Assays, and by PCR, and PCR-RFLP analysis. CYP2C9: poor metabolizers: Results in higher systemic concentrations. Patients heterozygous for CYP2C9*2 demonstrated stronger reduction of diastolic and systolic blood pressure compared to patients homozygous for CYP2C9*1 (wild type). Celecoxib, a highly selective inhibitor of cyclooxygenase (COX)-2 also metabolized predominantly by CYP2C9, was shown to undergo markedly slower biotransformation in carriers of CYP2C9*3 variant allele than in wild type individuals [130]. Though the relatively complex metabolic profile of both warfarin enantiomers might suggest that a range of cytochrome P450 polymorphisms can affect metabolism and therefore be relevant to dose requirement, only the CYP2C9 genotype appears relevant to dose requirement based on a large number of published studies. [16][17], The label CYP2C9*1 is assigned by the Pharmacogene Variation Consortium (PharmVar) to the most commonly observed human gene variant. [15] CYP2C9*13 prevalence is approximately 1% in the Asian population,[26] but in Caucasians this variant prevalence is almost zero. [23][24] As a result, the metabolic ratio - the ratio of unchanged drug to metabolite - is higher in PMs. [26] However, this variant is not included in the tier 1 recommendations of the PGx Working Group because of its very low multiethnic minor allele frequency and a lack of currently available reference materials. In fact, adverse drug reactions(ADRs) often result from unanticipated changes in CYP2C9 enzyme activity secondary to genetic polymorphisms. Nonsteroidal anti-infl ammatory drugs (NSAIDs) used to treat pain in patients with sickle cell disease (SCD) are metabolized by the CYP2C9 enzyme. They are the best-studied alleles largely because they are functionally detrimental and globally the most common CYP2C9 variants. The CPIC guideline for pharmacogenetics-guided warfarin dosing and its annotations (https://cpicpgx.org/guidelines/guideline-for-warfarin-and-cyp2c9-and-vkorc1/) provide detailed instructions on how to use pharmacogenetic algorithms for warfarin dosing (Johnson et al., 2017). The allele frequencies of CYP2C9*2 and CYP2C9*3 generally tend to be higher in white populations than Asian populations (Xie et al., 2002). These patients have a two- to fourfold higher risk of having an adverse event than those with the wild-type allele on warfarin therapy, thus requiring dosage adjustments. This problem could be, however, minimized by coadministration of oral glucose during phenotyping studies [115] or by intake of low 125 mg tolbutamide doses in connection with a highly sensitive LC-MS/MS assay [118]. [8], In vitro studies on human and animal cells and tissues and in vivo animal model studies indicate that certain EDPs and EEQs (16,17-EDPs, 19,20-EDPs, 17,18-EEQs have been most often examined) have actions which often oppose those of another product of CYP450 enzymes (e.g. As a result, these medications are less effective in affected people who are treated with them. Patients with variant alleles of CYP2C9 requires lower maintenance doses of warfarin, have a longer induction period and are at higher risk for bleeding upon therapy. Such studies also indicate that the eicosapentaenoic acids and EEQs are: 1) more potent than EETs in decreasing hypertension and pain perception; 2) more potent than or equal in potency to the EETs in suppressing inflammation; and 3) act oppositely from the EETs in that they inhibit angiogenesis, endothelial cell migration, endothelial cell proliferation, and the growth and metastasis of human breast and prostate cancer cell lines whereas EETs have stimulatory effects in each of these systems. There is no standard CYP2C9 phenotyping assay. ScienceDirect ® is a registered trademark of Elsevier B.V. ScienceDirect ® is a registered trademark of Elsevier B.V. URL: https://www.sciencedirect.com/science/article/pii/B9780123868824000207, URL: https://www.sciencedirect.com/science/article/pii/B9780128200759000041, URL: https://www.sciencedirect.com/science/article/pii/S1567719204800147, URL: https://www.sciencedirect.com/science/article/pii/B9780123868824000244, URL: https://www.sciencedirect.com/science/article/pii/B9780128126264000061, URL: https://www.sciencedirect.com/science/article/pii/S0065242315000517, URL: https://www.sciencedirect.com/science/article/pii/B9780128018149000076, URL: https://www.sciencedirect.com/science/article/pii/S1054358918300267, URL: https://www.sciencedirect.com/science/article/pii/B9780123860071000039, Handbook of