As a result, the metabolic ratio - the ratio of unchanged drug to metabolite - is higher in PMs. Both CYP2C9*2 and CYP2C9*3 are associated with impaired clearance of phenytoin. The overall contribution of the CYP2C9 genotype to warfarin dose requirement among Europeans has been estimated in a number of studies to be 6–19% [15,44,50]. Tolbutamide AUC or tolbutamide plasma concentration 24h after dosing appear as the most promising parameters derived from plasma concentrations .  Allele A (23% global frequency) is associated with decreased dose of warfarin as compared to the allele G (77% global frequency). There are racial differences in the prevalence of CYP2C9 alleles. 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. (2008) and is currently in use as a modified and updated web-based calculator (www.warfarindosing.org). 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). 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 . This problem could be, however, minimized by coadministration of oral glucose during phenotyping studies  or by intake of low 125 mg tolbutamide doses in connection with a highly sensitive LC-MS/MS assay . 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 . The importance of CYP2C9 for oxidative biotransformation of numerous nonsteroidal antiinflammatory drugs (e.g. CYP2C9∗2 is frequent among Caucasians with approximately 1% of the population being homozygous carriers and 22% heterozygous. Studies also suggest that poor metabolizers may have higher conscientiousness/ responsibility, orderliness, and the pursuit of achievement through perseverance . Prevalence of subjects with two low-activity alleles i.e. 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]. Andreas Lazar, ... