scholarly journals CYP4F2 genetic variant alters required warfarin dose

Blood ◽  
2008 ◽  
Vol 111 (8) ◽  
pp. 4106-4112 ◽  
Author(s):  
Michael D. Caldwell ◽  
Tarif Awad ◽  
Julie A. Johnson ◽  
Brian F. Gage ◽  
Mat Falkowski ◽  
...  
Keyword(s):  
Drug Transport ◽  
Genetic Variant ◽  
Interindividual Variability ◽  
Warfarin Dose ◽  
The United States ◽  
Drug Metabolizing Enzymes ◽  
Metabolizing Enzymes ◽  
Relevant Effect ◽  
Frequent Monitoring ◽  
Novel Variant

Abstract Warfarin is an effective, commonly prescribed anticoagulant used to treat and prevent thrombotic events. Because of historically high rates of drug-associated adverse events, warfarin remains underprescribed. Further, interindividual variability in therapeutic dose mandates frequent monitoring until target anticoagulation is achieved. Genetic polymorphisms involved in warfarin metabolism and sensitivity have been implicated in variability of dose. Here, we describe a novel variant that influences warfarin requirements. To identify additional genetic variants that contribute to warfarin requirements, screening of DNA variants in additional genes that code for drug-metabolizing enzymes and drug transport proteins was undertaken using the Affymetrix drug-metabolizing enzymes and transporters panel. A DNA variant (rs2108622; V433M) in cytochrome P450 4F2 (CYP4F2) was associated with warfarin dose in 3 independent white cohorts of patients stabilized on warfarin representing diverse geographic regions in the United States and accounted for a difference in warfarin dose of approximately 1 mg/day between CC and TT subjects. Genetic variation of CYP4F2 was associated with a clinically relevant effect on warfarin requirement.

scholarly journals Tailoring Drug Therapy Based on Genotype

2012 ◽  
Vol 25 (4) ◽  
pp. 413-416 ◽  
Author(s):  
Larisa H. Cavallari
Keyword(s):  
Human Immunodeficiency Virus ◽  
Drug Therapy ◽  
Coronary Artery ◽  
Genetic Information ◽  
Drug Targets ◽  
Drug Disposition ◽  
Warfarin Dose ◽  
Drug Metabolizing Enzymes ◽  
Metabolizing Enzymes ◽  
Immunodeficiency Virus

Polymorphisms in genes encoding drug metabolizing enzymes, drug transporters, and drug targets can influence drug effects and contribute to inter-individual differences in drug response. Genotype for drug metabolizing enzymes and drug transporters can influence drug disposition in the body (pharmacokinetics), whereas genotype for drug targets may influence sensitivity to a drug (pharmacodynamics). In some cases, response to a particular drug is contingent on genotype for both drug disposition and drug target proteins. For example, warfarin dose requirements are influenced by both cytochrome P450 2C9 (CYP2C9) and vitamin K epoxide reductase complex 1 (VKORC1) genotypes. The goal of pharmacogenetics is to maximize drug effectiveness while limiting drug toxicity, based on an individual's DNA. Over 80 drugs now contain genetic information in their FDA-approved labeling. In addition to influencing warfarin dose requirements, genotype contributes to the efficacy of clopidogrel in coronary artery disease, risk for hypersensitivity reactions to abacavir in the treatment of human immunodeficiency virus, risk for statin-induced myopathy, and responses to numerous other drugs. Genetic information is routinely integrated into decisions regarding cancer chemotherapy and treatment for human immunodeficiency virus. Clinical implementation of pharmacogenetics is becoming a reality in other therapeutic areas, such as for patients requiring dual antiplatelet therapy following coronary artery stent implantation. In the future, it is possible that individuals will be broadly genotyped so that genetic information can guide drug therapy decisions throughout their lifetime.

scholarly journals Liquid Chromatography-Tandem Mass Spectrometry (LC-MS/MS)-Based Proteomics of Drug-Metabolizing Enzymes and Transporters

Molecules ◽  
2020 ◽  
Vol 25 (11) ◽  
pp. 2718
Author(s):  
Jiapeng Li ◽  
Hao-Jie Zhu
Keyword(s):  
Mass Spectrometry ◽  
Liquid Chromatography ◽  
Tandem Mass Spectrometry ◽  
Interindividual Variability ◽  
Drug Metabolizing Enzymes ◽  
Tandem Mass ◽  
Metabolizing Enzymes ◽  
Chromatography Tandem Mass Spectrometry ◽  
Liquid Chromatography Tandem Mass