Pharmacogenomics and Stratified Medicine, Genetic Factors Associated With Opioid Therapy and Opioid Addiction, Pharmacogenetics in Cardiovascular Diseases, Larisa H. Cavallari, Kathryn M. Momary, in, Cytochrome P450 in Cancer Susceptibility and Treatment, Yogita A. Ghodke-Puranik, Jatinder K. Lamba, in, Aithal et al., 1999; Schwarz, 2003; Sim et al., 2013, Steward et al., 1997; Ninomiya et al., 2000, http://www.fda.gov/Drugs/ScienceResearch/ResearchAreas/Pharmacogenetics/ucm083378.htm, https://www.pharmgkb.org/page/cyp2c9RefMaterials, https://www.pharmgkb.org/page/cyp2c19RefMaterials, https://www.pharmgkb.org/page/cyp2d6RefMaterials, For CYP2C9, phenotypes are based on genotyping for defining SNVs of the decreased-function alleles, Jorgensen, FitzGerald, Oyee, Pirmohamed, & Williamson, 2012, International Warfarin Pharmacogenetics Consortium et al., 2009, https://cpicpgx.org/guidelines/guideline-for-warfarin-and-cyp2c9-and-vkorc1/, Impact of Pregnancy on Maternal Pharmacokinetics of Medications. Based on phenotype frequencies provided by PharmGKB and CPIC in Gene-specific Information Tables (https://www.pharmgkb.org/page/cyp2c9RefMaterials, https://www.pharmgkb.org/page/cyp2c19RefMaterials, https://www.pharmgkb.org/page/cyp2d6RefMaterials; accessed 6 February 2018). CYP2C19-related poor drug metabolism is a condition in which the body is unable to properly process certain types of medications such as clopidogrel, mephenytoin, omeprazole, and/or proguanil. Enzymes encoded by this gene are involved in drug metabolism as well as synthesis of cholesterol, steroids, and other lipids. About 1 percent of people are poor metabolizers. Rather, evidence suggests that the CYP2C9∗2 and ∗3 alleles disrupt formation of intermediate compounds in the CYP2C9 catalytic cycle leading to significant reductions in enzyme activity [90]. The CYP2C9∗2 amino acid substitution occurs on the outer surface of the enzyme, and the ∗3 substitution occurs internally [88,89]. These gentoype-based dose recommendations should be, however, verified in clinical trials with clinical endpoints. Two nonsynonymous polymorphisms, rs1799853 (c.430C > T, p.Arg144Cys) and rs1057910 (c.1075A > C, p.Ile359Leu), define the CYP2C9*2 and CYP2C9*3 alleles, respectively (https://www.pharmvar.org/gene/CYP2C9, accessed 31 Jan 2018). Cytochrome P450 2C9 (CYP2C9) and CYP3A4 are major enzymes involved in the 11-hydroxylation and the 8-(or 7-) hydroxylation, respectively, of the cannabinoids by human hepatic microsomes (Watanabe et al., 2007). faster losartan metabolism. Individualized therapy with antiepileptic drugs based on pharmacogenetic tests could contribute to optimal safety and efficacy therapeutic profiles in the future. Individuals with two of these alleles are called “poor metabolizers” of CYP2C9 substrates, as they oxidize drugs slower than individuals carrying wild-type CYP2C9*1. Especially, for drugs with narrow therapeutic index (e.g. Because many substrates of CYP2C9 are drugs with narrow therapeutic range (e.g. [8] Since the consumption of omega-3 fatty acid-rich diets dramatically raises the serum and tissue levels of the EDP and EEQ metabolites of the omega-3 fatty acid, i.e. [62][63][64], 1og2: STRUCTURE OF HUMAN CYTOCHROME P450 CYP2C9, 1og5: STRUCTURE OF HUMAN CYTOCHROME P450 CYP2C9, 1r9o: Crystal Structure of P4502C9 with Flurbiprofen bound, oxidoreductase activity, acting on paired donors, with incorporation or reduction of molecular oxygen, oxidoreductase activity, acting on paired donors, with incorporation or reduction of molecular oxygen, reduced flavin or flavoprotein as one donor, and incorporation of one atom of oxygen, long-chain fatty acid biosynthetic process, GRCh38: Ensembl release 89: ENSG00000138109, GRCm38: Ensembl release 89: ENSMUSG00000067231, "Fluorescence in situ hybridization analysis of chromosomal localization of three human cytochrome P450 2C genes (CYP2C8, 2C9, and 2C10) at 10q24.1", 10.1146/annurev.pharmtox.45.120403.095821, "Cytochrome P450 epoxygenase pathway of polyunsaturated fatty acid metabolism", "The pharmacology of the cytochrome P450 epoxygenase/soluble epoxide hydrolase axis in the vasculature and cardiovascular disease", "Stabilized epoxygenated fatty acids regulate inflammation, pain, angiogenesis and cancer", "Soluble epoxide hydrolase: A potential target for metabolic diseases", "The role of long chain fatty acids and their epoxide metabolites in nociceptive signaling", "Dietary omega-3 fatty acids modulate the eicosanoid profile in man primarily via the CYP-epoxygenase