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gender CYP2C8

Reni Tzveova, Galya Naydenova, Teodora Yaneva, Georgi Dimitrov, Silviya Vandeva, Yoanna Matrozova, Diana Pendicheva-Duhlenska, Ivan Popov, Olga Beltheva, Cyrill Naydenov, Rumiana Tarnovska-Kadreva, Gencho Nachev, Vanio Mitev, Radka Kaneva
We conducted a case-control study to determine the contribution of polymorphisms in CYP2C8 (CYP2C8*3) and CYP2J2 (CYP2J2*7) to increased risk of coronary artery disease and essential hypertension in Bulgarians. The current analysis included 192 unrelated hypertensive patients, 261 patients with angiographically documented CAD (153 with myocardial infarction and 108 without myocardial infarction), and 496 population controls. The CYP2C8*3 and CYP2J2*7 polymorphisms were genotyped by TaqMan SNP Genotyping Assay...
December 2015: Biochemical Genetics
Dolores Ochoa, Rocío Prieto-Pérez, Manuel Román, María Talegón, Angela Rivas, Ignacio Galicia, Francisco Abad-Santos, Teresa Cabaleiro
AIM: To evaluate the effect of polymorphisms in CYP2C9 and CYP2C8 and gender on the pharmacokinetics of the enantiomeric forms of ibuprofen. MATERIALS & METHODS: 122 healthy volunteers were genotyped for polymorphisms in CY2C8 and CYP2C9 using real-time PCR. RESULTS: CYP2C8 polymorphisms affected neither R- nor S-ibuprofen. CYP2C9*3 and CYP2C9*2 carriers had a lower S-ibuprofen clearance and a higher S-ibuprofen AUC and half-life. R-ibuprofen clearance was decreased in CYP2C9*3 carriers...
2015: Pharmacogenomics
Albert P Li, Kari E Schlicht
A higher throughput platform was developed for the determination of K(M) values for isoformselective P450 substrates in human hepatocytes via incubation of the hepatocytes with substrates in 384- well plates and metabolite quantification by RapidFire™ mass spectrometry. Isoform-selective P450 substrates were incubated at 8 concentrations in triplicate with cryopreserved human hepatocytes from 16 donors. The metabolic pathways examined were the CYP1A2-catalyzed tacrine 1-hydroxylation, CYP2B6-catalyzed bupropion hydroxylation, CYP2C8-catalyzed amodiaquine N-deethylation, CYP2C9- catalyzed diclofenac 4'-hydroxylation, CYP2D6-catalyzed dextromethorphan O-demethylation, and CYP3A4-catalyzed midazolam 1'-hydroxylation...
2014: Drug Metabolism Letters
Brahim Achour, Matthew R Russell, Jill Barber, Amin Rostami-Hodjegan
Cytochrome P450 (P450) and uridine 5'-diphospho-glucuronosyltransferase (UGT) enzymes mediate a major proportion of phase I and phase II metabolism of xenobiotics. In vitro-in vivo extrapolation (IVIVE) of hepatic clearance in conjunction with physiologically-based pharmacokinetics (PBPK) has become common practice in drug development. However, prediction of xenobiotic kinetics in virtual populations requires knowledge of both enzyme abundances and the extent to which these correlate. A multiplexed quantification concatemer (QconCAT) strategy was used in this study to quantify the expression of several P450 and UGT enzymes simultaneously and to establish correlations between various enzyme abundances in 24 individual liver samples (ages 27-66, 14 male)...
April 2014: Drug Metabolism and Disposition: the Biological Fate of Chemicals
Paulo Arnaldo, Ricardo Estevão Thompson, Márcia Quinhones Lopes, Philip Noel Suffys, Adalberto Rezende Santos
BACKGROUND: The cytochrome P450 enzymes (CYP) play an important role in the metabolism of many therapeutic agents. The activities of different enzymes exhibit variability in different populations, which causes variations in drug response or toxicity. The CYP2B6 and CYP2C8 enzymes are encoded by polymorphic genes characterised by different single nucleotide polymorphisms (SNPs). Several of these CYP variants are often associated with slow metabolism phenotypes. This study aimed to analyse the frequencies of allelic variants of CYP2B6 and CYP2C8 in the Mozambican population...
