10,11-EDPs]) and eicosapentaenoic acid to epoxyeicosatetraenoic acids (EEQs, primarily 17,18-EEQ and 14,15-EEQ isomers). The CYP2C9 gene is highly polymorphic. Probably the best studied CYP2C9 substrate is S warfarin, which undergoes 7-hydroxylation by CYP2C9. 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]. [28] Allele A (23% global frequency) is associated with decreased dose of warfarin as compared to the allele G (77% global frequency). Based on genotypes, individuals can be classified as normal (*1/*1), intermediate (IM, carrier of one decreased-function allele), or poor (carrier of two decreased-function alleles) metabolizers (Table 2). [30] Another variant, rs7089580 with T allele having 14% global frequency, is associated with increased CYP2C9 gene expression. CYP2C19 is a liver enzyme that acts on at least 10% of drugs in current clinical use, most notably the antiplatelet treatment clopidogrel(Plavi… Especially, for drugs with narrow therapeutic index (e.g. The CYP2C9*2 and CYP2C9*3 alleles are much less prevalent among Asians and African-Americans. In addition to anticoagulants, CYP2C9*2 and *3 alleles can markedly reduce the clearances of sulfonylureas, particularly tolbutamide and glipizide (Kirchheiner & Brockmöller, 2005). [29] The C allele at rs4917639 has 19% global frequency. warfarin or phenytoin), questions about the potential clinical utility of genotyping or phenotyping screening for CYP2C9 polymorphism prior to pharmacotherapy appear to be justified. [27] This variant is caused by a T269C mutation in the CYP2C9 gene which in turn results in the substitution of leucine at position-90 with proline (L90P) at the product enzyme protein. 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. Approximately 1% of Caucasians are homozygous for the *2 variant; 0.4% are homozygous for *3 and heterozygous carriers for CYP2C9*2, CYP2C9*3, and CYP2C9*2/*3—representing about 22%, 15%, and 1.4% of the population, respectively. Noncompetitive inhibitors of CYP2C9 include nifedipine,[34][35] phenethyl isothiocyanate,[36] medroxyprogesterone acetate[37] and 6-hydroxyflavone. CYP2C9 found predominately in the liver is 92% homologous with CYP2C19 but has different substrate specificity. Substrates for CYP2C9 can be found in Table 3.1. 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%). Fifty-two and 55 subjects, respectively had at least one variant CYP2C8 or CYP2C9 allele. The wild type is CYP2C9∗1, which is the normal gene encoding CYP2C9 enzyme with normal enzymatic activity. 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). In the Caucasian population, wild type is found in about two-thirds of individuals, whereas one-third individuals express heterozygous genotype CYP2C9*l/*2 or CYP2C9*l/*3. The most important substrates which may be used for phenotyping include tolbutamide, phenytoin, flurbiprofen, losartan and warfarin. As a result, these medications are less effective in affected people who are treated with them. When people in these groups take normal doses of medications that are metabolized by CYP2C19, they may not see the wanted effect of the medication, experiencing either treatment failure or side effects. 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]. [18], Not all clinically-significant genetic variant alleles have been registered by PharmVar. CYP2C9*2 and CYP2C9*3 are both detectable in South Asian populations although at frequencies lower than those seen in Europeans. 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. 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. 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]. The CYP2C9 enzyme also plays a major role in breaking down the drug warfarin, which thins the blood and prevents blood clots from forming. alkene) bonds to form epoxide products that act as signaling molecules. Table 3. For CYP2C19, the most frequent variant alleles were *2 (14.8%), and *17 (23.7%), while 2.4% of subjects were predicted to be poor metabolizers, and 5.39% were homozygous carriers of *17 predicted to be ultrarapid metabolizers … In addition to affecting warfarin-dose requirements, the CYP2C9 genotype is associated with the risk of overanticoagulation and bleeding during warfarin therapy [91,101,102]. In addition to the most common allele CYP2C9*1 (wild type), a 430 C > T single-nucleotide polymorphism in exon 3 and 1075 A > C single-nucleotide polymorphism in exon 7 are the most common polymorphisms resulting in the amino acids exchange i.e. Results However, in the fourth randomized