keyword
MENU ▼
Read by QxMD icon Read
search

CYP2C8

keyword
https://www.readbyqxmd.com/read/29345044/preclinical-characterisation-of-absorption-distribution-metabolism-and-excretion-properties-of-tak-063
#1
Kimio Tohyama, Miyako Sudo, Akio Morohashi, Suguru Kato, Junzo Takahashi, Yoshihiko Tagawa
TAK-063 is currently being developed to treat schizophrenia. In this study, we investigated the absorption, distribution, metabolism and excretion (ADME) properties of TAK-063 using several paradigms. Following oral administration of TAK-063 at 0.3 mg/kg, bioavailability of TAK-063 was 27.4% in rats and 49.5% in dogs with elimination half-lives of 3.1 hr in rats and 3.7 hr in dogs. TAK-063 is a highly permeable compound without P-glycoprotein (P-gp) or breast cancer resistance protein substrate liability and can be readily absorbed into systemic circulation via the intestine...
January 17, 2018: Basic & Clinical Pharmacology & Toxicology
https://www.readbyqxmd.com/read/29320899/in-vitro-analysis-of-itraconazole-cis-diastereoisomers-inhibition-of-nine-cytochrome-p450-enzymes-stereoselective-inhibition-of-cyp3a
#2
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/29297772/assessment-of-drug-drug-interaction-potential-and-pbpk-modeling-of-cc-223-a-potent-inhibitor-of-the-mammalian-target-of-rapamycin-kinase
#3
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
#4
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/29247736/metabolic-pathway-of-icotinib-in-vitro-the-differential-roles-of-cyp3a4-cyp3a5-and-cyp1a2-on-potential-pharmacokinetic-drug-drug-interaction
#5
TianHong Zhang, KeRong Zhang, Li Ma, Zheng Li, Juan Wang, YunXia Zhang, Chuang Lu, MingShe Zhu, XiaoMei Zhuang
Icotinib is the self-developed small molecule drug in China for targeted therapy of non-small-cell lung cancer. To date, systematic studies on the pharmacokinetic drug-drug interaction (DDI) of icotinib were limited. By identifying metabolite generation in human liver microsomes (HLM) and revealing the contributions of major CYPs in the formation of major metabolites, the aim of the present work is to understand the mechanisms underlying pharmacokinetic and pharmacological variability in clinic. A LC/UV/HRMS method was developed to characterize the icotinib metabolites...
December 13, 2017: Journal of Pharmaceutical Sciences
https://www.readbyqxmd.com/read/29246313/assessment-of-the-drug-interaction-potential-of-unconjugated-and-galnac3-conjugated-2-moe-asos
#6
Colby S Shemesh, Rosie Z Yu, Mark S Warren, Michael Liu, Mirza Jahic, Brandon Nichols, Noah Post, Song Lin, Daniel A Norris, Eunju Hurh, Jane Huang, Tanya Watanabe, Scott P Henry, Yanfeng Wang
Antisense oligonucleotides are metabolized by nucleases and drug interactions with small drug molecules at either the cytochrome P450 (CYP) enzyme or transporter levels have not been observed to date. Herein, a comprehensive in vitro assessment of the drug-drug interaction (DDI) potential was carried out with four 2'-O-(2-methoxyethyl)-modified antisense oligonucleotides (2'-MOE-ASOs), including a single triantennary N-acetyl galactosamine (GalNAc3)-conjugated ASO. Several investigations to describe the DDI potential of a 2'-MOE-ASO conjugated to a high-affinity ligand for hepatocyte-specific asialoglycoprotein receptors are explored...
December 15, 2017: Molecular Therapy. Nucleic Acids
https://www.readbyqxmd.com/read/29233455/genetic-variation-of-cytochrome-p450-in-uyghur-chinese-population
#7
Guangzhao Qi, Duolu Li, Xiaojian Zhang
Interindividual and interethnic variability of drug responses could be attributed to the differences of genetic polymorphisms in the drug metabolizing enzymes and transporters genes among the populations. Here we reviewed the studies of genetic variations in Uyghur Chinese of fifteen CYP450 genes including CYP1A1, CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP2E1, CYP2J2, CYP2W1, CYP3A4, CYP3A5, CYP4A11, and CYP17A1, which totally covered 277 variants. We also collected the data of 277 variants covered in our study in two extensive population sequencing projects, the International HapMap Project (Hap-Map) and the 1000 Genomes Project and compared them with the data of Uyghur Chinese...
