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https://www.readbyqxmd.com/read/28606510/in-vitro-inhibitory-mechanisms-and-molecular-docking-of-1-s-1-acetoxychavicol-acetate-on-human-cytochrome-p450-enzymes
#1
A K M Mahmudul Haque, Kok Hoong Leong, Yoke Lin Lo, Khalijah Awang, Noor Hasima Nagoor
BACKGROUND: The compound, 1'-S-1'-acetoxychavicol acetate (ACA), isolated from the rhizomes of a Malaysian ethno-medicinal plant, Alpinia conchigera Griff. (Zingiberaceae), was previously shown to have potential in vivo antitumour activities. In the development of a new drug entity, potential interactions of the compound with the cytochrome P450 superfamily metabolizing enzymes need to be ascertain. PURPOSE: The concomitant use of therapeutic drugs may cause potential drug-drug interactions by decreasing or increasing plasma levels of the administered drugs, leading to a suboptimal clinical efficacy or a higher risk of toxicity...
July 15, 2017: Phytomedicine: International Journal of Phytotherapy and Phytopharmacology
https://www.readbyqxmd.com/read/28604257/genetic-factors-related-with-early-onset-of-osteonecrosis-of-the-jaw-in-patients-with-multiple-myeloma-under-zoledronic-acid-therapy
#2
Efstathios Kastritis, Pelagia Melea, Tina Bagratuni, Ioannis Melakopoulos, Maria Gavriatopoulou, Maria Roussou, Magdalini Migkou, Evangelos Eleutherakis-Papaiakovou, Evangelos Terpos, Meletios A Dimopoulos
Specific genetic polymorphisms (SNPs) have been correlated with the development of bisphosphonate-related osteonecrosis of the jaw (BRONJ) in small series. We screened 140 myeloma patients (36 patients with and 104 without BRONJ) for the presence of previously identified SNPs in PPARG and CYP2C8 genes. All the patients received exclusively zolendronic acid (ZA) therapy and were followed prospectively for BRONJ. SNPs in both genes were associated with a higher risk of development of early BRONJ, occurring within less than 2 years of ZA therapy (59% vs...
June 11, 2017: Leukemia & Lymphoma
https://www.readbyqxmd.com/read/28603631/hepatic-expression-profiles-in-retroviral-infection-relevance-to-drug-hypersensitivity-risk
#3
Yat Yee Wong, Brian Johnson, Thomas C Friedrich, Lauren A Trepanier
HIV-infected patients show a markedly increased risk of delayed hypersensitivity (HS) reactions to potentiated sulfonamide antibiotics (trimethoprim/sulfamethoxazole or TMP/SMX). Some studies have suggested altered SMX biotransformation in HIV infection, but hepatic biotransformation pathways have not been evaluated directly. Systemic lupus erythematosus (SLE) is another chronic inflammatory disease with a higher incidence of sulfonamide HS, but it is unclear whether retroviral infection and SLE share risk factors for drug HS...
June 2017: Pharmacology Research & Perspectives
https://www.readbyqxmd.com/read/28600193/functional-and-molecular-responses-of-the-blue-mussel-mytilus-edulis-hemocytes-exposed-to-cadmium-an-in-vitro-model-and-transcriptomic-approach
#4
Philippine Granger Joly de Boissel, Michel Fournier, Juan Carlos Rodriguez-Lecompte, Patty McKenna, Frederick Kibenge, Ahmed Siah
The bivalve mollusk, Mytilus edulis, is used as a sentinel species in several monitoring programs due to its ability to bio-accumulate contaminants. Its immune system consists of hemocytes and humoral components, which constitute the main part of the hemolymph. The present study is aimed at understanding the effects of Cd on the differentially expressed genes involved in the phagocytosis of M. edulis' hemocytes. Our approach focuses on an in vitro model by exposing hemocytes to different concentrations of Cd ranging from 10(-9) M to 10(-3) M...
June 6, 2017: Fish & Shellfish Immunology
https://www.readbyqxmd.com/read/28594339/cardiac-dysrhythmias-associated-with-substitutive-use-of-loperamide-a-systematic-review
#5
Irbaz Bin Riaz, Muhammad Shahzeb Khan, Muhammad Umar Kamal, Qurat-Ul-Ain Riaz Sipra, Anum Riaz, Umar Zahid, Sandipan Bhattacharjee
BACKGROUND: Recently, several deaths secondary to cardiac arrhythmias have been reported in association with substitutive use of loperamide. Therefore, we conducted a systematic review of all reported cases to overview the epidemiologic patterns and clinical outcomes to better elucidate loperamide-induced cardiac complications. AREAS OF UNCERTAINTY: Association between substitutive use of loperamide and cardiac arrhythmias. DATA SOURCES: A comprehensive literature search was conducted across 6 databases using variety of keywords to identify all reports of cardiac side effects associated with loperamide abuse...
April 27, 2017: American Journal of Therapeutics
https://www.readbyqxmd.com/read/28593920/influence-of-cyp3a4-and-cyp3a5-polymorphisms-on-tacrolimus-and-sirolimus-exposure-in-stable-kidney-transplant-recipients
#6
Erika Y Tamashiro, Claudia R Felipe, Fabiana D V Genvigir, Alice C Rodrigues, Antony B Campos, Rosario D C Hirata, Helio Tedesco-Silva, Jose O Medina-Pestana
BACKGROUND: Polymorphisms in genes encoding for drug-metabolizing enzymes and drug transporters are among multiple factors that modulate the pharmacokinetic variability of tacrolimus (TAC) and sirolimus (SRL). This study aimed to evaluate the influence of single nucleotide polymorphisms (SNPs) on TAC and SRL dose-adjusted concentrations (C0/D) in stable kidney transplant recipients. METHODS: This is an exploratory and prospective study, which includes 46 stable kidney transplant recipients...
May 24, 2017: Drug Metabolism and Personalized Therapy
https://www.readbyqxmd.com/read/28513222/the-contribution-of-cyp2c-gene-subfamily-involved-in-epoxygenase-pathway-of-arachidonic-acids-metabolism-to-hypertension-susceptibility-in-russian-population
#7
Alexey Polonikov, Marina Bykanova, Irina Ponomarenko, Svetlana Sirotina, Anna Bocharova, Kseniya Vagaytseva, Vadim Stepanov, Mikhail Churnosov, Olga Bushueva, Maria Solodilova, Yaroslav Shvetsov, Vladimir Ivanov
Numerous studies demonstrated an importance of cytochrome P-450 epoxygenase pathway of arachidonic acids metabolism for the pathogenesis of essential hypertension (EH). The present study was designed to investigate whether common single-nucleotide polymorphisms (SNP) of CYP2C gene subfamily such as CYP2C8 (rs7909236 and rs1934953), CYP2C9 (rs9332242), and CYP2C19 (rs4244285) are associated with susceptibility to EH in Russian population. A total of 816 unrelated Russian individuals comprising 425 EH patients and 391 normotensive controls were included into the study...
2017: Clinical and Experimental Hypertension: CHE
https://www.readbyqxmd.com/read/28484907/inhibition-of-cytochrome-p450-and-uridine-5-diphospho-glucuronosyltransferases-by-mam-2201-in-human-liver-microsomes
#8
Tae Yeon Kong, Ju-Hyun Kim, Soon-Sang Kwon, Jae Chul Cheong, Hee Seung Kim, Moon Kyo In, Hye Suk Lee
MAM-2201, a synthetic cannabinoid, is a potent agonist of the cannabinoid receptors and is increasingly used as an illicit recreational drug. The inhibitory effects of MAM-2201 on major drug-metabolizing enzymes such as cytochrome P450s (CYPs) and uridine 5'-diphospho-glucuronosyltransferases (UGTs) have not yet been investigated although it is widely abused, sometimes in combination with other drugs. We evaluated the inhibitory effects of MAM-2201 on eight major human CYPs (CYPs 1A2, 2A6, 2B6, 2C8, 2C9, 2C19, 2D6, and 3A4) and six UGTs (UGTs 1A1, 1A3, 1A4, 1A6, 1A9, and 2B7) of pooled human liver microsomes; we thus explored potential MAM-2201-induced drug interactions...
May 8, 2017: Archives of Pharmacal Research
https://www.readbyqxmd.com/read/28483778/mechanisms-and-predictions-of-drug-drug-interactions-of-the-hepatitis-c-virus-three-direct-acting-antiviral-regimen-paritaprevir-ritonavir-ombitasvir-and-dasabuvir
#9
Mohamad Shebley, Jinrong Liu, Olga Kavetskaia, Jens Sydor, Sonia M de Morais, Volker Fischer, Marjoleen J M A Nijsen, Daniel A J Bow
To assess drug-drug interaction (DDI) potential for the three direct-acting antiviral (3D) regimen of ombitasvir, dasabuvir, and paritaprevir, in vitro studies profiled drug-metabolizing enzyme and transporter interactions. Using mechanistic static and dynamic models, DDI potential was predicted for CYP3A, CYP2C8, UDP-glucuronosyltransferase (UGT) 1A1, organic anion-transporting polypeptide (OATP) 1B1/1B3, breast cancer resistance protein (BCRP), and P-glycoprotein (P-gp). Perpetrator static model DDI predictions for metabolizing enzymes were within 2-fold of the clinical observations, but additional physiologically based pharmacokinetic modeling was necessary to achieve the same for drug transporters...
July 2017: Drug Metabolism and Disposition: the Biological Fate of Chemicals
https://www.readbyqxmd.com/read/28479356/quantitative-analysis-of-complex-drug-drug-interactions-between-repaglinide-and-cyclosporin-a-gemfibrozil-using-physiologically-based-pharmacokinetic-models-with-in-vitro-transporter-enzyme-inhibition-data
#10
Soo-Jin Kim, Kota Toshimoto, Yoshiaki Yao, Takashi Yoshikado, Yuichi Sugiyama
Quantitative analysis of transporter- and enzyme-mediated complex drug-drug interactions (DDIs) is challenging. Repaglinide (RPG) is transported into the liver by OATP1B1 and then is metabolized by CYP2C8 and CYP3A4. The purpose of this study is to describe the complex DDIs of RPG quantitatively based on unified physiologically-based pharmacokinetic (PBPK) models using in vitro Ki values for OATP1B1, CYP3A4, and/or CYP2C8. Cyclosporin A (CsA) or gemfibrozil (GEM) increased the blood concentrations of RPG. The time profiles of RPG and the inhibitors were analyzed by PBPK models, considering the inhibition of OATP1B1 and CYP3A4 by CsA, or OATP1B1 inhibition by GEM and its glucuronide and the mechanism-based inhibition of CYP2C8 by GEM glucuronide...
May 4, 2017: Journal of Pharmaceutical Sciences
https://www.readbyqxmd.com/read/28468305/inhibitory-effects-of-dimethyllirioresinol-epimagnolin-a-eudesmin-fargesin-and-magnolin-on-cytochrome-p450-enzyme-activities-in-human-liver-microsomes
#11
Ju-Hyun Kim, Soon-Sang Kwon, Hyeon-Uk Jeong, Hye Suk Lee
Magnolin, epimagnolin A, dimethyllirioresinol, eudesmin, and fargesin are pharmacologically active tetrahydrofurofuranoid lignans found in Flos Magnoliae. The inhibitory potentials of dimethyllirioresinol, epimagnolin A, eudesmin, fargesin, and magnolin on eight major human cytochrome P450 (CYP) enzyme activities in human liver microsomes were evaluated using liquid chromatography-tandem mass spectrometry to determine the inhibition mechanisms and inhibition potency. Fargesin inhibited CYP2C9-catalyzed diclofenac 4'-hydroxylation with a Ki value of 16...
May 1, 2017: International Journal of Molecular Sciences
https://www.readbyqxmd.com/read/28457856/the-effect-of-milk-thistle-silybum-marianum-and-its-main-flavonolignans-on-cyp2c8-enzyme-activity-in-human-liver-microsomes
#12
Ahmed A Albassam, Reginald F Frye, John S Markowitz
Milk thistle is a widely-consumed botanical used for an array of purported health benefits. The primary extract of milk thistle is termed silymarin, a complex mixture that contains a number of structurally-related flavonolignans, the flavonoid, taxifolin, and a number of other constituents. The major flavonolignans present in most extracts are silybin A, silybin B, isosilybin A and isosilybin B, silydianin, silychristin and isosilychristin. Silymarin itself has been reported to inhibit CYP2C8 activity in vitro, but the effect of the individual flavonolignans on this enzyme has not been studied...