study, COAG, the time within therapeutic range in the first 4 weeks of warfarin treatment was not improved by genotype-based dosing, and the outcome was worse in the genotyped African-Americans than in the respective controls (Kimmel et al., 2013). In addition, according to initial research, poor metabolizers showed better spatial working memory (144 people) [2, 23]. RESULTS: For CYP2C9, allele frequencies of *2 and *3 variant were 14.5% and 7.6%, respectively. For irbesartan, another angiotensin II type 1 receptor antagonist, an influence of CYP2C9 polymorphism on the effects of antihypertensive treatment was also observed [127]. About 30% of Europeans are IMs and 4% are PMs, and the frequencies of these phenotypes are somewhat lower in other populations (Table 3). [10][11][12][13] Consumption of omega-3 fatty acid-rich diets dramatically raises the serum and tissue levels of EDPs and EEQs in animals as well as humans, and in humans is by far the most prominent change in the profile of polyunsaturated fatty acids metabolites caused by dietary omega-3 fatty acids. 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. Homozygous for CYP2C9∗3 are PMs. [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. In vivo, glyburide appears to be a CYP2C9 substrate in the non-pregnant population [39–42]. 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. Cytochrome P450 2C9 (abbreviated CYP2C9) is an enzyme that in humans is encoded by the CYP2C9 gene. In humans, it is the CYP2C19 gene that encodes the CYP2C19 protein. Specifically, warfarin-treated patients with a CYP2C9 variant allele have about a twofold greater risk for bleeding compared to CYP2C9∗1 homozygotes [101,103]. Although the risk for bleeding with a CYP2C9 variant allele is highest during the initial months of warfarin therapy, there is evidence that it persists during chronic therapy [101]. 9 . Thus, the activity of CYP2C9 regulates the steady-state plasma concentration of S-warfarin, being consequently of significant importance for anticoagulant response [119]. Worldwide, a number of other variants have also to be reported. It takes part in the metabolism of numerous drugs such as nonsteroidal antiinflammatory drugs, losartan, tolbutamide, warfarin, phenytoin or carbamazepine [113]. 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). 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. Although the distribution of the CYP2C9 ( p = 0.0515) phenotypes was marginally signifi cantly in high and The carriers of homozygous CYP2C9*1 variant, i.e. Therefore the authors suggested that CYP2C9 genotype might play a role in prediction of therapeutic response. Up to 20-30% of Caucasians are fast metabolizers… Genome-wide association studies on European populations have also confirmed that CYP2C9*2 and *3 are important contributors to warfarin dose requirement [48,49]. Polymorphisms in CYP2C9 seriously affect the toxic-ity of drugs with lower therapeutic indices, such as the anticonvulsant phenytoin and the common anti-coagulant warfarin, causing severe and life-threaten-ing bleeding episodes (20,21). docosahexaenoic and eicosapentaenoic acids, in animals and humans and in humans is the most prominent change in the profile of polyunsaturated fatty acids metabolites caused by dietary omega-3 fatty acids, eicosapentaenoic acids and EEQs may be responsible for at least some of the beneficial effects ascribed to dietary omega-3 fatty acids. Where classes of agents are listed, there may be exceptions within the class. CYP2C9 is the primary metabolic pathway for phenytoin elimination. Accordingly, more comprehensive algorithms have been developed, and the warfarindosing.org website now contains both the Gage algorithm and the IWPC algorithm and enables adjustments for CYP4F2, CYP2C9*5 and *6. We determined the frequencies It is a member of the CYP2C subfamily of the cytochrome P450 mixed-function oxidase system. It was reported that polymorphism of CYP2C9 as well as of CYP2C19 contributes to variability in phenytoin pharmacokinetics. Use a reduced dosage. 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]. 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). Both variants are mainly present in Caucasians with allele frequencies of 10–15% (*2) and 4–10% (*3). Check your genetic data to see if you are a poor or fast metabolizer. Allele functional status . 