July 2013: Malaysian Journal of Medical Sciences: MJMS
Rocío Prieto-Pérez, Dolores Ochoa, Teresa Cabaleiro, Manuel Román, Sergio Daniel Sánchez-Rojas, María Talegón, Francisco Abad-Santos
Celecoxib is metabolized by enzymes of the cytochrome P450 (CYP450) superfamily, mainly CYP2C9 and CYP3A4. Polymorphisms in the CYP2C9 gene have been associated with decreased enzyme activity and alteration of celecoxib pharmacokinetic parameters. However, literature reports are limited, and some results are contradictory. We enrolled 24 healthy volunteers in a single-dose replicated crossover trial with celecoxib 200 mg. We evaluated the association between single-nucleotide polymorphisms in the CYP2C8 and CYP2C9 genes (CYP2C8*2, CYP2C8*3, CYP2C8*4, CYP2C9*2, and CYP2C9*3) of these individuals and the pharmacokinetic parameters of celecoxib...
December 2013: Journal of Clinical Pharmacology
José M Ladero, José A G Agúndez, Carmen Martínez, Gemma Amo, Pedro Ayuso, Elena García-Martín
In addition to the known effects on drug metabolism and response, functional polymorphisms of genes coding for xenobiotic-metabolizing enzymes (XME) play a role in cancer. Genes coding for XME act as low-penetrance genes and confer modest but consistent and significant risks for a variety of cancers related to the interaction of environmental and genetic factors. Consistent evidence supports a role for polymorphisms of the cytochrome P450 CYP2C9 gene as a protecting factor for colorectal cancer susceptibility...
2012: Frontiers in Genetics
Yan-Ling He
Vildagliptin is an orally active, potent and selective dipeptidyl peptidase-4 (DPP-4) inhibitor, shown to be effective and well tolerated in patients with type 2 diabetes mellitus (T2DM) as either monotherapy or in combination with other anti-diabetic agents. Vildagliptin possesses several desirable pharmacokinetic properties that contribute to its lower variability and low potential for drug interaction. Following oral administration, vildagliptin is rapidly and well absorbed with an absolute bioavailability of 85%...
March 1, 2012: Clinical Pharmacokinetics
Orianne Videau, Sylvain Pitarque, Sylvie Troncale, Patrick Hery, Etienne Thévenot, Marcel Delaforge, Henri Bénech
We recently designed the CIME cocktail consisting of 10 drugs to assess the activity of the major human CYPs (CYP1A2, CYP2C8, CYP2C9, CYP2C19, CYP2D6 and CYP3A), a phase II enzyme (UGT1A1/6/9), two drug transporters (P-gp and OATP1B1) and a component of the renal function ( Videau et al. 2010 ). The present work aimed at studying the usefulness of the CIME cocktail in the rat.The CIME cocktail was given per os to three male and three female rats, or incubated with rat liver microsomes. Parent substrates and metabolites were quantified by LC-MS/MS in plasma, urine and hepatic microsomal media, and phenotyping index were subsequently calculated...
April 2012: Xenobiotica; the Fate of Foreign Compounds in Biological Systems
Wardah Yusof, Gan Siew Hua
CONTEXT: Artesunate (AS) and amodiaquine (AQ) are two prodrugs widely used as antimalarial agents and are metabolized by the CYP P450 2A6 (CYP 2A6) and CYP P450 2C8 (CYP 2C8) enzymes, respectively. OBJECTIVE: In this study, we aim to investigate the association of both genes on AS and AQ's tolerabilities in the hope of identifying a pharmacogenetic approach that could be useful in prediction and prevention of adverse drug reactions (ADRs) among Malaysian population...
