Estimation of Drug-Metabolizing Capacity by Cytochrome P450 Genotyping and Expression

Temesvári, Manna; Kopper, László; Paulik, József; Sárváry, Enikő; Belič, Aleš; Monostory, Katalin

doi:10.1124/jpet.111.189597

Cited by 59 publications

(89 citation statements)

References 29 publications

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“…It was previously shown that the mRNA expression levels of CYP2D6 are well correlated with CYP2D6 activity levels (correlation coefficients range from 0.85 to 0.91) (Carcillo et al, 2003;Temesvári et al, 2012). The correlation coefficients between CYP2D6 mRNA and activity levels were comparable to those observed for CYP3A4, in which its expression and activity are governed at the transcriptional level.…”

Section: Interindividual Variability In Cyp2d6-mediated Drugsupporting

confidence: 52%

Interindividual Variability in Cytochrome P450-Mediated Drug Metabolism

Tracy¹,

Chaudhry²,

Prasad³

et al. 2015

Drug Metabolism and Disposition

139

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The cytochrome P450 (P450) enzymes are the predominant enzyme system involved in human drug metabolism. Alterations in the expression and/or activity of these enzymes result in changes in pharmacokinetics (and consequently the pharmacodynamics) of drugs that are metabolized by this set of enzymes. Apart from changes in activity as a result of drug-drug interactions (by P450 induction or inhibition), the P450 enzymes can exhibit substantial interindividual variation in basal expression and/or activity, leading to differences in the rates of drug elimination and response. This interindividual variation can result from a myriad of factors, including genetic variation in the promoter or coding regions, variation in transcriptional regulators, alterations in microRNA that affect P450 expression, and ontogenic changes due to exposure to xenobiotics during the developmental and early postnatal periods. Other than administering a probe drug or cocktail of drugs to obtain the phenotype or conducting a genetic analysis to determine genotype, methods to determine interindividual variation are limited. Phenotyping via a probe drug requires exposure to a xenobiotic, and genotyping is not always well correlated with phenotype, making both methodologies less than ideal. This article describes recent work evaluating the effect of some of these factors on interindividual variation in human P450-mediated metabolism and the potential utility of endogenous probe compounds to assess rates of drug metabolism among individuals.

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Section: Interindividual Variability In Cyp2d6-mediated Drugsupporting

confidence: 52%

Interindividual Variability in Cytochrome P450-Mediated Drug Metabolism

Tracy¹,

Chaudhry²,

Prasad³

et al. 2015

Drug Metabolism and Disposition

139

View full text Add to dashboard Cite

show abstract

“…Genomic 142 DNA and leukocytes were isolated from the samples of peripheral blood according to the 143 methods described by Temesvári et al [18]. CYP2C9 genotyping was carried out by 144 hydrolysis single nucleotide polymorphism analysis for CYP2C9*2 and CYP2C9*3 using 145…”

Section: Patients and Methods 117mentioning

confidence: 99%

“…The cutoff values for the CYP2C9 mRNA levels in leukocytes were previously established on 152 the basis of the cutoff values for the hepatic CYP2C9 activity (tolbutamide hydroxylation), 153 allowing a distinction between low, normal (medium) and high expressers (5*10 -6 and 154 2.5*10 -5 , respectively) [18]. 155…”

Section: Patients and Methods 117mentioning

confidence: 99%

Phenoconversion of CYP2C9 in Epilepsy Limits the Predictive Value of CYP2C9 Genotype in Optimizing Valproate Therapy

et al. 2015

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Aim: Since prominent role in valproate metabolism is assigned to CYP2C9 in pediatric patients, the association between children's CYP2C9-status and serum valproate concentrations or dose-requirements was evaluated. Materials & Methods: The contribution of CYP2C9 genotype and CYP2C9 expression in children (n = 50, Caucasian) with epilepsy to valproate pharmacokinetics was analyzed. Results: Valproate concentrations were significantly lower in normal expressers with CYP2C9*1/*1 than in low expressers or in patients carrying polymorphic CYP2C9 alleles. Consistently, the dose-requirement was substantially higher in normal expressers carrying CYP2C9*1/*1 (33.3 mg/kg vs 13.8–17.8 mg/kg, p < 0.0001). Low CYP2C9 expression significantly increased the ratio of poor metabolizers predictable from CYP2C9 genotype (by 46%). Conclusion: Due to the substantial downregulation of CYP2C9 expression in epilepsy, inferring patients’ valproate metabolizing phenotype merely from CYP2C9 genotype results in false prediction.

