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Emi Kimoto, Rui Li, Renato J Scialis, Yurong Lai, Manthena V S Varma
Gemfibrozil (GEM), which decreases serum triglycerides and low density lipoprotein, perpetrates drug-drug interactions (DDIs) with several drugs. These DDIs are primarily attributed to the inhibition of drug transporters and metabolic enzymes, particularly cytochrome P450 (CYP) 2C8 by the major circulating metabolite gemfibrozil 1-O-β-glucuronide (GG). Here, we characterized the transporter-mediated hepatic disposition of GEM and GG using sandwich-cultured human hepatocytes (SCHH) and transporter-transfect systems...
November 2, 2015: Molecular Pharmaceutics
Kristyna Krasulova, Michal Siller, Ondrej Holas, Zdenek Dvorak, Pavel Anzenbacher
1. The aim of this work was to examine the differences in the inhibitory potency of individual enantiomers and racemic mixtures of selected chiral drugs on human liver microsomal cytochromes P450. 2. The interaction of enantiomeric forms of six drugs (tamsulosin, tolterodine, citalopram, modafinil, zopiclone, ketoconazole) with nine cytochromes P450 (CYP3A4, CYP2E1, CYP2D6, CYP2C19, CYP2C9, CYP2C8, CYP2B6, CYP2A6, CYP1A2) was examined. HPLC methods were used to estimate the extent of the inhibition of specific activity in vitro...
2016: Xenobiotica; the Fate of Foreign Compounds in Biological Systems
Boram Lee, Zhexue Wu, Taeho Lee, Xue Fei Tan, Ki Hun Park, Kwang-Hyeon Liu
1. 4'-(p-Toluenesulfonylamide)-4-hydroxychalcone (TSAHC) is a synthetic sulfonylamino chalcone compound possessing anti-cancer properties. The aim of this study was to elucidate the metabolism of TSAHC in human liver microsomes (HLMs) and to characterize the cytochrome P450 (P450) enzymes that are involved in the metabolism of TSAHC. 2. TSAHC was incubated with HLMs or recombinant P450 isoforms (rP450) in the presence of an nicotinamide adenine dinucleotide phosphate, reduced form (NADPH)-regenerating system...
2016: Xenobiotica; the Fate of Foreign Compounds in Biological Systems
Toshiyuki Kudo, Yuya Ozaki, Tomomi Kusano, Eri Hotta, Yuka Oya, Seina Komatsu, Hitomi Goda, Kiyomi Ito
1. Buffer conditions in in vitro metabolism studies using human liver microsomes (HLM) have been reported to affect the metabolic activities of several cytochrome P450 (CYP) isozymes in different ways, although there are no reports about the dependence of CYP2C8 activity on buffer conditions. 2. The present study investigated the effect of buffer components (phosphate or Tris-HCl) and their concentration (10-200 mM) on the CYP2C8 and CYP3A4 activities of HLM, using paclitaxel and triazolam, respectively, as marker substrates...
2016: Xenobiotica; the Fate of Foreign Compounds in Biological Systems
Guillermo Gervasini, Montserrat García-Cerrada, Esther Vergara, Guadalupe García-Pino, Raul Alvarado, Maria Jesús Fernández-Cavada, Sergio Barroso, Emilio Doblaré, Juan José Cubero
BACKGROUND: Arachidonic acid (AA) is metabolized by cytochrome P450 (CYP) enzymes to vasoactive metabolites (mainly epoxyeicosatrienoic acids) which are known to play a protective role against damaging processes that may occur after re-oxygenation of the graft. We aimed to investigate whether the presence of functional polymorphisms along these metabolic routes may play a role in the outcome of renal transplantation. DESIGN: One-hundred and forty Caucasian renal transplant recipients and 137 donors were included...
October 2015: European Journal of Clinical Investigation
Muhammad Suleman Khan, Daniel T Barratt, Andrew A Somogyi
1. Imatinib is metabolized to N-desmethyl imatinib by CYPs 3A4 and 2C8. The effect of CYP2C8*3 genotype on N-desmethyl imatinib formation was unknown. 2. We examined imatinib N-demethylation in human liver microsomes (HLMs) genotyped for CYP2C8*3, in CYP2C8*3/*3 pooled HLMs and in recombinant CYP2C8 and CYP3A4 enzymes. Effects of CYP-selective inhibitors on N-demethylation were also determined. 3. A single-enzyme Michaelis-Menten model with autoinhibition best fitted CYP2C8*1/*1 HLM (n = 5) and recombinant CYP2C8 kinetic data (median ± SD Ki = 139 ± 61 µM and 149 µM, respectively)...