March 6, 2017: Drug Metabolism and Pharmacokinetics
https://www.readbyqxmd.com/read/29226313/model-based-assessments-of-cyp-mediated-drug-drug-interaction-risk-of-alectinib-physiologically-based-pharmacokinetic-modeling-supported-clinical-development
#8
Yumi Cleary, Michael Gertz, Peter N Morcos, Li Yu, Kuresh Youdim, Alex Phipps, Stephen Fowler, Neil Parrott
Alectinib is a selective anaplastic lymphoma kinase (ALK) inhibitor approved for the treatment of ALK-positive non-small cell lung cancer. Alectinib and its major active metabolite M4 exhibited drug-drug interaction (DDI) potential through cytochrome P450 (CYP) enzymes CYP3A4 and CYP2C8 in vitro. Clinical relevance of the DDI risk was investigated as part of a rapid development program to fulfil the breakthrough therapy designation. Therefore, a strategy with a combination of physiologically based pharmacokinetic (PBPK) modeling and limited clinical trials focused on generating informative data for modeling was taken to ensure extrapolation ability of DDI risk...
December 11, 2017: Clinical Pharmacology and Therapeutics
https://www.readbyqxmd.com/read/29223619/differential-effects-of-hepatic-cirrhosis-on-the-intrinsic-clearances-of-sorafenib-and-imatinib-by-cyps-in-human-liver
#9
Michael Murray, Tina B Gillani, Sussan Ghassabian, Robert J Edwards, Tristan Rawling
The tyrosine kinase inhibitors sorafenib and imatinib are important in the treatment of a range of cancers but adverse effects in some patients necessitate dosage modifications. CYP3A4 has a major role in the oxidation of sorafenib to its N-oxide and N-hydroxymethyl metabolites and also acts in concert with CYP2C8 to mediate imatinib N-demethylation. CYP3A4 expression and function are impaired in patients with advanced liver disease, whereas the functions of CYP2C enzymes are relatively preserved. We evaluated the biotransformation of sorafenib and imatinib in well-characterized microsomal fractions from 17 control subjects and 19 individuals with hepatic cirrhosis of varying severity...
December 6, 2017: European Journal of Pharmaceutical Sciences
https://www.readbyqxmd.com/read/29218011/pharmacogenetic-variation-in-over-100-genes-in-patients-receiving-acenocumarol
#10
Vanessa Gonzalez-Covarrubias, Javier Urena-Carrion, Beatriz Villegas-Torres, J Eduardo Cossío-Aranda, Sergio Trevethan-Cravioto, Raul Izaguirre-Avila, O Javier Fiscal-López, Xavier Soberon
Coumarins are widely prescribed worldwide, and in Mexico acenocumarol is the preferred form. It is well known that despite its efficacy, coumarins show a high variability for dose requirements. We investigated the pharmacogenetic variation of 110 genes in patients receiving acenocumarol using a targeted NGS approach. We report relevant population differentiation for variants on CYP2C8, CYP2C19, CYP4F11, CYP4F2, PROS, and GGCX, VKORC1, CYP2C18, NQO1. A higher proportion of novel-to-known variants for 10 genes was identified on 41 core pharmacogenomics genes related to the PK (29), PD (3), of coumarins, and coagulation proteins (9) including, CYP1A1, CYP3A4, CYP3A5, and F8, and a low proportion of novel-to-known variants on CYP2E1, VKORC1, and SULT1A1/2...
2017: Frontiers in Pharmacology
https://www.readbyqxmd.com/read/29205295/protein-abundance-of-clinically-relevant-drug-metabolizing-enzymes-in-the-human-liver-and-intestine-a-comparative-analysis-in-paired-tissue-specimens
#11
M Drozdzik, D Busch, J Lapczuk, J Müller, M Ostrowski, M Kurzawski, S Oswald
The work revises and complements existing findings on the distribution of drug metabolizing enzymes' in the first-pass effect organs. We explored gene expression (qPCR) and protein abundance (LC-MS/MS) of CYP1A2, CYP2B6, CYP2C8/9/19, CYP2D6, CYP2E1, CYP3A4/5, UGT1A1/3, UGT2B7/15 in the liver, duodenum, jejunum, ileum and colon in paired tissues from 9 organ donors. All proteins were detected in the liver, but in the intestine CYP2C9/19, CYP2D6, CYP3A4/5, UGT1A1/3 and UGT2B7 were found. CYP3A4 showed comparable abundance in the liver and jejunum, whereas other enzymes were markedly higher in the hepatic tissue...
December 5, 2017: Clinical Pharmacology and Therapeutics
https://www.readbyqxmd.com/read/29203276/effect-of-ugt2b7-2-and-cyp2c8-4-polymorphisms-on-diclofenac-metabolism
