Recent detailed studies have investigated genetic contributions to a variety of end points relevant to warfarin response in addition to dose requirement. The CYP2C9∗8 allele is one of the most common variant CYP2C9 alleles in African Americans but is virtually absent in other populations [94]. The CYP2C9 allele in poor metabolizers has a frequency of approximately 2-6% in white populations (22). 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. A difference in allelic frequencies has been well documented in populations with diverse ethnic origins. 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. Both CYP2C9*2 and CYP2C9*3 are associated with impaired clearance of phenytoin. The CYP2C9 enzyme also plays a major role in breaking down the drug warfarin, which thins the blood and prevents blood clots from forming. 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. 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. 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. Worldwide, a number of other variants have also to be reported. The potential clinical importance of CYP2C9 polymorphism during therapy with NSAID was subject to evaluation in some clinical trails. CYP2C9 is the main enzyme involved in the metabolic elimination of S warfarin. Interestingly, both CYP2C9*2 (4–7%) and CYP2C9*3 (4%) are present in Asian-Indians [38]. Mary F. Hebert, in Clinical Pharmacology During Pregnancy, 2013. Wood (2001) discussed pointers to genetic differences underlying racial differences in the response to drugs. 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. 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]. [15] In fact, adverse drug reactions (ADRs) often result from unanticipated changes in CYP2C9 enzyme activity secondary to genetic polymorphisms. In Asians, roughly 12% to 23% are poor metabolizers for CYP2C19. CYP2C9: poor metabolizers: Results in higher systemic concentrations. 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). 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]. 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. 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). 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 … The CYP2C9*2 variant appears absent in Asians and Africans. These studies have highlighted the importance of the CYP2C9∗2 and ∗3 alleles. Phenytoin, a hydantoin anticonvulasant, is another drug with a narrow therapeutic index and individual dose requirements. For instance, hydroxylation of S-ibuprofen was significantly decreased in heterozygous and homozygous carriers of CYP2C9*3 allele, whereas CYP2C9*2 variant exerted no significant effect [128]. 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. Although the distribution of the CYP2C9 ( p = 0.0515) phenotypes was marginally signifi cantly in high and [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. CYP2C9 variant alleles recommended as Tier 1 by the PGx Working Group include CYP2C9 *2, *3, *5, *6, *8, and *11. 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]. The CYP2C9 gene codes for an enzyme that metabolizes quite a few medications in the liver. Warfarin, a racemic mixture of the enantiomers, S- and R-warfarin, is the most widely prescribed anticoagulant agent. All other star alleles are rare in major populations. On the basis of their ability to metabolize CYP2C9 substrates, individuals can be categorized by groups. The proton-pump inhibitor omeprazole is … Results Studies also suggest that poor metabolizers may have higher conscientiousness/ responsibility, orderliness, and the pursuit of achievement through perseverance . 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]. It along with CYP2C8, CYP2C19, CYP2J2, and possibly CYP2S1 are the principle enzymes which metabolizes 1) arachidonic acid to various epoxyeicosatrienoic acids (also termed EETs); 2) linoleic acid to 9,10-epoxy octadecaenoic acids (also termed vernolic acid, linoleic acid 9:10-oxide, or leukotoxin) and 12,13-epoxy-octadecaenoic (also termed coronaric acid, linoleic acid 12,13-oxide, or isoleukotoxin); 3) docosahexaenoic acid to various epoxydocosapentaenoic acids (also termed EDPs); and 4) eicosapentaenoic acid to various epoxyeicosatetraenoic acids (also termed EEQs). For example, in African populations, the CYP2C9 allele distributions are very different from those described for Europeans. Carriers of AT and TT genotypes at rs7089580 had increased CYP2C9 expression levels comparing to wild-type AA genotype. Similarly, lower warfarin-dose requirements have been reported in individuals with a CYP2C9∗5, ∗6, or ∗11 allele [78,80,100]. Various algorithms have been developed to guide warfarin dosing on the basis of these factors. alkene) bonds to form epoxide products that act as signaling molecules. 