunaprevir-in-subjects-with-hepatitis-c-virus-infection
#18
Li Zhu, Hanbin Li, Phyllis Chan, Timothy Eley, Yash Gandhi, Marc Bifano, Mayu Osawa, Takayo Ueno, Eric Hughes, Malaz AbuTarif, Richard Bertz, Tushar Garimella
INTRODUCTION: Asunaprevir (ASV) is a potent, pangenotypic, twice-daily hepatitis C virus (HCV) NS3 inhibitor indicated for the treatment of chronic HCV infection. METHODS: A population pharmacokinetic (PPK) model was developed using pooled ASV concentration data from 1239 HCV-infected subjects who received ASV either as part of the DUAL regimen with daclatasvir or as part of the QUAD regimen with daclatasvir and peg-interferon/ribavirin. RESULTS: A two-compartment model with first-order elimination from the central compartment, an induction effect on clearance, and an absorption model consisted of zero-order release followed by first-order absorption adequately described ASV PK after oral administration...
March 27, 2018: Infectious Diseases and Therapy
https://www.readbyqxmd.com/read/29588194/using-chemical-bond-based-method-to-predict-site-of-metabolism-for-five-biotransformations-mediated-by-cyp-3a4-2d6-and-2c9
#19
XuYan Fu, ShuaiBing He, Li Du, ZhaoLei Lv, Yi Zhang, Qian Zhang, Yun Wang
Although it has been proposed for decades to predict site of metabolism (SOM) by in silico methods, identifying SOM correctly remains an unsolved fundamental problem and is an active area of research. In our prior works, we proposed a chemical bond-based approach to construction of SOM prediction models by integrating chemical bond descriptors and drug-metabolizing enzymes data. Although it has been evaluated with both 10-fold cross-validation and independent validation, we believe comparisons between this method and prior methods using publicly accessible external datasets are indispensable and more desirable...
March 24, 2018: Biochemical Pharmacology
https://www.readbyqxmd.com/read/29572563/assessment-of-inter-racial-variability-in-cyp3a4-activity-and-inducibility-among-healthy-adult-males-of-caucasian-and-south-asian-ancestries
#20
Madelé van Dyk, Jean-Claude Marshall, Michael J Sorich, Linda S Wood, Andrew Rowland
PURPOSE: Cytochrome P450 (CYP) 3A4 is responsible for the metabolism of more than 30% of clinically used drugs. Inherent between subject variability in clearance of CYP3A4 substrates is substantial; by way of example, midazolam clearance varies by > 10-fold between individuals before considering the impact of extrinsic factors. Relatively little is known about inter-racial variability in the activity of this enzyme. METHODS: This study assessed inter-racial variability in midazolam exposure in a cohort (n = 30) of CYP3A genotyped, age-matched healthy males of Caucasian and South Asian ancestries...
March 23, 2018: European Journal of Clinical Pharmacology
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