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https://www.readbyqxmd.com/read/29325225/influence-of-cyp2d6-cyp3a4-cyp3a5-and-abcb1-polymorphisms-on-pharmacokinetics-and-safety-of-aripiprazole-in-healthy-volunteers
#1
Carmen Belmonte, Dolores Ochoa, Manuel Román, Miriam Saiz-Rodríguez, Aneta Wojnicz, Clara Isabel Gómez-Sánchez, Samuel Martín-Vilchez, Francisco Abad-Santos
The aim of this study was to investigate the effect of polymorphisms in cytochrome P450 (CYP) 2D6, CYP3A4 and CYP3A5 enzymes and in P-glycoprotein (P-gp) on the pharmacokinetics and safety of aripiprazole and, its active metabolite, dehydro-aripiprazole, in 148 healthy volunteers from 6 bioequivalence trials receiving a single oral dose of aripiprazole. The plasma concentrations of both analytes were measured by LC-MS/MS. CYP2D6 (*3,*4,*5,*6,*7,*9 and copy number variations), CYP3A4 (*20 and *22), CYP3A5*3 and C3435T, C1236T and G2677T/A in ABCB1 gene were determined...
January 11, 2018: Basic & Clinical Pharmacology & Toxicology
https://www.readbyqxmd.com/read/29322841/the-effect-of-lycopene-on-cytochrome-p450-isoenzymes-and-p-glycoprotein-by-using-human-liver-microsomes-and-caco-2-cell-monolayer-model
#2
Lingti Kong, Chunli Song, Linhu Ye, Jian Xu, Daohua Guo, Qingping Shi
Lycopene is widely used as a dietary supplement. However, the effects of lycopene on cytochrome P450 (CYP) enzymes or P-glycoprotein (P-gp) are not comprehensive. The present study was performed to investigate the effects of lycopene on the CYP enzymes and P-gp activity. A cocktail method was used to evaluate the activities of CYP3A4, CYP2C9, CYP2C19, CYP2D6 and CYP2E1. Caco-2 cell monolayer model was carried out to assay lycopene on P-gp activity. The results indicated that lycopene had a moderate inhibitory effect on CYP2E1, with IC50 value of 43...
January 11, 2018: International Journal of Food Sciences and Nutrition
https://www.readbyqxmd.com/read/29320899/in-vitro-analysis-of-itraconazole-cis-diastereoisomers-inhibition-of-nine-cytochrome-p450-enzymes-stereoselective-inhibition-of-cyp3a
#3
Kristyna Krasulova, Zdenek Dvorak, Pavel Anzenbacher
Itraconazole (ITZ), an antifungal azole derivate is a chiral drug that consists of four cis-diastereoisomers ((+)-2R,4S,2'R-ITZ-A; (+)-2R,4S,2'S-ITZ-B; (-)2S,4R,2'S-ITZ-C and (-) 2S,4R,2'R-ITZ-D) which may differ in their pharmacokinetics and pharmacodynamics. As itraconazole is known as a CYP3A4 inhibitor causing severe drug-drug interaction, the inhibitory potencies of its individual optical isomers towards nine drug-metabolising cytochrome P450 (including CYP3A, CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6 and CYP2E1), were investigated...
January 10, 2018: Xenobiotica; the Fate of Foreign Compounds in Biological Systems
https://www.readbyqxmd.com/read/29320849/a-dft-study-on-the-demethylation-reaction-between-methylamine-dimethylamine-trimethylamine-and-tamoxifen-catalyzed-by-a-fe-iv-oxo-porphyrin-complex
#4
Nerea Alberro, Miquel Torrent-Sucarrat, Ana Arrieta, Gloria Rubiales, Fernando P Cossio
In this work, we have studied computationally the N-demethylation reaction of methylamine, dimethylamine and trimethylamine as archetypal examples of primary, secondary and tertiary amines catalyzed by high field low spin Fe-containing enzymes such as cytochromes P450. Using DFT calculations, we have obtained that the expected C-H hydroxylation process is achieved for trimethylamine. When dimethylamine and methylamine were studied, two different reaction mechanisms (C-H hydroxylation and a double hydrogen atom transfer) were computed to be energetically accessible and both are equally preferred...