June 1, 2017: Chemico-biological Interactions
https://www.readbyqxmd.com/read/28447211/paclitaxel-induced-sensory-peripheral-neuropathy-is-associated-with-an-abcb1-single-nucleotide-polymorphism-and-older-age-in-japanese
#13
Yuko Tanabe, Chikako Shimizu, Akinobu Hamada, Kenji Hashimoto, Kazutaka Ikeda, Daisuke Nishizawa, Junko Hasegawa, Akihiko Shimomura, Yukinori Ozaki, Nobuko Tamura, Harukaze Yamamoto, Mayu Yunokawa, Kan Yonemori, Toshimi Takano, Hidetaka Kawabata, Kenji Tamura, Yasuhiro Fujiwara
PURPOSE: Whether age and inter-individual variability of pharmacogenetics are risk factors for paclitaxel-induced peripheral neuropathy (PIPN) is inconclusive. This study was conducted to evaluate the influence of previously investigated single nucleotide polymorphisms (SNPs) and age, using genotype data from a prospective study of paclitaxel-related toxicity in Japanese patients with breast cancer. METHODS: Peripheral blood mononuclear cells from 127 Japanese women with breast cancer who received weekly adjuvant paclitaxel were used to genotypes SLCO1B3 T334G (rs4149117), CYP2C8 A1196G (rs10509681), ABCB1 C1236T (rs1128503), ABCB1 G2677T/A (rs2032582), and ABCB1 C3435T (rs1045642)...
June 2017: Cancer Chemotherapy and Pharmacology
https://www.readbyqxmd.com/read/28444890/utilizing-pbpk-modeling-to-evaluate-the-potential-of-a-significant-drug-drug-interaction-between-clopidogrel-and-dasabuvir-a-scientific-perspective
#14
V Arya, P Zhao, K S Reynolds, P Mishra, I R Younis
Dasabuvir, a component of VIEKIRA PAK, is a substrate of CYP2C8 enzymes. Prescribing information for VIEKIRA PAK contraindicates gemfibrozil, a strong CYP2C8 inhibitor, because coadministration significantly increases dasabuvir exposures, which may increase the risk of QT prolongation. Clopidogrel may increase dasabuvir exposures primarily due to CYP2C8 inhibition by clopidogrel-acyl-β-D-glucuronide. This commentary outlines the US Food and Drug Administration (FDA) interdisciplinary review team's scientific perspective to address the potential for a significant drug-drug interaction (DDI) between clopidogrel and VIEKIRA PAK...
April 26, 2017: Clinical Pharmacology and Therapeutics
https://www.readbyqxmd.com/read/28427759/polymorphisms-in-cyp2c8-and-cyp3a5-genes-in-the-nigerian-population
#15
Ayorinde Adehin, Oluseye Oladotun Bolaji, Martin A Kennedy
Polymorphisms in CYP2C8 and CYP3A5 genes have implications for responses elicited by the ingestion of some xenobiotics, the metabolism of which are mediated by these enzymes. CYP2C8*2, CYP2C8*3, CYP3A5*3, CYP3A5*6 and CYP3A5*7 are a few functionally-relevant variants of these genes which this study provides data for, in the Nigerian population. Blood samples were processed for genomic DNA from 178 unrelated subjects spread across Nigerian ethnicities and screened for these polymorphism through the Sequenom iPLEX MassARRAY platform...
June 2017: Drug Metabolism and Pharmacokinetics
https://www.readbyqxmd.com/read/28411400/physiologically-based-pharmacokinetic-modeling-suggests-limited-drug-drug-interaction-between-clopidogrel-and-dasabuvir
#16
M Shebley, W Fu, P Badri, Daj Bow, V Fischer
Dasabuvir, a nonnucleoside NS5B polymerase inhibitor, is a sensitive substrate of cytochrome P450 (CYP) 2C8 with a potential for drug-drug interaction (DDI) with clopidogrel. A physiologically based pharmacokinetic (PBPK) model was developed for dasabuvir to evaluate the DDI potential with clopidogrel, the acyl-β-D glucuronide metabolite of which has been reported as a strong mechanism-based inhibitor of CYP2C8 based on an interaction with repaglinide. In addition, the PBPK model for clopidogrel and its metabolite were updated with additional in vitro data...
April 15, 2017: Clinical Pharmacology and Therapeutics
https://www.readbyqxmd.com/read/28396637/membrane-associated-progesterone-receptors-promiscuous-proteins-with-pleiotropic-functions-focus-on-interactions-with-cytochromes-p450
#17
REVIEW
Chang S Ryu, Kathrin Klein, Ulrich M Zanger
Membrane-associated progesterone receptors (MAPR) are a group of four rather small, partially homologous proteins, which share a similar non-covalent heme-binding domain that is related to cytochrome b5, a well-known functional interaction partner of microsomal cytochrome P450 (CYP) monooxygenase systems. Apart from their structural similarities the four proteins progesterone membrane component 1 (PGRMC1, also referred to as IZA, sigma-2 receptor, Dap1), PGRMC2, neudesin (NENF) and neuferricin (CYB5D2) display surprisingly divergent and multifunctional physiological properties related to cholesterol/steroid biosynthesis, drug metabolism and response, iron homeostasis, heme trafficking, energy metabolism, autophagy, apoptosis, cell cycle regulation, cell migration, neural functions, and tumorigenesis and cancer progression...