April 2012: Toxicology Mechanisms and Methods
Osman Gökalp, Arzu Gunes, Hakan Cam, Erkan Cure, Osman Aydın, Mehmet Numan Tamer, Maria Gabriella Scordo, Marja-Liisa Dahl
AIM: To evaluate the impact of polymorphisms in the cytochrome P450 (CYP) 2C9, 2C19 and 2C8 genes on the risk of mild hypoglycaemic attacks in patients treated with sulphonylureas. METHODS: One hundred and eight type 2 diabetic patients (50 men, 58 women), treated with oral antidiabetics, including at least one from the sulphonylurea group (glimepiride n = 50, gliclazide n = 46, or glipizide n = 12) for 3 months or longer, were included in the study...
December 2011: European Journal of Clinical Pharmacology
T K Bergmann, C Brasch-Andersen, H Gréen, M Mirza, R S Pedersen, F Nielsen, K Skougaard, J Wihl, N Keldsen, P Damkier, L E Friberg, C Peterson, W Vach, M O Karlsson, K Brosen
The primary purpose of this study was to evaluate the effect of CYP2C8*3 and three genetic ABCB1 variants on the elimination of paclitaxel. We studied 93 Caucasian women with ovarian cancer treated with paclitaxel and carboplatin. Using sparse sampling and nonlinear mixed effects modeling, the individual clearance of unbound paclitaxel was estimated from total plasma paclitaxel and Cremophor EL. The geometric mean of clearance was 385 l h⁻¹ (range 176-726 l h⁻¹). Carriers of CYP2C8*3 had 11% lower clearance than non-carriers, P=0...
April 2011: Pharmacogenomics Journal
Suresh Babu Naraharisetti, Yvonne S Lin, Mark J Rieder, Kristin D Marciante, Bruce M Psaty, Kenneth E Thummel, Rheem A Totah
Research investigating CYP2C8 as a drug-metabolizing enzyme has gained momentum over the past few years. CYP2C8 is estimated to oxidatively metabolize approximately 5% of therapeutically prescribed drugs. It is polymorphically expressed, and several single nucleotide polymorphisms have been identified with varying effects on the clearance of CYP2C8 substrates. However, the human liver expression of CYP2C8 and effects of genetic variation, age, and gender on mRNA and protein levels have not been fully explored...
June 2010: Drug Metabolism and Disposition: the Biological Fate of Chemicals
Mette T Skaanild, Christian Friis
The cytochrome P450 2C (CYP2C) subfamily in human beings includes four different isoenzymes that metabolize different substrates although with some cross reactivity. Some of these substrates (e.g. diclofenac and tolbutamide), have been investigated in porcine microsomes, but without identifying the specific CYP catalysing the reactions. The objective of this study was therefore to test some CYP2C substrates and identify the porcine CYP2C responsible for the reaction. Three substrates, paclitaxel, tolbutamide and omeprazole, were chosen, as they are metabolized by three different CYP2C isoenzymes in human beings...
November 2008: Basic & Clinical Pharmacology & Toxicology
Carmen Martínez, Elena García-Martín, Hortensia Alonso-Navarro, Félix Javier Jiménez-Jiménez, Julián Benito-León, Isabel García-Ferrer, Pilar Vázquez-Torres, Inmaculada Puertas, José M Zurdo, Tomás López-Alburquerque, José A G Agúndez
To identify low-penetrance genes related to sporadic essential tremor (ET) at the CYP2C locus, located in chromosome 10 q23.33. Leukocytary DNA from 200 ET patients and a control group of 300 unrelated healthy individuals with known CYP2C19 genotypes was studied for common CYP2C8 and CYP2C9 allelic variants by using amplification-restriction analyses. Patients with ET showed the following differences compared with healthy subjects: a 1.6-fold reduction in the frequency for CYP2C8*3 (p=0.006), a 1.35-fold reduction of CYP2C9*2 (p=0...