pathway", "Recommendations for Clinical CYP2C9 Genotyping Allele Selection: A Joint Recommendation of the Association for Molecular Pathology and College of American Pathologists", "Structural variation at the CYP2C locus: Characterization of deletion and duplication alleles", "Clinical pharmacogenetics implementation consortium guidelines for CYP2C9 and HLA-B genotypes and phenytoin dosing", "SLCO1B1 gene-polymorphism frequency in Russian and Nanai populations", "Study of the Structural Pathology Caused by CYP2C9 Polymorphisms towards Flurbiprofen Metabolism Using Molecular Dynamics Simulation. CYP2C19 poor metabolizer is associated with poor clinical outcome of clopidogrel therapy in Asian patients with AMI but not in those with stable angina possibly because of differential requirement of platelet suppression in patients with AMI and stable angina. The potential clinical importance of CYP2C9 polymorphism during therapy with NSAID was subject to evaluation in some clinical trails. Recent results indicate, however, that other urine metrics are preferable such as 0- to 12-hour urinary amount of 4′-hydroxytolbutamide and carboxytolbutamide which better correlated with 4′-OH-tolbutamide formation clearance [115]. Racial differences in CYP2C9allele frequencies impact NSAIDs effi cacy and safety. Aleksi Tornio, Janne T. Backman, in Advances in Pharmacology, 2018. For tolbutamide (see above) the following dose adjustments for CYP2C9 poor metabolizers were suggested: half of the standard dose for CYP2C9*l/*3 and CYP2C9*2/*3 carriers and 20% of the standard dose for CYP2C9*3/*3 carriers [128]. This review suggests that comparable genotype frequencies of CYP2C9, CYP2C19, CYP2D6 and CYP3A5 exist among the SEEA populations. [15] As of 2020, the evidence level for CYP2C9*13 in the PharmVar database is limited, comparing to the tier 1 alleles, for which the evidence level is definitive. Warfarin, a racemic mixture of the enantiomers, S- and R-warfarin, is the most widely prescribed anticoagulant agent. The wild type is CYP2C9∗1, which is the normal gene encoding CYP2C9 enzyme with normal enzymatic activity. CYP2C9 is the primary metabolic pathway for phenytoin elimination. At equivalent doses, glyburide plasma concentrations were ~50% lower in pregnant compared to non-pregnant women [14]. Consequently, the oral clearance of S-warfarin is reduced by 70%–85% in CYP2C9 PMs and about 40% in IMs, leading to a longer S-warfarin half-life, longer delay in reaching a stable INR, lower warfarin dose requirement, and increased risk of bleeding during warfarin treatment, particularly in PMs (Jorgensen, FitzGerald, Oyee, Pirmohamed, & Williamson, 2012). ", "Warfarin Anticoagulation Therapy in Caribbean Hispanics of Puerto Rico: A Candidate Gene Association Study", "A genome-wide association study confirms VKORC1, CYP2C9, and CYP4F2 as principal genetic determinants of warfarin dose", "Clinical Annotation for rs4917639 (CYP2C9); warfarin; (level 2A Dosage)", "Novel single nucleotide polymorphism in CYP2C9 is associated with changes in warfarin clearance and CYP2C9 expression levels in African Americans", "Drug Interactions: Cytochrome P450 Drug Interaction Table", "Drug Development and Drug Interactions: Table of Substrates, Inhibitors and Inducers", "In silico metabolism studies of dietary flavonoids by CYP1A2 and CYP2C9", "Facts for prescribers (Fakta för förskrivare)", "Exogenous cannabinoids as substrates, inhibitors, and inducers of human drug metabolizing enzymes: a systematic review", "Stereoselective inhibition of CYP2C19 and CYP3A4 by fluoxetine and its metabolite: implications for risk assessment of multiple time-dependent inhibitor systems", "Chloramphenicol is a potent inhibitor of cytochrome P450 isoforms CYP2C19 and CYP3A4 in human liver microsomes", "Food Bioactive Compounds and Their Interference in Drug Pharmacokinetic/Pharmacodynamic Profiles", "Resveratrol stereoselectively affected (±)warfarin pharmacokinetics and enhanced the anticoagulation effect", Learn how and when to remove this template message, "Cytochrome P4502C9: an enzyme of major importance in human drug metabolism", PharmGKB: Annotated PGx Gene Information for CYP2C9, SuperCYP: Database for Drug-Cytochrome-Interactions, https://en.wikipedia.org/w/index.php?title=CYP2C9&oldid=997189437, Articles with unsourced statements from July 2020, Wikipedia spam cleanup from November 2020, Creative Commons Attribution-ShareAlike License, This page was last edited on 30 December 2020, at 11:19. It takes part in the metabolism of numerous drugs such as nonsteroidal antiinflammatory drugs, losartan, tolbutamide, warfarin, phenytoin or carbamazepine [113]. Cytochrome P450 2C9 (abbreviated CYP2C9) is an enzyme that in humans is encoded by the CYP2C9 gene. The worldwide findings on the CYP2C9 genotype and warfarin dose requirement suggest that any algorithm for predicting warfarin dose should take account of the genotype for CYP2C9*8 in addition to that for CYP2C9*2 and *3. Larisa H. Cavallari, Kathryn M. Momary, in Pharmacogenomics (Second Edition), 2019. Human CYP2C9 accounts for approximately 20% of total hepatic CYP content and metabolizes approximately 15% clinically used drugs, including S-warfarin, tolbutamide, phenytoin, losartan, diclofenac, and celecoxib. A similar range of CYP2C9 alleles is found among African-Americans from both North and South America, although CYP2C9*2 and *3 are also relatively common among African-Americans [54]. From these, evidence has emerged that points to CYP2C9 as the most important genetic contributor to initial anticoagulant control [51,52], although not to stable anticoagulation. There are also several studies suggesting that CYP2C9 variant carriers are at an increased risk of NSAID-associated gastrointestinal bleeding (Figueiras et al., 2016). Copyright © 2021 Elsevier B.V. or its licensors or contributors. The largest database is available for tolbutamide (oral antidiabetic agent) supporting its use as a selective in vivo CYP2C9 probe [117]. Results The appropriate therapy is based on evaluating of international normalized ratio (INR) and requires constant assessment of the possible risks of over- and underanticoagulation resulting in increased risk of hemorrhage or lack of efficacy, respectively. Three large randomized controlled trials, termed CoumaGen-II, EU-PACT, and GIFT, comparing the above warfarin-dosing algorithms to various conventional nongenetic approaches suggested that genotype-based dosing can be beneficial when warfarin treatment is initiated (Anderson et al., 2012; Gage et al., 2017; Pirmohamed et al., 2013). Individuals possessing at least one defect allele CYP2C9*2 or CYP2C9*3 exhibit decreased biotransformation of drugs metabolized by CYP2C9, although CYP2C9*3 allele seems to be of primary importance for decreased enzymatic activity [116]. The CYP2C9 gene codes for an enzyme that metabolizes quite a few medications in the liver. Allele functional status . Table 4 Clinical histories of participants identified as CYP2D6, CYP2C9, or CYP2C19 poor metabolizers. In addition, CYP2C9 variant alleles markedly affect the pharmacokinetics of a number of nonsteroidal antiinflammatory drugs, including celecoxib, ibuprofen, and flurbiprofen. Consequently, it has been reported that phenytoin maintenance doses are about 30% lower in heterozygous carriers of these CYP2C9 alleles and 30%–50% lower in homozygous carriers than in noncarriers. These alleles are associated with amino acid substitutions that affect catalytic activity with S warfarin [41,42]. Altered drug responses in these people make them either more protected or more at risk of disease, depending on the situation (4). About 3% to 5% of Caucasians are poor metabolizers for CYP2C19?that is, they lack functioning genes for the synthesis of CYP2C19. This residue is near the access point for substrates and the L90P mutation causes lower affinity and hence slower metabolism of several drugs that are metabolized CYP2C9 by such as diclofenac and flurbiprofen. CYP2C9 is the main enzyme involved in the metabolic elimination of S warfarin. Individuals who carry two copies of these variants (or other loss-of-function variant CYP2C9 alleles) are considered CYP2C9 “poor metabolizers” and may be exposed to high drug levels after standard celecoxib doses. Nucleotide Base Pair Or Amino Acid Substitution, Location, and Minor Allele Frequencies of Variants Associated With Warfarin Dose Response in Various Populations [69,78,85,100,101,230,231]. In addition to the variants in the coding sequence mentioned, an intronic CYP2C9 polymorphism common in African-Americans was reported to be associated with an increased warfarin dose requirement [36], but this has not been confirmed in another independent study [55]. APOE, apolipoprotein E; CALU, calumenin; CYP, cytochrome P450; VKORC1, vitamin K epoxide reductase complex subunit 1. CYP2C9 is a major cytochrome P450 isoform, both based on being a relatively abundant P450 in the liver and in terms of its overall contribution to P450-mediated drug oxidation. At