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*2/*2, CYP2C9*2/*3 and CYP2C9*3/*3 accounted for less than 2.5% in these populations. There is no standard CYP2C9 phenotyping assay. Inhibitors of CYP2C9 can be classified by their potency, such as: CYP2C9 attacks various long-chain polyunsaturated fatty acids at their double (i.e. [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. [15], CYP2C9*13 is defined by a missense variant in exon 2 (NM_000771.3:c.269T>C, p.Leu90Pro, rs72558187). Amitava Dasgupta, in Fighting the Opioid Epidemic, 2020. 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]. CYP2C9 makes up about 18% of the cytochrome P450 protein in liver microsomes. Glyburide is another agent that is metabolized by CYP2C9, although CYP3A and CYP2C19 are also involved in its metabolism in vitro [36–38]. The allele frequencies of CYP2C9*2 and CYP2C9*3 are around 12% and 6% in European subjects (Zhou et al., 2017). 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 and phenytoin), it appears to be preferable to proceed with the prospective evaluation of genotype to facilitate optimal efficacy of therapy and limit adverse drug reactions in patients. CYP2C9*2 and CYP2C9*3 are the most studied alleles as well as the most common variants with varying frequencies reported across different populations or ethnicities. Up to 20-30% of Caucasians are fast metabolizers… 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). These gentoype-based dose recommendations should be, however, verified in clinical trials with clinical endpoints. Poor metabolizers – These patients have little or no working CYP2C9. There is more limited evidence that CYP2C9*5, *11 (which is seen at a low frequency among both Europeans and Africans), and *13 should also be considered (see Daly [57]). [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]. CYP2C9 found predominately in the liver is 92% homologous with CYP2C19 but has different substrate specificity. [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 addition to affecting warfarin-dose requirements, the CYP2C9 genotype is associated with the risk of overanticoagulation and bleeding during warfarin therapy [91,101,102]. [31] Another variant, rs1934969 (in studies of 2012 and 2014) have been shown to affect the ability to metabolize losartan: carriers of TT genotype have increased CYP2C9 hydroxylation capacity for losartan comparing to AA genotype, and, as a result, lower metabolic ratio of losartan, i.e. Apart from CYP2C9*2 and CYP2C9*3, some of the alleles are also relatively common and at least CYP2C9*5, CYP2C9*6, CYP2C9*11, CYP2C9*12, and CYP2C9*13 can produce an enzyme with markedly reduced activity (Daly et al., 2018). Altered drug responses in these people make them either more protected or more at risk of disease, depending on the situation (4). 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. These alleles are associated with amino acid substitutions that affect catalytic activity with S warfarin [41,42]. 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]. A possible hypoglycemia in poor metabolizers of CYP2C9 upon administration of standard phenotyping tolbutamide dose (500 mg) was reported to limit tolbutamide use as phenotypic probe [117]. The importance of CYP2C9 for oxidative biotransformation of numerous nonsteroidal antiinflammatory drugs (e.g. Following is a table of selected substrates, inducers and inhibitors of CYP2C9. 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. Normal enzyme function (wild-type) is denoted CYP2C9*1, with the two most common allelic variants, CYP2C9*2 (p.R144C) and CYP2C9*3 (p.I359L) causing reductions in enzyme activity of 30% and 80%, respectively [121,122]. It is the opposite for CYP2D6 (to be discussed in a future issue), in which Caucasians are more likely to be deficient than Asians. 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). As discussed, S warfarin is also subject to metabolism at other positions by other CYP isoforms [6]. 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. Drugs metabolized by CYP2C9 arecalled CYP2C9 substrates. Probably the best studied CYP2C9 substrate is S warfarin, which undergoes 7-hydroxylation by CYP2C9. Individuals with clopidogrel resistance can be classified into two groups: intermediate metabolizers or poor metabolizers. 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