2007: Neuromolecular Medicine
Gregory S Gorman, Lori Coward, Corenna Kerstner-Wood, Lea Cork, Izet M Kapetanovic, Wayne J Brouillette, Donald D Muccio
The present study was conducted to compare the in vitro phase I and phase II metabolic profiles of (2E,4E,6Z,8E)-8-(3',4'-dihydro-1'(2'H)-naphthalen-1'-ylidene)-3,7-dimethyl-2,4,6-octatrienoic acid (9cUAB30) in human, rat, and dog microsomes and to characterize and identify the associated metabolic kinetics and specific isozymes from human liver microsomes (HLM) responsible for metabolism, respectively. Data from these experiments revealed that nine (M1-M9) phase I metabolites along with a single glucuronide conjugate were observed across the species investigated...
July 2007: Drug Metabolism and Disposition: the Biological Fate of Chemicals
Lorraine M King, James V Gainer, Gloria L David, Ding Dai, Joyce A Goldstein, Nancy J Brown, Darryl C Zeldin
CYP2J2 and CYP2C8 metabolize arachidonic acid (AA) to cis-epoxyeicosatrienoic acids (EETs), which play a central role in regulating renal tubular fluid-electrolyte transport and vascular tone. We hypothesized that functionally relevant polymorphisms in the CYP2J2 or CYP2C8 genes influence hypertension risk. We examined associations between CYP2J2*7 (G-50 T promoter) and CYP2C8*3 (Arg139Lys and Lys399Arg, which are in 100% linkage disequilibrium) polymorphisms and hypertension in a biethnic population from Tennessee...
January 2005: Pharmacogenetics and Genomics
Andrew Parkinson, Daniel R Mudra, Cory Johnson, Anne Dwyer, Kathleen M Carroll
We have measured cytochrome P450 (CYP) activity in nearly 150 samples of human liver microsomes and 64 samples of cryopreserved human hepatocytes, and we have performed induction studies in over 90 preparations of cultured human hepatocytes. We have analyzed these data to examine whether the expression of CYP enzyme activity in liver microsomes and isolated hepatocytes or the inducibility of CYP enzymes in cultured hepatocytes is influenced by the gender, age, or ethnicity of the donor (the latter being limited to Caucasians, African Americans, and Hispanics due to a paucity of livers from Asian donors)...
September 15, 2004: Toxicology and Applied Pharmacology
M Beconi, A Mao, M Creighton, C E C A Hop, S H L Chiu, R Eydelloth, R Franklin, F Tang, N Yu, S Vincent
1. The metabolism of a substituted 2,4-thiazolidinedione (P1) with dual PPARalpha/gamma activity was evaluated in male and female rats, dogs and monkeys. A para-hydroxylated metabolite (M1) with potent PPARgamma-selective agonist, was a major circulating drug-related component in female rats, dogs and monkeys, but not in male rats (M1-to-P1 exposure ratio of <1, 3-5, 5 and 5-11 in male rat, monkey, female rat, and dog, respectively). 2. M1 (%) formed in vitro (5, 53, 57-65, 67 and 67% in male rat, monkey, female rat, dog, and human liver microsomes, respectively), rank ordered with M1 (%) formed in vivo (24-45, 53-57, 78, 75-85%, for male rat, monkey, female rat and dog, respectively, after oral administration of P1)...
July 2003: Xenobiotica; the Fate of Foreign Compounds in Biological Systems
J R Baker, S Satarug, P E Reilly, R J Edwards, N Ariyoshi, T Kamataki, M R Moore, D J Williams
This study was undertaken to assess associations between age, gender, cigarette smoke and non-workplace cadmium exposure, and liver pathology and inter-individual variation in cytochrome P450 (CYP) expression in human tissues. Autopsy specimens of twenty-eight Queensland residents whose ages ranged from 3 to 89 years were analyzed for the presence of nine CYP protein isoforms by immunoblotting. All subjects were Caucasians and their liver cadmium contents ranged from 0.11 to 3.95 microg/g wet weight, while their kidney cadmium contents were in the range of 2 to 63 microg/g wet weight...
September 15, 2001: Biochemical Pharmacology
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