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“…However, several medications (eg, clopidogrel, metoprolol, warfarin) are metabolized by cytochrome P450 enzymes that are known to be highly variable in activity among individuals. Hepatic gene expression profiling correlates with cytochrome P450 activity, and one study has linked peripheral blood cytochrome P450 gene expression with hepatic cytochrome P450 activity, 40 thus laying the foundation for a novel set of biomarkers to inform drug dosing and selection.…”

Section: Musunuru Et Al Expressed Genome In Cardiovascular Diseases Amentioning

confidence: 99%

The Expressed Genome in Cardiovascular Diseases and Stroke: Refinement, Diagnosis, and Prediction: A Scientific Statement From the American Heart Association

Musunuru¹,

Ingelsson²,

Fornage³

et al. 2017

Circ Cardiovasc Genet

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Abstract-There have been major advances in our knowledge of the contribution of DNA sequence variations to cardiovascular disease and stroke. However, the inner workings of the body reflect the complex interplay of factors beyond the DNA sequence, including epigenetic modifications, RNA transcripts, proteins, and metabolites, which together can be considered the "expressed genome." The emergence of high-throughput technologies, including epigenomics, transcriptomics, proteomics, and metabolomics, is now making it possible to address the contributions of the expressed genome to cardiovascular disorders. This statement describes how the expressed genome can currently and, in the future, potentially be used to diagnose diseases and to predict who will develop diseases such as coronary artery disease, stroke, heart failure, and arrhythmias. (Circ Cardiovasc Genet. 2017;10:e000037. DOI: 10.1161/HCG.0000000000000037.)Key Words: AHA Scientific Statements ◼ cardiovascular diseases ◼ DNA ◼ epigenomics ◼ genome ◼ metabolomics ◼ proteomics ◼ strokeThe American Heart Association makes every effort to avoid any actual or potential conflicts of interest that may arise as a result of an outside relationship or a personal, professional, or business interest of a member of the writing panel. Specifically, all members of the writing group are required to complete and submit a Disclosure Questionnaire showing all such relationships that might be perceived as real or potential conflicts of interest.This statement was approved by the American Heart Association Science Advisory and Coordinating Committee on March 13, 2017, and the American Heart Association Executive Committee on April 17, 2017. A copy of the document is available at http://professional.heart.org/statements by using either "Search for Guidelines & Statements" or the "Browse by Topic" area. To purchase additional reprints, call 843-216-2533 or e-mail kelle.ramsay@ wolterskluwer.com.The American Heart Association requests that this document be cited as follows: Expert peer review of AHA Scientific Statements is conducted by the AHA Office of Science Operations. For more on AHA statements and guidelines development, visit http://professional.heart.org/statements. Select the "Guidelines & Statements" drop-down menu, then click "Publication Development."Permissions: Multiple copies, modification, alteration, enhancement, and/or distribution of this document are not permitted without the express permission of the American Heart Association. Instructions for obtaining permission are located at http://www.heart.org/HEARTORG/General/CopyrightPermission-Guidelines_UCM_300404_Article.jsp. A link to the "Copyright Permissions Request Form" appears on the right side of the page. I n no small part as a result of the completion of the Human Genome Project, considerable effort has been invested over the past few decades in understanding the contribution of genetics to the risk of cardiovascular diseases and stroke. Genomewide association studies, candidate gene sequencing studies, a...

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Estimation of Drug-Metabolizing Capacity by Cytochrome P450 Genotyping and Expression

Cited by 59 publications

References 29 publications

Interindividual Variability in Cytochrome P450-Mediated Drug Metabolism

Interindividual Variability in Cytochrome P450-Mediated Drug Metabolism

Phenoconversion of CYP2C9 in Epilepsy Limits the Predictive Value of CYP2C9 Genotype in Optimizing Valproate Therapy

The Expressed Genome in Cardiovascular Diseases and Stroke: Refinement, Diagnosis, and Prediction: A Scientific Statement From the American Heart Association

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