2017: Frontiers in Pharmacology
https://www.readbyqxmd.com/read/28396528/human-enterocytes-as-an-in-vitro-model-for-the-evaluation-of-intestinal-drug-metabolism-characterization-of-drug-metabolizing-enzyme-activities-of-cryopreserved-human-enterocytes-from-twenty-four-donors
#18
Ming-Chih David Ho, Nick Ring, Kirsten Amaral, Utkarsh Doshi, Albert Li
We report here successful isolation and cryopreservation of enterocytes from human small intestine. The enterocytes were isolated by enzyme digestion of the intestinal lumen followed by partial purification via differential centrifugation. The enterocytes were cryopreserved directly after isolation without culturing to maximize retention of in vivo drug metabolizing enzyme activities. Post-thaw viability of the cryopreserved enterocytes was consistently over 80% based on trypan blue exclusion. Cryopreserved enterocytes pooled from 8 donors (4 male and 4 female) were evaluated for their metabolism of 14 pathway-selective substrates: CYP1A2 (phenacetin hydroxylation), CYP2A6 (coumarin 7-hydroxylation), CYP2B6 (bupropion hydroxylation), CYP2C8 (paclitaxel 6α-hydroxylation), CYP2C9 (diclofenac 4-hydroxylation), CYP2C19 (s-mephenytoin 4-hydroxylation), CYP2D6 (dextromethorphan hydroxylation), CYP2E1 (chlorzoxazone 6-hydroxylation), CYP3A4 (midazolam 1'-hydroxylation and testosterone 6β-hydroxylation), CYP2J2 (astemizole O-demethylation), UDP-glucuronosyltransferase (UGT; 7-hydroxycoumarin glucuronidation), sulfotransferase (SULT; 7-hydroxycoumarin sulfation), and carboxylesterase 2 (CES2; irinotecan hydrolysis) activities...
April 10, 2017: Drug Metabolism and Disposition: the Biological Fate of Chemicals
https://www.readbyqxmd.com/read/28384415/downregulation-of-cytochrome-p450-2c8-by-3-methylcholanthrene-in-human-hepatocellular-carcinoma-cell-lines
#19
Rucha Utgikar, David S Riddick
The marked induction of cytochromes P450 such as CYP1A1 caused by polycyclic aromatic hydrocarbons (PAHs) like 3-methylcholanthrene (MC) is often accompanied by suppression of other hepatic P450s. The molecular mechanisms, functional consequences, and human relevance of P450 downregulation by PAHs are poorly understood. MC suppresses mRNA levels for CYP2C8, an important human P450, in cultured human hepatocytes. To avoid hepatocyte lot-to-lot variability, we assessed CYP2C8 regulation by MC in HepaRG cells, a terminally differentiated human hepatocellular carcinoma cell line that maintains high P450 expression...
April 6, 2017: Canadian Journal of Physiology and Pharmacology
https://www.readbyqxmd.com/read/28383355/influence-of-cyp2c8-polymorphisms-on-imatinib-steady-state-trough-level-in-chronic-myeloid-leukemia-and-gastrointestinal-stromal-tumor-patients
#20
Michiel C Verboom, Loes Visser, Sander Kouwen, Jesse J Swen, Jeroen Diepstraten, Ward F Posthuma, Hans Gelderblom, Daniëlle van Lammeren, Erik B Wilms
Imatinib trough levels have been associated with its clinical effects. During chronic use of imatinib, CYP2C8 becomes an important metabolizing enzyme because of cytochrome P450 3A4 (CYP3A4) autoinhibition. Single nucleotide polymorphisms (SNPs) in CYP2C8 may affect imatinib trough levels. This study investigates the effect of common CYP2C8 polymorphisms [*1B (rs7909236), *1C (rs17110453), *3 (rs11572080 and rs10509681), and *4 (rs1058930)] on steady-state trough levels imatinib during chronic imatinib use in 43 patients with chronic myeloid leukemia or gastrointestinal stromal tumors...
June 2017: Pharmacogenetics and Genomics
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