January 11, 2018: Journal of Physical Chemistry. A
https://www.readbyqxmd.com/read/29319893/possible-role-of-cyp2b6-genetic-polymorphisms-in-ifosfamide-induced-encephalopathy-report-of-three-cases
#5
Thomas Duflot, Aude Marie-Cardine, Céline Verstuyft, Bruno Filhon, Tony Pereira, Nathalie Massy Guillemant, Robinson Joannidès, Jérémy Bellien, Fabien Lamoureux
Ifosfamide (IFA) is a potent alkylating antitumoral agent but its use is limited by neurological side effects. IFA is a racemic mixture of two enantiomeric forms, R-IFA and S-IFA with a stereoselective metabolism by CYP3A4 and CYP2B6, leading either to bioactive or to toxic pathways. In 3 consecutive cases of pediatric patients who exhibited ifosfamide-induced encephalopathy (IIE), genotyping of clinically relevant single nucleotide polymorphisms associated with decreased CYP3A4 and CYP2B6 activities was performed...
January 10, 2018: Fundamental & Clinical Pharmacology
https://www.readbyqxmd.com/read/29318894/attempted-validation-of-44-reported-snps-associated-with-tacrolimus-troughs-in-a-cohort-of-kidney-allograft-recipients
#6
William S Oetting, Baolin Wu, David P Schladt, Weihua Guan, Rory P Remmel, Casey Dorr, Roslyn B Mannon, Arthur J Matas, Ajay K Israni, Pamala A Jacobson
AIM: Multiple genetic variants have been associated with variation in tacrolimus (TAC) trough concentrations. Unfortunately, additional studies do not confirm these associations, leading one to question if a reported association is accurate and reliable. We attempted to validate 44 published variants associated with TAC trough concentrations. MATERIALS & METHODS: Genotypes of the variants in our cohort of 1923 kidney allograft recipients were associated with TAC trough concentrations...
January 10, 2018: Pharmacogenomics
https://www.readbyqxmd.com/read/29314710/different-in-vitro-and-in-vivo-tools-for-elucidating-the-human-metabolism-of-alpha-cathinone-derived-drugs-of-abuse
#7
Sascha K Manier, Lilian H J Richter, Jan Schäper, Hans H Maurer, Markus R Meyer
In vitro and in vivo experiments are widely used for studying the metabolism of new psychoactive substances (NPS). The availability of such data is required for toxicological risk assessments and development of urine screening approaches. This study investigated the in vitro metabolism of the five pyrrolidinophenone-derived NPS alpha-pyrrolidinobutyrophenone (alpha-PBP), alpha-pyrrolidinopentiothiophenone (alpha-PVT), alpha-pyrrolidinohexanophenone (alpha-PHP), alpha-pyrrolidinoenanthophenone (alpha-PEP, PV8), and alpha-pyrrolidinooctanophenone (alpha-POP, PV9)...
January 4, 2018: Drug Testing and Analysis
https://www.readbyqxmd.com/read/29311482/population-pharmacokinetics-and-adverse-events-of-erlotinib-in-japanese-patients-with-non-small-cell-lung-cancer-impact-of-genetic-polymorphisms-in-metabolizing-enzymes-and-transporters
#8
Chihiro Endo-Tsukude, Ji-Ichiro Sasaki, Sho Saeki, Norihiro Iwamoto, Megumi Inaba, Sunao Ushijima, Hiroto Kishi, Shinji Fujii, Hiroshi Semba, Kosuke Kashiwabara, Yukari Tsubata, Mitsuhiro Hayashi, Yuki Kai, Hideyuki Saito, Takeshi Isobe, Hirotsugu Kohrogi, Akinobu Hamada
Determinants of interindividual variability in erlotinib pharmacokinetics (PK) and adverse events remain to be elucidated. This study with 50 Japanese non-small-cell lung cancer patients treated with oral erlotinib at a standard dose of 150 mg aimed to investigate whether genetic polymorphisms affect erlotinib PK and adverse events. Single nucleotide polymorphisms (SNPs) in genes encoding metabolizing enzymes (CYP1A1, CYP1A2, CYP2D6, CYP3A4, CYP3A5, UGT1A1, UGT2B7, GSTM1, and GSTT1) or efflux transporters (ABCB1, and ABCG2) were analyzed as covariates in a population PK model...
2018: Biological & Pharmaceutical Bulletin
https://www.readbyqxmd.com/read/29311093/characterization-of-the-preclinical-pharmacology-of-the-new-2-aminomethylphenol-jpc-3210-for-malaria-treatment-and-prevention
#9
Geoffrey W Birrell, Gavin D Heffernan, Guy A Schiehser, John Anderson, Arba L Ager, Pablo Morales, Donna MacKenzie, Karin van Breda, Marina Chavchich, Laura R Jacobus, G Dennis Shanks, David P Jacobus, Michael D Edstein
The new 2-aminomethylphenol JPC-3210 has potent in vitro antimalarial activity against multidrug-resistant Plasmodium falciparum lines, low cytotoxicity and high in vivo efficacy against murine malaria. Here we report on the pharmacokinetics of JPC-3210 in mice and monkeys and in vitro screening assays including the inhibition of cytochrome (CYP) P450 isozymes. In mice JPC-3210 is rapidly absorbed, has extensive tissue distribution with a brain tissue to plasma concentration ratio of about 5.4 and a lengthy plasma elimination half-life of about 4...
January 8, 2018: Antimicrobial Agents and Chemotherapy
https://www.readbyqxmd.com/read/29310431/the-binding-specificity-determines-the-cytochrome-p450-3a4-mediated-enantioselective-metabolism-of-metconazole
#10
Shulin Zhuang, Leili Zhang, Tingjie Zhan, Liping Lu, Lu Zhao, Haifei Wang, Joseph A Morrone, Weiping Liu, Ruhong Zhou
Cytochrome CYP3A4 is the most promiscuous enzyme mediating biotransformations of ~50% of clini-cally used drugs with many of them chiral molecules. Probing the interactions between CYP3A4 and chiral chemicals is thus essential for the elucidation of molecular mechanisms of the enantioselective metabolism. We developed a step-wise restrained molecular dynamics (MD) method to model the hu-man CYP3A4 in a complex with the cis-Metconazole (MEZ) isomers and performed conventional MD simulations with a total simulation time of 2...
January 8, 2018: Journal of Physical Chemistry. B
https://www.readbyqxmd.com/read/29304859/a-phase-1-evaluation-of-the-pharmacokinetic-pharmacodynamic-interaction-of-the-anti-malarial-agents-kaf156-and-piperaquine
#11
F Joel Leong, Jay Prakash Jain, Yiyan Feng, Budhaditya Goswami, Daniel S Stein
BACKGROUND: KAF156 is a novel imidazolopiperazine anti-malarial with activity against pre-erythrocytic liver stages, asexual and sexual blood stages. Based on in vitro data, a two-way pharmacokinetic interaction was hypothesized for KAF156 use in combination with piperaquine (PPQ) as both drugs are CYP3A4 substrates and inhibitors. Potential combination effects on the QT interval were also assessed. METHODS: This was an open-label, parallel-group, single-dose study in healthy volunteers randomized to three parallel arms (1:1:1) of 800 mg KAF156 + 1280 mg PPQ, 800 mg KAF156 alone and 1280 mg PPQ alone...
January 5, 2018: Malaria Journal
https://www.readbyqxmd.com/read/29301387/pharmacogenetics-of-vascular-risk-factors-in-alzheimer-s-disease
#12
REVIEW
Ramón Cacabelos, Arun Meyyazhagan, Juan C Carril, Pablo Cacabelos, Óscar Teijido
Alzheimer's disease (AD) is a polygenic/complex disorder in which genomic, epigenomic, cerebrovascular, metabolic, and environmental factors converge to define a progressive neurodegenerative phenotype. Pharmacogenetics is a major determinant of therapeutic outcome in AD. Different categories of genes are potentially involved in the pharmacogenetic network responsible for drug efficacy and safety, including pathogenic, mechanistic, metabolic, transporter, and pleiotropic genes. However, most drugs exert pleiotropic effects that are promiscuously regulated for different gene products...