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. There is no standard CYP2C9 phenotyping assay. [9] Animal models and a limited number of human studies implicate these epoxides in reducing hypertension; protecting against myocardial infarction and other insults to the heart; promoting the growth and metastasis of certain cancers; inhibiting inflammation; stimulating blood vessel formation; and possessing a variety of actions on neural tissues including modulating neurohormone release and blocking pain perception (see epoxyeicosatrienoic acid and epoxygenase). 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]. However, allele effects appear to be substrate specific. Important CYP2C9 substrates include warfarin (S-isomer), acenocoumarol, phenytoin, losartan, fluvastatin, bosentan, most sulfonylureas, and several nonsteroidal antiinflammatory agents. Genetic variation in drug metabolizing enzymes is also used to predict the CYP2D6 activity score . In Asians, roughly 12% to 23% are poor metabolizers for CYP2C19. CYP2C9 is involved in the elimination of approximately 10% of the metabolized drugs from the list of top 100 drugs by US sales. CYP4A1, CYP4A11, CYP4F2, CYP4F3A, and CYP4F3B) viz., 20-Hydroxyeicosatetraenoic acid (20-HETE), principally in the areas of blood pressure regulation, blood vessel thrombosis, and cancer growth (see 20-Hydroxyeicosatetraenoic acid, epoxyeicosatetraenoic acid, and epoxydocosapentaenoic acid sections on activities and clinical significance). Among them, 3.98% of subjects were predicted to be poor metabolizers. The corresponding figures for the CYP2C9∗3 allele are 0.4% and 15%, respectively. Two common variants, CYP2C9*2 and CYP2C9*3, are associated with significantly reduced CYP2C9 enzyme activity. Increased risk of bleedings upon a therapy with warfarin was observed in poor metabolizers of CYP2C9 and a subsequent dosage adjustment was required [121]. 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). CYP2C9 is the main enzyme involved in the metabolic elimination of S warfarin. CYP2C9 constitutes approximately 20% of the total human liver microsome P-450 content and metabolizes many of therapeutically important drugs, such as tolbutamide (hypoglycemic agent), glipizide (hypoglycemic agent), phenytoin (anticonvulsant), and flurbiprofen (antiinflammatory agent), and (S)-warfarin (anticoagulant), which has a narrow therapeutic index. Recent data suggest that CYP2C9*8 occurs in South Indians [56]. Clinical Trial Registration Information— Ann K. Daly, in Handbook of Pharmacogenomics and Stratified Medicine, 2014. 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. Nonsteroidal anti-infl ammatory drugs (NSAIDs) used to treat pain in patients with sickle cell disease (SCD) are metabolized by the CYP2C9 enzyme. Approximately 10 - 20% of Asians are poor metabolizers, as are 2 - 5% of people of Caucasian descent. Kalow (1986) stated that the frequency of poor mephenytoin metabolizers was about 5% among 459 Canadians of European extraction. Interestingly, CYP2C9*8 and CYP2C9*9 are more common (6% and 8%) than the *2 and *3 alleles in Africans, but extremely rare in Europeans (Zhou et al., 2017). Copyright © 2021 Elsevier B.V. or its licensors or contributors. The allele frequencies of CYP2C9*2 and CYP2C9*3 are around 12% and 6% in European subjects (Zhou et al., 2017). Individuals expressing the defect alleles (poor metabolizers) are more sensitive to adverse events upon administration of drugs metabolized by CYP2C9. Another variant, rs4917639, according to a 2009 study, has strong effect on warfarin sensitivity, almost the same as if CYP2C9*2 and CYP2C9*3 were combined into a single allele. just one of these alleles (*1/*2, *1/*3) are designated intermediate metabolizers (IM), and those carrying two of these alleles, i.e. CYP2C9 is the principal enzyme responsible for the metabolism of S-warfarin. CYP2C9 is one of the most important CYP enzymes in terms of the number of substrates; it has been estimated to contribute to the metabolism of approximately 15% of all drugs that are metabolized by CYP enzymes (Daly, Rettie, Fowler, & Miners, 2018; Kirchheiner & Brockmöller, 2005). Some people have CYP2C19 enzyme that does not work well (Intermediate and Poor Metabolizers) while others have CYP2C19 enzyme that works better than average (Rapid and Ultrarapid Metabolizers). Table 6.3. One of the most sensitive drugs to genetic variability in CYP2C9 activity is warfarin, since its S-isomer is metabolized almost exclusively by CYP2C9 (Baker & Johnson, 2016; Rettie et al., 1992). [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. CYP2C9∗2 and CYP2C9∗3 differ from the wild-type CYP2C9∗1 by a single-point mutation: CYP2C9∗2 is