2016: Xenobiotica; the Fate of Foreign Compounds in Biological Systems
F Dalle Vedove, C Fava, H Jiang, G Zanconato, J Quilley, M Brunelli, G Vattemi, P Minuz
OBJECTIVE: Plasma concentration of epoxyeicosatrienoic acids (EETs) derived from cytochrome P450 (CYP)-dependent metabolism of arachidonic acid is increased in women with preeclampsia (PE) as compared to normal pregnancy (N), and is even higher in fetal plasma (Herse et al. Circulation 2012, Jiang et al. Am J Hypertens 2013). We hypothesized that differences in EET synthesis or metabolism in the feto-placental unit underlie the observed differences in circulating EETs. DESIGN AND METHOD: To evaluate EETs generation as well the expression of the relavant CYP isoforms and of the metabolizing enzyme soluble epoxide hydrolase (sEH), biopsies of placenta were collected from 19 N and 10 PE at the time of surgical delivery...
June 2015: Journal of Hypertension
Francesca Toselli, Isabelle de Waziers, Mary Dutheil, Marc Vincent, Peter A Wilce, Peter R Dodd, Philippe Beaune, Marie-Anne Loriot, Elizabeth M J Gillam
1. Ethanol consumption and smoking alter the expression of certain drug-metabolizing enzymes and transporters, potentially influencing the tissue-specific effects of xenobiotics. 2. Amygdala (AMG) and prefrontal cortex (PFC) are brain regions that modulate the effects of alcohol and smoking, yet little is known about the expression of cytochrome P450 enzymes (P450s) and ATP-binding cassette (ABC) transporters in these tissues. 3. Here, we describe the first study on the expression of 19 P450s, their redox partners, three ABC transporters and four related transcription factors in the AMG and PFC of smokers and alcoholics by quantitative RT-PCR...
2015: Xenobiotica; the Fate of Foreign Compounds in Biological Systems
Yoshihiko Shimokawa, Noriaki Yoda, Satoshi Kondo, Yoshiya Yamamura, Yoshiharu Takiguchi, Ken Umehara
The direct inhibitory potential of twenty five anti-tuberculosis drugs on eight CYP-specific reactions in human liver microsomes was investigated to predict in vivo drug-drug interactions (DDIs) from in vitro data. Rifampicin, rifabutin, and thioacetazone inhibited one CYP reaction. Isoniazid and clofazimine had inhibitory effects on four CYP reactions, and rifapentine, ethionamide, and prothionamide widely inhibited CYP reactions. Based on the inhibition constant (Ki) and the therapeutic total inhibitor concentrations [I]max of eight drugs in human plasma, [I]max/Ki values were calculated to evaluate clinical DDIs...
2015: Biological & Pharmaceutical Bulletin
Steven Lacy, Bih Hsu, Dale Miles, Dana Aftab, Ronghua Wang, Linh Nguyen
Metabolism and excretion of cabozantinib, an oral inhibitor of receptor tyrosine kinases, was studied in 8 healthy male volunteers after a single oral dose of 175 mg cabozantinib l-malate containing (14)C-cabozantinib (100 µCi/subject). Total mean radioactivity recovery within 48 days was 81.09%; radioactivity was eliminated in feces (53.79%) and urine (27.29%). Cabozantinib was extensively metabolized with 17 individual metabolites identified by liquid chromatography-tandem mass spectrometry (LC-MS/MS) in plasma, urine, and feces...