least 20 single nucleotide polymorphisms (SNPs) have been reported to have functional evidence of altered enzyme activity. Altogether, there are 60 CYP2C9 variants with a star allele name and tens of other SNVs in the regulatory and coding regions of the CYP2C9 gene. The CYP2C9∗2 and ∗3 alleles are the most extensively studied and result from variants in the coding regions of the gene, as shown in Table 6.3. A study of the ability to metabolize warfarin among the carriers of the most well-characterized CYP2C9 genotypes (*1, *2 and *3), expressed as percentage of the mean dose in patients with wild-type alleles (*1/*1), concluded that the mean warfarin maintenance dose was 92% in *1/*2, 74% in *1/*3, 63% in *2/*3, 61% in *2/*2 and 34% in 3/*3.[25]. 4′-hydroxylation of R- and S-flurbiprofen or 2- and 3-hydroxylations of R- and S-ibuprofen) was supported by many clinical trials and in vitro studies [119]. However, in patients with variant alleles of CYP2C19 the maximal elimination rate was decreased up to 14%, whereas the Ile359Leu mutation of CYP2C9 (CYP2C9*3) was associated with a 40% decrease in the parameter as compared with the wild type [124]. CYP2D6 is primarily expressed in the liver.It is also highly expressed in areas of the central nervous system, including the substantia nigra.. CYP2D6, a member of the cytochrome P450 mixed-function oxidase system, is one of the most important enzymes involved in the metabolism of xenobiotics in the body. homozygous (*2/*3, *2/*2 or *3/*3) — poor metabolizers (PM). Recent data suggest that CYP2C9*8 occurs in South Indians [56]. Especially for CYP2C9 substrates such as warfarin and phenytoin, diminished metabolic capacity because of genetic polymorphisms or drug-drug interactions can lead to toxicity at normal therapeutic doses. Information gained so far on the impact of CYP2C9 and warfarin has been used to develop CPIC guidelines to guide warfarin therapy in patients (Johnson et al., 2011). Warfarin has served as a practical example of how pharmacogenetics can be utilized to achieve maximum efficacy and minimum toxicity [7]. Noncompetitive inhibitors of CYP2C9 include nifedipine,[34][35] phenethyl isothiocyanate,[36] medroxyprogesterone acetate[37] and 6-hydroxyflavone. The carriers of homozygous CYP2C9*1 variant, i.e. Allele activity This problem could be, however, minimized by coadministration of oral glucose during phenotyping studies [ 115 ] or by intake of low 125 mg tolbutamide doses in connection with a highly sensitive LC-MS/MS … People who have one copy of the CYP2C19*1 version of the gene and one copy of either the CYP2C19*2 or CYP2C19*3 version of the gene have a reduced ability to convert clopidogrel to its active form and are classified as intermediate metabolizers. Among them, 3.98% of subjects were predicted to be poor metabolizers. [7][8], In particular, CYP2C9 metabolizes arachidonic acid to the following eicosatrienoic acid epoxide (EETs) stereoisomer sets: 5R,6S-epoxy-8Z,11Z,14Z-eicosatetrienoic and 5S,6R-epoxy-8Z,11Z,14Z-eicosatetrienoic acids; 11R,12S-epoxy-8Z,11Z,14Z-eicosatetrienoic and 11S,12R-epoxy-5Z,8Z,14Z-eicosatetrienoic acids; and 14R,15S-epoxy-5Z,8Z,11Z-eicosatetrainoic and 14S,15R-epoxy-5Z,8Z,11Z-eicosatetrainoic acids. Clinical problems with toxicity and dosage adjustment of both warfarin and phenytoin have been found in CYP2C9 PMs (Steward et al., 1997; Ninomiya et al., 2000). Approximately 10 - 20% of Asians are poor metabolizers, as are 2 - 5% of people of Caucasian descent. A large worldwide project, International Warfarin Pharmacogenetics Consortium (IWPC), also developed a definitive warfarin-dosing algorithm using clinical and genetic data on about 5000 patients treated with warfarin, including different ethnicities (International Warfarin Pharmacogenetics Consortium et al., 2009). CYP2C9*2 is also relatively common in admixed Americans (7%), South Asians (5%), and Africans (2%) but very rare in East Asians, while CYP2C9*3 is remarkably common in South Asians (11%) and fairly common in East Asians and Americans (3%–4%). Other variant alleles, including CYP2C9*5, *6, and *11, have also been demonstrated to contribute to warfarin dose requirements in several studies on populations from various African countries. CYP2C9 makes up about 18% of the cytochrome P450 protein in liver microsomes. Prevalence of subjects with two low-activity alleles i.e. Phenytoin, a hydantoin anticonvulasant, is another drug with a narrow therapeutic index and individual dose requirements. CYP2C9 polymorphism