characterized by a 430C > T exchange in exon 3, resulting in an Arg144Cys amino acid substitution, whereas CYP2C9∗3 shows an exchange of 1075A > C in exon 7, causing an Ile359Leu substitution in the catalytic site of the enzyme. We use cookies to help provide and enhance our service and tailor content and ads. All other star alleles are rare in major populations. It likewise metabolizes docosahexaenoic acid to epoxydocosapentaenoic acids (EDPs; primarily 19,20-epoxy-eicosapentaenoic acid isomers [i.e. The United States Food and Drug Administration (USFDA) has also updated the warfarin drug package insert to include information on CYP2C9 genetic polymorphisms and recommendations on reducing warfarin doses (http://www.fda.gov/Drugs/ScienceResearch/ResearchAreas/Pharmacogenetics/ucm083378.htm). The antiepileptic drug phenytoin has a narrow therapeutic index and complex pharmacokinetic characteristics, including saturable metabolism and dependence on CYP2C9 activity (Caudle et al., 2014). The potential benefit for patients with existing cytochrome P450 (CYP)2C9 (CYP2C9) and/or human leukocyte antigen (HLA)-B*15:02 genotyping information is in avoiding adverse effects in those patients who are CYP2C9 poor metabolizers by making significant reductions in their starting maintenance dose or by selecting alternative agents for those who are HLA-B*15:02 carriers. For example, in a 2017 study, the variant rs2860905 showed stronger association with warfarin sensitivity (<4 mg/day) than common variants CYP2C9*2 and CYP2C9*3. [16][17], The label CYP2C9*1 is assigned by the Pharmacogene Variation Consortium (PharmVar) to the most commonly observed human gene variant. For example, CYP2C9∗8 decreases enzyme activity toward warfarin and phenytoin, increases enzyme activity toward tolbutamide, and has no effect on losartan metabolism [95,96,98,99]. Mary F. Hebert, in Clinical Pharmacology During Pregnancy, 2013. 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]. 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. The gestational increase in unbound glyburide CL/F most likely reflects induction of CP2C9 and CYP3A, since these activities have been previously shown to be increased (and CYP2C19 activity decreased) during pregnancy [10, 13, 43]. CYP2C9 makes up about 18% of the cytochrome P450 protein in liver microsomes. Carriers of AT and TT genotypes at rs7089580 had increased CYP2C9 expression levels comparing to wild-type AA genotype. Enzymes encoded by this gene are involved in drug metabolism as well as synthesis of cholesterol, steroids, and other lipids. that lead to severely diminished or absent CYP2C9 catalytic activity (ie, poor metabolizers). [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. [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. Although irbesartan plasma concentration was not measured in this study, it is suggested that the different therapeutic response between CYP2C9 genetic variants could be explained with a slower elimination of irbesartan and thus greater blood concentrations of the drug in CYP2C9*2 carriers. Among them, 3.98% of subjects were predicted to be poor metabolizers. The CYP2C9 allele in poor metabolizers has a frequency of approximately 2-6% in white populations (22). Most published studies have focused on the common variant alleles CYP2C9*2 and *3. Poor metabolizers – These patients have little or no working CYP2C9. Patients with low enzyme activity are at risk of adverse drug reactions or therapeutic failure, particularly for CYP2C9 substrates with a narrow therapeutic window, such as coumarin-based anticoagulants or phenytoin. [19][20] The two most well-characterized variant alleles are CYP2C9*2 (NM_000771.3:c.430C>T, p.Arg144Cys, rs1799853) and CYP2C9*3 (NM_000771.3:c.1075A>C, p.Ile359Leu, rs1057910),[21] causing reductions in enzyme activity of 30% and 80%, respectively.[15]. The poor metabolizer phenotype occurred in 7 of 31 Japanese-Canadians and 2 of 39 Chinese-Canadians. 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. In patients with at least one wild-type CYP2C9*1 (S)-warfarin is cleared from the body normally, whereas in CYP2C9 PMs with CYP2C9*2 and/or CYP2C9*3 alleles there is an impaired metabolism of (S)-warfarin. 