#12
Katarzyna E Lazarska, Stefan J Dekker, Nico P E Vermeulen, Jan N M Commandeur
The use of diclofenac is associated with rare but severe drug-induced liver injury (DILI) in a very small number of patients. The factors which predispose susceptible patients to hepatotoxicity of diclofenac are still incompletely understood. Formation of protein-reactive metabolites by UDP-glucuronosyl transferases and cytochromes P450 is commonly considered to play an important role, as indicated by the detection of covalent protein adducts and antibodies in the serum of patients suffering from diclofenac-induced liver injury...
December 1, 2017: Toxicology Letters
https://www.readbyqxmd.com/read/29198326/the-molecular-genetics-of-chemotherapy-induced-peripheral-neuropathy-a-systematic-review-and-meta-analysis
#13
REVIEW
J Cliff, A L Jorgensen, R Lord, F Azam, L Cossar, D F Carr, M Pirmohamed
Chemotherapy-induced peripheral neuropathy (CIPN) can adversely affect completion of systemic anti-cancer treatment and cause long-term morbidity. Increasingly pharmacogenetic studies have been performed to explore susceptibility to this important adverse effect. A systematic review was conducted to identify pharmacogenetic studies, assess their quality and findings and undertake meta-analysis where possible. 93 studies were included. Notable methodological issues included lack of standardisation and detail in phenotype definition and acknowledgement of potential confounding factors...
December 2017: Critical Reviews in Oncology/hematology
https://www.readbyqxmd.com/read/29194718/prediction-of-olanzapine-exposure-in-individual-patients-using-physiologically-based-pharmacokinetic-modelling-and-simulation
#14
Thomas M Polasek, Geoffrey T Tucker, Michael J Sorich, Michael D Wiese, Titus Mohan, Amin Rostami-Hodjegan, Porntipa Korprasertthaworn, Vidya Perera, Andrew Rowland
AIM: To predict olanzapine (OLZ) exposure in individual patients using physiologically-based pharmacokinetic modelling and simulation (PBPK M&S). METHODS: A 'bottom-up' PBPK model for OLZ was constructed in Simcyp® (V14.1) and validated against pharmacokinetic studies and data from therapeutic drug monitoring (TDM). The physiological, demographic and genetic attributes of the 'healthy volunteer population' file in Simcyp® were then individualised to create 'virtual twins' of 14 patients...
November 30, 2017: British Journal of Clinical Pharmacology
https://www.readbyqxmd.com/read/29174535/prediction-of-inter-individual-variability-on-the-pharmacokinetics-of-cyp2c8-substrates-in-human
#15
Kenta Haraya, Motohiro Kato, Koji Chiba, Yuichi Sugiyama
Inter-individual variability in pharmacokinetics can lead to unexpected side effects and treatment failure, and is therefore an important factor in drug development. CYP2C8 is a major drug-metabolizing enzyme known to be involved in the metabolism of over 100 drugs. In this study, we predicted the inter-individual variability in AUC/Dose of CYP2C8 substrates in healthy volunteers using the Monte Carlo simulation. Inter-individual variability in the hepatic intrinsic clearance of CYP2C8 substrates (CLint,h,2C8) was estimated from the inter-individual variability in pharmacokinetics of pioglitazone, which is a major CYP2C8 substrate...
September 15, 2017: Drug Metabolism and Pharmacokinetics
https://www.readbyqxmd.com/read/29171020/clopidogrel-but-not-prasugrel-significantly-inhibits-the-cyp2c8-mediated-metabolism-of-montelukast-in-humans
#16
Matti K Itkonen, Aleksi Tornio, Anne M Filppula, Mikko Neuvonen, Pertti J Neuvonen, Mikko Niemi, Janne T Backman
The oxidation of montelukast is mainly mediated by cytochrome P450 (CYP) 2C8, but other mechanisms may contribute to its disposition. In healthy volunteers, we investigated the effects of two widely used P2Y12 inhibitors on montelukast pharmacokinetics. Clopidogrel (300 mg on day 1 and 75 mg on day 2) increased the area under the plasma concentration-time curve (AUC) of montelukast 2.0-fold (90% confidence interval (CI) 1.72-2.28, P < 0.001) and decreased the M6:montelukast AUC0-7h ratio to 45% of control (90% CI 40-50%, P < 0...
November 24, 2017: Clinical Pharmacology and Therapeutics