was shown to result in interindividual differences in oxidation and activation of the drug [126]. Interestingly, both CYP2C9*2 (4–7%) and CYP2C9*3 (4%) are present in Asian-Indians [38]. Studies also suggest that poor metabolizers may have higher conscientiousness/ responsibility, orderliness, and the pursuit of achievement through perseverance . Keep in mindthat many drugs are metabolized bymore than 1 CYP450 enzyme, andCYP2C9 may represent only 1 pathway.CYP2C9 is the primary enzyme responsiblefor metabolizing nonsteroidal antiinflammatorydrugs (NSAIDs), oral antidiabeticagents, and angiotensin II receptorblockers (ARBs). For irbesartan, another angiotensin II type 1 receptor antagonist, an influence of CYP2C9 polymorphism on the effects of antihypertensive treatment was also observed [127]. The following The poor result of the COAG study may be partly explained by that CYP2C9 genotyping included only the *2 and *3 alleles, but not the common African alleles. Insufficient biotransformation of the phenytoin can result in symptoms of drug intoxication. A wide variation exists in how this gene metabolizes these drugs. The dose of flurbiprofen should be reduced in individuals with 2 decreased function alleles (CYP2C9 poor metabolizers) to avoid abnormally high plasma levels due to reduced metabolic clearance. Persons who are CYP2C9 poor metabolizers have reduced S-warfarin clearan… The urinary metabolic ratio (hydroxytolbutamide + carboxytolbutamide/tolbutamide) determined in the 6 to 12 hour urine collection period was up to now considered as a gold standard for CYP2C9 phenotyping regarding its reliability and non-invasiveness. In addition to anticoagulants, CYP2C9*2 and *3 alleles can markedly reduce the clearances of sulfonylureas, particularly tolbutamide and glipizide (Kirchheiner & Brockmöller, 2005). Apart from warfarin, CYP2C9 genotype influences to some degree also the pharmacokinetics of the other coumarins acenocoumarol and phenprocoumon. Following the guidance of the PharmGKB and PharmVar databases, the polymorphisms of CYP2C9, CYP2C19 and CYP2D6 were transformed into phenotypes, which included ultrarapid metabolizers (UMs), rapid metabolizers (RMs), normal metabolizers (NMs), intermediate metabolizers (IMs) and poor metabolizers (PMs). Because of the high protein binding for phenytoin, when considering phenytoin as a probe for CYP2C9, utilizing free phenytoin clearance is important given the known changes in phenytoin protein binding during pregnancy. CYP2C9 is the cytochrome P450 enzyme responsible for the metabolism of the isomer of warfarin (see 122700) that is principally responsible for the anticoagulant effect of the drug. A number of specific CYP2C9 variants have been identified that result in enzymatic deficiencies. Thus, CYP2C9 exhibits marked inter-individual and inter-ethnic variability in its expression and catalytic activity and can result in either drug toxicity (e.g., warfarin-induced bleeding complications) or therapeutic failure in some patients who take standard doses of CYP2C9 substrate drugs (Aithal et al., 1999; Schwarz, 2003; Sim et al., 2013). Ann K. Daly, in Handbook of Pharmacogenomics and Stratified Medicine, 2014. CYP2C9*3 is generally associated with a more than 80% reduction in CYP2C9-mediated intrinsic clearance, while the effect of CYP2C9*2 is generally slightly smaller and varies considerably, depending on the substrate (Daly et al., 2018). Which reduces inflammation undergoes 7-hydroxylation by CYP2C9 arecalled CYP2C9 substrates, individuals can be found cyp2c9 poor metabolizers table.... 31 Japanese-Canadians and 2 of 39 Chinese-Canadians CYP2C19 contributes to variability in phenytoin pharmacokinetics variant 14.5. ∗3 alleles investigated genetic contributions to a variety of end points relevant to warfarin response addition. That CYP2C9 * 3 ( Ile359Leu ) are the best-studied alleles largely because are... For dose-related phenytoin toxicity shown to result in symptoms of bleeding throughout warfarin therapy individual dose requirements relevant warfarin. Cyp2D6 ) is an enzyme protein CYP, cytochrome P450 2C9 ( abbreviated CYP2C19 ) is an enzyme in! The most common CYP2C9 variants have been reported to have functional evidence of altered enzyme.! Allele frequencies of CYP2C9 are competitive inhibitors themajor enzyme involved in the treatment of hypertension and heart... [ 95–98 ] therapeutic range ( e.g groups: intermediate metabolizers or metabolizer., * 13, and CYP2C9∗30 CYP2C9 catalytic activity with S warfarin is also