August 2015: Drug Metabolism and Disposition: the Biological Fate of Chemicals
Juhee Sim, Eunhwa Choi, You-Mie Lee, Gil-Saeng Jeong, Sangkyu Lee
Cudratricusxanthone A (CTXA) isolated from the roots of Cudrania tricuspidata Bureau (Moraceae) has several biological activities, including hepatoprotective, neuroprotective, anti-inflammatory, monoamine oxidase inhibitory, and antithrombotic activities. In this study, we investigated the potential herb-drug interaction of CTXA and nine cytochrome P450 (CYP) isoforms in pooled human liver microsomes (HLMs) using a cocktail probe assay. CTXA reversibly inhibited the CYP1A2-catalyzed phenacetin O-deethylation, CYP2C8-catalyzed paclitaxel 6-hydroxylation, and CYP2C9-catalyzed diclofenac 4'-hydroxylation with half-maximal inhibitory concentration (IC50) values of 3...
July 2015: Food and Chemical Toxicology
Linh Nguyen, Jaymes Holland, Dale Miles, Caroline Engel, Natacha Benrimoh, Terry O'Reilly, Steven Lacy
Cabozantinib is a small-molecule tyrosine kinase inhibitor that has been approved for the treatment of patients with progressive, metastatic medullary thyroid cancer. In vitro data indicate that (1) cytochrome P450 (CYP) 3A4 is the primary CYP isoenzyme involved in the metabolism of cabozantinib, and (2) CYP2C8 is the CYP isoenzyme most potently inhibited by cabozantinib with potential for in vivo inhibition at clinically relevant plasma exposures. Pharmacokinetic (PK) drug-drug interactions (DDIs) were evaluated clinically between cabozantinib and (1) a CYP3A inducer (rifampin) in healthy volunteers, (2) a CYP3A inhibitor (ketoconazole) in healthy volunteers, and (3) a CYP2C8 substrate (rosiglitazone) in patients with solid tumors...
September 2015: Journal of Clinical Pharmacology
Maria Thomas, Christine Bayha, Silvia Vetter, Ute Hofmann, Michael Schwarz, Ulrich M Zanger, Albert Braeuning
The WNT/β-catenin signaling pathway has been identified as an important endogenous regulator of hepatic cytochrome P450 (P450) expression in mouse liver. In particular, it is involved in the regulation of P450 expression in response to exposure to xenobiotic agonists of the nuclear receptors constitutive androstane receptor (CAR), aryl hydrocarbon receptor (AhR), and Nrf2. To systematically elucidate the effect of the WNT/β-catenin pathway on the regulation and inducibility of major human P450 enzymes, HepaRG cells were treated with either the WNT/β-catenin signaling pathway agonist, WNT3a, or with small interfering RNA directed against β-catenin, alone or in combination with a panel of activating ligands for AhR [2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD)], CAR [6-(4-chlorophenyl)imidazo[2,1-b][1,3]thiazole-5-carbaldehyde-O-(3,4-dichlorobenzyl)oxime (CITCO)], pregnane X receptor (PXR) [rifampicin], and peroxisome proliferator-activated receptor (PPAR) α [4-chloro-6-(2,3-xylidino)-2-pyrimidinylthioacetic acid (WY14,643)]...
June 2015: Molecular Pharmacology
Ming Chang, Mao Mao Söderberg, Maria Gabriella Scordo, Gunnel Tybring, Marja-Liisa Dahl
PURPOSE: We aimed to assess the influence of CYP2C19*17 on R-warfarin clearance as well as the effect of CYP2C19, CYP2C8, CYP2C9, and VKORC1 polymorphisms together with non-genetic factors on warfarin international normalized ratio (INR)/daily dose. METHODS: One hundred fifty Caucasian Italian outpatients with data on steady-state plasma concentrations of S- and R-warfarin were genotyped for CYP2C19 (*2, *3, *4, *17), CYP2C9 (*2, *3), CYP2C8*3, and VKORC1*2. The statistical analysis was performed on the effect of genotypes/haplotypes, age, sex, and body weight on the clearance of warfarin enantiomers and dose-normalized INR...
April 2015: European Journal of Clinical Pharmacology
Cheedy Jaja, Latanya Bowman, Leigh Wells, Niren Patel, Hongyan Xu, Matt Lyon, Abdullah Kutlar
Interindividual variability in analgesic effects of nonsteroidal anti-inflammatory drugs prescribed for sickle cell disease (SCD) pain is attributed to polymorphisms in the CYP2C8 and CYP2C9 enzymes. We described CYP2C8 and CYP2C9 genotype/phenotype profiles and frequency of emergency department (ED) visits for pain management in an African American SCD patient cohort. DNA from 165 unrelated patients was genotyped for seven CYP2C8 and 15 CYP2C9 alleles using the iPLEX ADME PGx multiplexed panel. CYP2C8*1 (0...