https://www.readbyqxmd.com/read/29166542/identification-of-cytochrome-p450-cyp-isoforms-involved-in-the-metabolism-of-artocarpin-and-assessment-of-its-drug-drug-interaction-ddi
#17
Wei Qu, Xuezheng Liu
Artocarpin isolated from an agricultural plant Artocarpus communis has shows anti-inflammation and anticancer activities. In this study, we utilized recombinant human UDP-glucuronosyltransferasesupersomes (UGTs) and human liver microsomes (HLMs) to explore its inhibitory effect on UGTs and cytochrome p450 enzymes(CYPs). Chemical inhibition studies and screening assays with recombinant human CYPs were used to identify if CYP isoform is involved in artocarpin metabolism. Artocarpin showed strong inhibition against UGT1A3, UGT1A6, UGT1A7, UGT1A8, UGT1A9, UGT1A10, UGT2B7, CYP2C8 and CYP3A4...
November 22, 2017: Biomedical Chromatography: BMC
https://www.readbyqxmd.com/read/29163177/assessment-of-pharmacogenomic-panel-assay-for-prediction-of-taxane-toxicities-preliminary-results
#18
Raffaele Di Francia, Luigi Atripaldi, Salvo Di Martino, Carla Fierro, Tommaso Muto, Anna Crispo, Sabrina Rossetti, Gaetano Facchini, Massimiliano Berretta
Backbone: Paclitaxel and docetaxel are the primary taxane anticancer drugs regularly used to treat, breast, gastric, ovarian, head/neck, lung, and genitourinary neoplasm. Suspension of taxane treatments compromising patient benefits is more frequently caused by peripheral neuropathy and allergy, than to tumor progression. Several strategies for preventing toxicity have been investigated so far. Recently, findings on the genetic variants associated with toxicity and resistance to taxane-based chemotherapy have been reported...
2017: Frontiers in Pharmacology
https://www.readbyqxmd.com/read/29138287/clopidogrel-carboxylic-acid-glucuronidation-is-mediated-mainly-by-ugt2b7-ugt2b4-and-ugt2b17-implications-for-pharmacogenetics-and-drug-drug-interactions
#19
Helina Kahma, Anne M Filppula, Mikko Neuvonen, E Katriina Tarkiainen, Aleksi Tornio, Mikko T Holmberg, Matti K Itkonen, Moshe Finel, Pertti J Neuvonen, Mikko Niemi, Janne T Backman
The antiplatelet drug clopidogrel is metabolized to an acyl-β-D-glucuronide, which causes time-dependent inactivation of CYP2C8. Our aim was to characterize the UDP-glucuronosyltransferase (UGT) enzymes that are responsible for the formation of clopidogrel acyl-β-D-glucuronide. Kinetic analyses and targeted inhibition experiments were performed using pooled human liver and intestine microsomes (HLM and HIM, respectively) and selected human recombinant UGTs based on preliminary screening. The effects of relevant UGT polymorphisms on the pharmacokinetics of clopidogrel were evaluated in 106 healthy volunteers...
November 14, 2017: Drug Metabolism and Disposition: the Biological Fate of Chemicals
https://www.readbyqxmd.com/read/29050321/interaction-among-cyp2c8-gpiiia-and-p2y12-variants-increase-susceptibility-to-ischemic-stroke-in-chinese-population
#20
Xingyang Yi, Jing Lin, Yanfen Wang, Ju Zhou, Qiang Zhou
PURPOSE: Genetic variants in cytochrome P450 (CYP), platelet membrane receptor (P2Y12, P2Y1), and glycoprotein IIIa (GPIIIa) genes are associated with the efficacy of clopidogrel and adverse clinical events on ischemic stroke (IS) patients. However, few studies have assessed whether gene-gene interactions among these genes influence the risk of IS. The aim of the present study was to investigate the association of fifteen variants with IS and to determine whether these gene-gene interactions increase the risk of IS...
September 19, 2017: Oncotarget
keyword
keyword
26970
1
2
Fetch more papers »
Fetching more papers... Fetching...
Read by QxMD. Sign in or create an account to discover new knowledge that matter to you.
Remove bar
Read by QxMD icon Read
×

Search Tips

Use Boolean operators: AND/OR

diabetic AND foot
diabetes OR diabetic

Exclude a word using the 'minus' sign

Virchow -triad

Use Parentheses

water AND (cup OR glass)

Add an asterisk (*) at end of a word to include word stems

Neuro* will search for Neurology, Neuroscientist, Neurological, and so on

Use quotes to search for an exact phrase

"primary prevention of cancer"
(heart or cardiac or cardio*) AND arrest -"American Heart Association"