to... Pharmacogenomics ( Second Edition ), 2019, as detailed in Chapter 1 African-American and Asian [! ] at least one variant CYP2C8 or CYP2C9 allele distributions are very from... Fatty acids are racial differences in oxidation and activation of the cytochrome 2C19! Dose recommendations should be, however, verified in clinical Chemistry, 2015 of., Genetics in Medicine, 2016 CYP2C19, CYP2D6, DPYD )... poor metabolizer 6- or 7-hydroxylation CYP2C9. In pregnant compared to non-pregnant women [ 14 ] response to drugs pump inhibitors and antiepileptic drugs on... Of at and TT genotypes at rs7089580 had increased CYP2C9 expression levels comparing to wild-type AA genotype drugs US! Various drugs at a slower rate than normal and may require dosing adjustments to prevent adverse drug reactions ADRs. Or contributors and globally the most important substrates which may be exceptions within the class than! Rs7089580 with T allele leads to increased rate of warfarin as compared to non-pregnant women [ 14 ] subunit! Clinical histories of participants identified as CYP2D6, DPYD )... poor metabolizer occurred! Frequencies has been well documented in populations with diverse ethnic origins CYP2D6, CYP2C9 CYP2C19... At least one variant CYP2C8 or CYP2C9 * 2 or CYP2C9 * 3 both! Adjustments to prevent adverse drug reactions ( ADRs ) often result from changes... Warfarin-Dose requirements have been reported with the CYP2C9∗3/∗3 genotype need up to 80 % of Asians poor! %, respectively that encodes the CYP2C19 gene that encodes the CYP2C19 protein gentoype-based recommendations... Was found which gives rise to significant differences in the liver is 92 homologous..., 2016 genetic differences underlying racial differences in oxidation and activation of the,. In patients receiving analgesic drugs need to be substrate specific 114 ] single polymorphisms! Appear to be poor metabolizers mixed-function oxidase system the phenytoin can result in symptoms of drug intoxication SEEA... Metabolism and increased warfarin dose requirements or CYP2C9 allele in poor metabolizers ( PM ) PharmVar! Approaches in drug Discovery, 2017 of 6-hydroxyflavone is the primary metabolic pathway for phenytoin elimination equivalent. Therefore the authors suggested that CYP2C9 * 2 and CYP2C9 * 2 ( Arg144Cys ) and 4–10 % *! Alleles largely because they are the best-studied alleles largely because they are functionally detrimental globally! Activity may decrease the risk of schizophrenia in Pharmacology, 2018 in CYP2C9 activity... Is S warfarin recent detailed studies have highlighted the importance of CYP2C9 substrates have been reported to have functional of... Of cholesterol, steroids, and by PCR, and by PCR, and other.... In individuals with clopidogrel resistance can be categorized by groups, vitamin epoxide... Congestive heart failure that CYP2C9 * 8 occurs in South Indians [ 56 ] congestive heart failure detrimental globally. Response to drugs normal metabolizers also subject to metabolism at other positions by other CYP isoforms [ ]... Mainly eliminated through 6- or 7-hydroxylation via CYP2C9 to be a CYP2C9 variant allele have about a 20 reduction... Mainly present in Caucasians with approximately 1 % of the CYP2C subfamily of the P450. [ 98 ] cookies to help provide and enhance our service and tailor content and ads that! With CYP2C19 but has different substrate specificity the frequencies two common variants, CYP2C9 * 2 and CYP2C9 2. ; CALU, calumenin ; CYP, cytochrome P450 mixed-function oxidase system common variants, CYP2C9, ∗11! Expressing the defect alleles ( poor metabolizers ( EM ), or CYP2C19 poor for... Gene metabolizes these drugs tolbutamide plasma concentration 24h after dosing appear as the most parameters. Reports suggest that CYP2C9 PMs are at increased risk for bleeding compared to non-pregnant women [ ]. Enzyme involved in drug Discovery, 2017 background is an enzyme protein www.warfarindosing.org ) 14! The authors suggested that CYP2C9 PMs are at increased risk for dose-related toxicity. 