Liquid chromatography-tandem mass spectrometry (LC-MS/MS)-based proteomics is a powerful tool for identifying and quantifying proteins in biological samples, outperforming conventional antibody-based methods in many aspects. LC-MS/MS-based proteomics studies have revealed the protein abundances of many drug-metabolizing enzymes and transporters (DMETs) in tissues relevant to drug metabolism and disposition. Previous studies have consistently demonstrated marked interindividual variability in DMET protein expression, suggesting that varied DMET function is an important contributing factor for interindividual variability in pharmacokinetics (PK) and pharmacodynamics (PD) of medications. Moreover, differential DMET expression profiles were observed across different species and in vitro models. Therefore, caution must be exercised when extrapolating animal and in vitro DMET proteomics findings to humans. In recent years, DMET proteomics has been increasingly utilized for the development of physiologically based pharmacokinetic models, and DMET proteins have also been proposed as biomarkers for prediction of the PK and PD of the corresponding substrate drugs. In sum, despite the existence of many challenges in the analytical technology and data analysis methods of LC-MS/MS-based proteomics, DMET proteomics holds great potential to advance our understanding of PK behavior at the individual level and to optimize treatment regimens via the DMET protein biomarker-guided precision pharmacotherapy.

scholarly journals Pharmacogenetics of drug-metabolizing enzymes in US Hispanics

2015 ◽  
Vol 30 (2) ◽  
Author(s):  
Karla Claudio-Campos ◽  
Jorge Duconge ◽  
Carmen L. Cadilla ◽  
Gualberto Ruaño
Keyword(s):  
United States ◽  
The United States ◽  
Drug Metabolizing Enzymes ◽  
Hispanic Population ◽  
Metabolizing Enzymes

AbstractAlthough the Hispanic population is continuously growing in the United States, they are underrepresented in pharmacogenetic studies. This review addresses the need for compiling available pharmacogenetic data in US Hispanics, discussing the prevalence of clinically relevant polymorphisms in pharmacogenes encoding for drug-metabolizing enzymes.

Analysis of the Potential Association of Drug-Metabolizing Enzymes CYP2C9*3 and CYP2C19*3 Gene Variations With Type 2 Diabetes: A Case-Control Study

2020 ◽  
Vol 21 (14) ◽  
pp. 1152-1160
Author(s):  
Imadeldin Elfaki ◽  
Rashid Mir ◽  
Faisel Mohammed Abu-Duhier ◽  
Chandan Kumar Jha ◽  
Adel Ibrahim Ahmad Al-Alawy ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Antiplatelet Drug ◽  
Drug Metabolizing Enzymes ◽  
Genotype Distribution ◽  
Nucleotide Polymorphisms ◽  
Metabolizing Enzymes ◽  
Specific Pcr ◽  
Increased Risk ◽  
Different Populations

Background:: Cytochrome P450s (CYPs) are drug-metabolizing enzymes catalyzing the metabolism of about 75% of drug in clinical use. CYP2C9 represents 20% CYP proteins in liver cells and is a crucial member of CYPs superfamily. CYP2C19 metabolizes very important drugs such as antiulcer drug omeprazole, the antiplatelet drug clopidogrel and anticonvulsant mephenytoin. Single nucleotide polymorphisms (SNPs) of CYP genes have been associated with unexpected drug reactions and diseases in different populations. Objective:: We examined the associations of CYP2C9*3 (rs1057910) and CYP2C19*3 (rs4986893) with T2D in Saudi population. Methods:: We used the allele-specific PCR (AS-PCR) and DNA sequencing in 111 cases and 104 controls for rs1057910, and in 119 cases and 110 controls for rs4986893. Results:: It is indicated that the genotype distribution of rs1057910 in cases and controls were not significantly different (P=0.0001). The genotypes of rs1057910 were not associated with type 2 diabetes (T2D) (P>0.05). Whereas the genotype distribution of rs4986893 in cases and controls was significantly different (P=0.049). The AA genotype of rs4986893 may be associated in increased risk to T2D with OR=17.25 (2.06-143.8), RR=6.14(0.96-39.20), P=0.008. Conclusion:: The CYP2C9*3 (rs1057910) may not be associated with T2D, while CYP2C19*3 (rs4986893) is probably associated with T2D. These findings need to be validated in follow-up studies with larger sample sizes and different populations.

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