January 3, 2018: Journal of Personalized Medicine
https://www.readbyqxmd.com/read/29297772/assessment-of-drug-drug-interaction-potential-and-pbpk-modeling-of-cc-223-a-potent-inhibitor-of-the-mammalian-target-of-rapamycin-kinase
#13
Zeen Tong, Rangaraj Narayanan, Christian Atsriku, Jim Nissel, Yan Li, Hong Liu, Xiaomin Wang, Sekhar Surapaneni
1. CC-223 was studied in vitro for metabolism and drug-drug interactions (DDI), and in clinic for interaction with ketoconazole. 2. In vitro, human metabolites of CC-223 included O-desmethyl CC-223 (M1), keto (M2), N-oxide (M3), and imine (M13), with M1 being the most prominent metabolite. 3. CC-223 was metabolized by CYP2C9 and CYP3A, while metabolism of M1 was mediated by CYP2C8 and CYP3A. Ketoconazole increased CC-223 and M1 exposure by 60-70% in healthy volunteers. 4. CC-223 (IC50 ≥ 27 µM) and M1 (IC50 ≥ 46 µM) were inhibitors of CYP2C9 and CYP2C19 in human liver microsomes...
January 3, 2018: Xenobiotica; the Fate of Foreign Compounds in Biological Systems
https://www.readbyqxmd.com/read/29297729/direct-and-quantitative-evaluation-of-the-major-human-cyp-contribution-fmcyp-to-drug-clearance-using-the-in-vitro-silensomes%C3%A2-model
#14
Yannick Parmentier, Corinne Pothier, Nicky Hewitt, Ludwig Vincent, Fabrice Caradec, Jia Liu, Feifei Lin, Marie-Michèle Trancart, Fabrice Guillet, Belkacem Bouaita, Christophe Chesne, Bernard Walther
1. We have applied the concept of using MBIs to produce CYP-Silensomes to quantify the contribution of the major CYPs to drug metabolism (fmCYP). 2. The target CYPs were extensively and selectivity inhibited by the selected MBIs, while non-target CYPs were inhibited by less than 20% of the homologous control activities. Only CYP2D6-Silensomes exhibited a CYP2B6 inhibition that could be easily and efficiently encountered by subtracting the fmCYP2B6 measured using CYP2B6-Silensomes to adjust the fmCYP2D6. 3. To validate the use of a panel of 6 CYP-Silensomes, we showed that the fmCYP values of mono- and multi-CYP metabolised drugs were well predicted, with 70% within ± 15% accuracy...
January 3, 2018: Xenobiotica; the Fate of Foreign Compounds in Biological Systems
https://www.readbyqxmd.com/read/29289430/design-synthesis-and-structure-activity-relationship-studies-of-novel-tetrazole-antifungal-agents-with-potent-activity-broad-antifungal-spectrum-and-high-selectivity
#15
Anran Qian, Yazhou Zheng, Ruilian Wang, Jianhai Wei, Yongmei Cui, Xufeng Cao, Yushe Yang
In this letter, we report our efforts to design, synthesize and evaluate biological activities of a series of novel hybridized compounds containing 1-tetrazole and 4-pyridinyl-1,2,4-triazole-3-one. An analysis of structure-activity data indicates that the target compounds with bulky and hydrophobic side chains exhibited stronger activities against the Candida spp and Cryptococcus neoformans tested than those of fluconazole and racemic VT-1161. Furthermore, 13k and 13ad were active against Microsporum gypseum, which was resistant to racemic VT-1161...
December 20, 2017: Bioorganic & Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/29285606/the-formation-of-estrogen-like-tamoxifen-metabolites-and-their-influence-on-enzyme-activity-and-gene-expression-of-adme-genes
#16
Janina Johänning, Patrick Kröner, Maria Thomas, Ulrich M Zanger, Astrid Nörenberg, Michel Eichelbaum, Matthias Schwab, Hiltrud Brauch, Werner Schroth, Thomas E Mürdter
Tamoxifen, a standard therapy for breast cancer, is metabolized to compounds with anti-estrogenic as well as estrogen-like action at the estrogen receptor. Little is known about the formation of estrogen-like metabolites and their biological impact. Thus, we characterized the estrogen-like metabolites tamoxifen bisphenol and metabolite E for their metabolic pathway and their influence on cytochrome P450 activity and ADME gene expression. The formation of tamoxifen bisphenol and metabolite E was studied in human liver microsomes and Supersomes™...