August 2015: Clinical and Translational Science
Kari L Kendra, Ruth Plummer, Ravi Salgia, Mary E R O'Brien, Elaine M Paul, A Benjamin Suttle, Natalie Compton, Chun-Fang Xu, Lone H Ottesen, Miguel A Villalona-Calero
This study was designed to evaluate the safety, pharmacokinetics, and clinical activity of pazopanib combined with paclitaxel to determine the recommended phase II dose in the first-line setting in patients with advanced solid tumors. Patients were enrolled in a 3+3 dose-escalation design to determine the maximum tolerated regimen (MTR) of once daily pazopanib plus paclitaxel administered every 3 weeks at four dose levels (DL1-4). Safety, pharmacokinetics, pharmacogenetics, and disease assessments were performed...
February 2015: Molecular Cancer Therapeutics
Toshiyuki Kudo, Yumiko Endo, Rina Taguchi, Masami Yatsu, Kiyomi Ito
1. Blood levels of S-warfarin have been reported to be increased by concomitant administration of metronidazole (MTZ), an antiprotozoal imidazole derivative. 2. To elucidate the mechanism of this interaction and to identify other possible drug-drug interactions, we conducted an in vitro study with the human hepatoma HepaRG cells and cryopreserved human hepatocytes on the ability of MTZ to reduce the expression of cytochrome P450 (CYP) as well as nuclear receptors that regulate the expression of these enzymes...
May 2015: Xenobiotica; the Fate of Foreign Compounds in Biological Systems
Natacha Lenuzza, Xavier Duval, Grégory Nicolas, Etienne Thévenot, Sylvie Job, Orianne Videau, Céline Narjoz, Marie-Anne Loriot, Philippe Beaune, Laurent Becquemont, France Mentré, Christian Funck-Brentano, Loubna Alavoine, Philippe Arnaud, Marcel Delaforge, Henri Bénech
This phase I, pilot clinical study was designed to evaluate the safety and the pharmacokinetic (PK) profiles of the CIME (Metabolic Identity Card) combination of ten drugs, with a view to its use as a phenotyping cocktail. Ten healthy Caucasian subjects were orally dosed with the CIME combination (caffeine-CYP1A2, repaglinide-CYP2C8, tolbutamide-CYP2C9, omeprazole-CYP2C19, dextromethorphan-CYP2D6, midazolam-CYP3A, acetaminophen-UGT1A1, 6&9 and 2B15, digoxin-P-gp, rosuvastatin-OATP1B1&3 and memantine-active renal transport)...
April 2016: European Journal of Drug Metabolism and Pharmacokinetics
Terence Ng, Mint Chan, Chiea Chuen Khor, Han Kiat Ho, Alexandre Chan
A systematic review was performed to describe the findings from 19 genetic association studies that have examined the genetic variants underlying four common treatment-induced chronic and late toxicities in breast cancer patients, and to evaluate the quality of reporting. Three out of 5 studies found an association between HER2 lle655Val polymorphisms and trastuzumab-induced cardiotoxicity. Two studies found a positive association between cognitive impairment and the Val allele of the COMT gene and the ε4 allele of the apolipoprotein E gene...
December 2014: Cancer Treatment Reviews
Ahmed A Albassam, Mohamed-Eslam F Mohamed, Reginald F Frye
1. Herbal supplements widely used in the US were screened for the potential to inhibit CYP2C8 activity in human liver microsomes. The herbal extracts screened were garlic, echinacea, saw palmetto, valerian, black cohosh and cranberry. N-desethylamodiaquine (DEAQ) and hydroxypioglitazone metabolite formation were used as indices of CYP2C8 activity. 2. All herbal extracts showed inhibition of CYP2C8 activity for at least one of three concentrations tested. A volume per dose index (VDI) was calculated to determine the volume in which a dose should be diluted to obtain IC50 equivalent concentration...
May 2015: Xenobiotica; the Fate of Foreign Compounds in Biological Systems
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