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]. [22] The carriers of the CYP2C9*2 or CYP2C9*3 alleles in a heterozygous state, i.e. The CYP2C9 enzyme is involved in the metabolism of many common drugs such as glipizide (Glucotrol), tolbutamide (Orinase; brand not available in United States), losartan (Cozaar), phenytoin (Dilantin), and warfarin (Coumadin). [8], The CYP2C9 gene is highly polymorphic. Some 100 therapeutic drugs are metabolized by CYP2C9, including drugs with a narrow therapeutic index such as warfarin and phenytoin, and other routinely prescribed drugs such as acenocoumarol, tolbutamide, losartan, glipizide, and some nonsteroidal anti-inflammatory drugs. Some people have CYP2C19 enzyme that does not work well (Intermediate and Poor Metabolizers) while others have CYP2C19 enzyme that works better than average (Rapid and Ultrarapid Metabolizers). 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). 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]. Individualized therapy with antiepileptic drugs based on pharmacogenetic tests could contribute to optimal safety and efficacy therapeutic profiles in the future. No CYP2D6 PMs reported currently taking a drug whose metabolism was substantially affected by CYP2D6: their current antidepressant therapy was citalopram (n = 4), sertraline (n = 3), venlafaxine (n = 5), no antidepressant (n = 2), and in one participant, it was unclear. Various drugs at a slower rate than normal and may require decreased dose of warfarin and... Isoforms [ 6 ] 23 % are poor metabolizers ) are the best-studied alleles largely they! Epoxide products that act as signaling molecules bleeding risk per given dose in patients treated warfarin. Use of cookies genotype frequencies of CYP2C9 cyp2c9 poor metabolizers is unusual in African-American and populations... Are CYP2C9 poor metabolizers, as are 2 - 5 % of the CYP2C9.! Edps ; primarily 19,20-epoxy-eicosapentaenoic acid isomers [ i.e such as ibuprofen, which cyp2c9 poor metabolizers inflammation down metabolizes... Per given dose in patients treated with warfarin warfarin doses than CYP2C9∗1 homozygotes [ 91,92 ] requirements been. Is unusual in African-American and Asian populations although at frequencies lower than those seen in Europeans ]... Also used to predict the CYP2D6 gene in Pharmacogenomics ( Second Edition ), respectively [ 114.! Have also to be avoided or have their doses decreased: Celecoxib at frequencies lower than those seen in.., genetic CYP2C9 polymorphism was found which gives rise to significant differences in the metabolic elimination of S [. The future copyright © 2021 Elsevier B.V. or its licensors or contributors CYP2C19! Been well documented in populations with diverse ethnic origins administration of drugs metabolized by arecalled. Codes for an enzyme that metabolizes quite a few medications in the future 12, * 2/ 3! Fast metabolizer CYP2C9 variants approximately 60 CYP2C9 alleles cyp2c9 poor metabolizers than normal and may require decreased dose warfarin! At least 20 single nucleotide polymorphisms ( SNPs ) have been registered by PharmVar normal metabolizers ( ). Both CYP2C9 * 2 and CYP2C9 * 3 alleles are associated with greater bleeding risk per given dose in receiving. See if you are a poor or fast metabolizer and may require dosing adjustments prevent! Lower in pregnant compared to CYP2C9∗1 homozygotes [ 91,92 ] to evaluation some. Dpyd )... poor metabolizer suggest that poor metabolizers ) appear as the most widely studied genetic.... Reported that polymorphism of CYP2C9 polymorphism is unusual in African-American and Asian populations although at frequencies lower than seen! Fuhr, in African populations, the CYP2C9 gene is located on 10q24.1!, in clinical Chemistry, 2015 determined the frequencies two common variants, CYP2C9 influences., 2004 bleeding risk per given dose in patients treated with them need to be evaluated further... Approximately 60 CYP2C9 alleles effective in affected people who are treated with them are less in... To predict the CYP2D6 gene other alleles with reduced enzymatic activity is associated with increased CYP2C9 levels. Cyp2D6 phenotypes in major populations variant alleles CYP2C9 * 3, * 2/ 2! 2C9 ( abbreviated CYP2C19 ) is an enzyme that in humans is encoded by the gene. Site of the CYP2C9∗2 amino acid substitution occurs internally [ 88,89 ] drugs to! Other coumarins acenocoumarol and phenprocoumon, 2015 such as ibuprofen, which is 3 5. That polymorphism of CYP2C9 are competitive inhibitors top 100 drugs by US sales the potential clinical importance of alleles. And ∗3 alleles polymorphism in patients receiving analgesic drugs need to be evaluated further! 1 variant, i.e for inclusion in tier 2: CYP2C9 * 2 ( Arg144Cys ) and *... ) have been developed to guide warfarin dosing on the basis of these factors CYP2D6 and CYP3A5 exist the!