December 28, 2017: Archives of Toxicology
https://www.readbyqxmd.com/read/29283173/cyp3a4-inducer-and-inhibitor-strongly-affect-the-pharmacokinetics-of-triptolide-and-its-derivative-in-rats
#17
Ye Xu, Yi-Fan Zhang, Xiao-Yan Chen, Da-Fang Zhong
Triptolide is the most active ingredient of Tripterygium wilfordii Hook F, which is used to treat rheumatoid arthritis. (5R)-5-Hydroxytriptolide is a hydroxylation derivative of triptolide with a reduced toxicity. To investigate the metabolic enzymes of the two compounds and the drug-drug interactions with enzyme inducers or inhibitors, a series of in vitro and in vivo experiments were conducted. In vitro studies using recombinant human cytochrome P450 enzyme demonstrated that cytochrome P450 3A4 (CYP3A4) was predominant in the metabolism of triptolide and (5R)-5-hydroxytriptolide, accounting for 94...
December 28, 2017: Acta Pharmacologica Sinica
https://www.readbyqxmd.com/read/29282674/correction-to-development-of-guanfacine-extended-release-dosing-strategies-in-children-and-adolescents-with-adhd-using-a-physiologically-based-pharmacokinetic-model-to-predict-drug-drug-interactions-with-moderate-cyp3a4-inhibitors-or-inducers
#18
Aiqun Li, Karen Yeo, Devin Welty, Haojing Rong
The article "Development of Guanfacine Extended-Release Dosing Strategies in Children and Adolescents with ADHD Using a PhysiologicallyBased Pharmacokinetic Model to Predict Drug-Drug Interactions with Moderate CYP3A4 Inhibitors or Inducers", written by Aiqun Li, Karen Yeo, Devin Welty, Haojing Rong, was originally published electronically on the publisher's internet portal (currently SpringerLink) on 02nd November, 2017 without open access.
December 28, 2017: Paediatric Drugs
https://www.readbyqxmd.com/read/29280762/brentuximab-vedotin-with-avd-shows-safety-in-the-absence-of-strong-cyp3a4-inhibitors-in-newly-diagnosed-hiv-associated-hodgkin-lymphoma
#19
Paul G Rubinstein, Page C Moore, Michelle A Rudek, David H Henry, Juan C Ramos, Lee Ratner, Erin Reid, Elad Sharon, Ariela Noy
OBJECTIVE: Brentuximab vedotin (BV) is an FDA approved anti-CD30 antibody drug conjugate potently active in Hodgkin lymphoma (HL). Trials of BV with doxorubicin, vinblastine, and dacarbazine (AVD-BV) excluded patients with HIV. We studied the safety of (AVD-BV) in newly diagnosed HIV-associated classical Hodgkin lymphoma (HIV-cHL). DESIGN AND METHODS: Patients diagnosed with Stage II-IV HIV-cHL received AVD-BV on days 1 and 15 every 28 days for 6 cycles. Anti-HIV medications with strong CYP3A4 inhibition were excluded...
December 26, 2017: AIDS
https://www.readbyqxmd.com/read/29279486/differences-in-the-serum-4%C3%AE-hydroxycholesterol-levels-of-patients-with-chronic-hcv-infection-a-possible-impact-on-the-efficacy-and-safety-of-ifn-free-treatment
#20
Takeshi Hirayama, Tadashi Ikegami, Akira Honda, Teruo Miyazaki, Sho-Ichiro Yara, Motoyuki Kohjima, Makoto Nakamuta, Yasushi Matsuzaki
Since the majority of direct-acting antivirals (DAAs) that are used in the treatment of HCV infection are mainly metabolized by CYP3A4, it is hypothesized that inter-individual differences in CYP3A4 activity may be associated with the bioavailability of these agents. Methods The level of serum 4β-hydroxycholesterol (4βHC), a surrogate marker of CYP3A4 activity, was determined by LC-MS/MS in samples obtained from patients with HCV infection (CHCs) as well as healthy control subjects (CTLs). Serum samples obtained from patients treated with either asunaprevir/daclatasvir (ASV/DCV) or ombitasvir/paritaprevir/ritonavir (OTV/PTV/r) were used for additional assays...
December 27, 2017: Internal Medicine
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