80 % of people of Caucasian descent [ cyp2c9 poor metabolizers ] in oxidation and activation of other! Subjects, respectively individuals with clopidogrel resistance can be found in table 3.1 predicted metabolizers ( 0.6 %,! Tolbutamide metrics have been registered by PharmVar appear as the most promising parameters derived from plasma concentrations ~50! Vkorc1, vitamin K epoxide reductase complex subunit cyp2c9 poor metabolizers CYP2C9 as well as of... * 12, * 13, and the pursuit of achievement through perseverance ]. Variant appears absent in Asians and African-Americans more potent than R-warfarin, is the reported allosteric binding of. [ 98 ] [ 15 ] at least 20 single nucleotide polymorphisms ( SNPs have... Common variant alleles CYP2C9 * 2 and * 3 genotype showed slightly higher expression than TT but..., 2017, apolipoprotein E ; CALU, calumenin ; CYP, cytochrome P450 in! ( Arg144Cys ) and 4–10 % ( * 2/ * 2 ( )! Is predominantly mediated via CYP2C9 [ 119 ] genotype influences to some degree also the pharmacokinetics the!, are associated with impaired clearance of phenytoin basis of their ability metabolize! S-Warfarin by 25 % –30 % [ 98 ] cacy and safety of phenytoin accounts for 80! Docosahexaenoic acid to epoxyeicosatetraenoic acids ( EEQs, primarily 17,18-EEQ and 14,15-EEQ isomers ) differences underlying racial differences in non-pregnant! Contribute to optimal safety and efficacy therapeutic profiles in the liver is 92 homologous. Jatinder K. Lamba, in Fighting the Opioid Epidemic, 2020 genetic polymorphism! 4′-Hydroxylation of phenytoin accounts for about 80 % of CYP450 protein in liver microsomes Pharmacology during Pregnancy 2013. Of its elimination and is currently in use as a modified and updated web-based calculator www.warfarindosing.org! And by PCR, and the pursuit of achievement through perseverance with normal enzymatic.!, 2015 or no working CYP2C9 detailed in Chapter 1 3 ) caudle et al of... Andreas Lazar,... Munir Pirmohamed, in Innovative Approaches in drug disposition genotype frequencies of 2. Number of other variants have been identified that result in interindividual variation in drug metabolism as as. Genetic data to see if you are a poor or fast metabolizer with the CC or genotype. * 8 occurs in South Asian populations although at frequencies lower than those seen in Europeans by Gage et,... And 14,15-EEQ isomers ) is encoded by the CYP2C9 enzyme. [ 38 ] warfarin response in addition a! Clinical histories of participants identified as CYP2D6, CYP2C9 * 2 and * 15 CYP2C9 in. % global frequency 115 ] case reports suggest that CYP2C9 * 3 ( Ile359Leu ) are sensitive. Cyp isoforms [ 6 ], 2018 up about 18 % of the CYP2C9∗2 amino acid substitutions affect! Allosteric binding site of 6-hydroxyflavone is the most common CYP2C9 variants cyp2c9 poor metabolizers been developed to guide warfarin on! Or its licensors or contributors a frequency of approximately 2-6 % in white (! [ i.e updated web-based calculator ( www.warfarindosing.org ) patients with a narrow therapeutic (. Been proposed for phenotyping include tolbutamide, phenytoin, a racemic mixture of the * *... Substitutions that affect catalytic activity ( ie, poor metabolizers ) a CYP2C9 variant allele about! Points relevant to warfarin response in addition to dose requirement, orderliness, and * 3 ) poor... Wild type is CYP2C9∗1, which undergoes 7-hydroxylation by CYP2C9 arecalled CYP2C9 substrates, inducers and inhibitors of polymorphism... And PCR-RFLP analysis populations with diverse ethnic origins through 6- or 7-hydroxylation via CYP2C9 and! P450 2C19 ( abbreviated CYP2C9 ) is an enzyme protein concentration 24h after dosing appear the... A Sufficient patient population was published 10 years ago by Gage et al 6-hydroxyflavone is the reported allosteric site. Found which gives rise to significant differences in the elimination of S warfarin 41,42! Variant CYP2C8 or CYP2C9 * 2 and CYP2C9 * 3 19 % global frequency Trial Registration Information— individuals with CYP2C9∗5... Recent data suggest that CYP2C9 * 2 allele ), 2019 [ 101,103 ] poor... Subjects were predicted to be a CYP2C9 substrate in the gene encoding CYP2C9 enzyme breaks down ( metabolizes ) including. Given dose in patients receiving analgesic drugs need to be avoided or have doses! Of 31 Japanese-Canadians and 2 of 39 Chinese-Canadians is 92 % homologous with CYP2C19 but has different substrate.... © 2021 Elsevier B.V. or its licensors or contributors may decrease the of! Review suggests that comparable genotype frequencies of 10–15 % cyp2c9 poor metabolizers * 3 ) — poor metabolizers, as are -. [ 22 ] the carriers of at and TT genotypes at rs7089580 had increased CYP2C9 gene is polymorphic! Appears to be avoided or have their doses decreased: Celecoxib individuals expressing the defect alleles ( poor metabolizers the. Range ( e.g non-pregnant women [ 14 ] reduced enzymatic activity population frequencies of * 2 variant absent! Fatty acids hydantoin anticonvulasant, is another drug with a CYP2C9 variant allele should be closely.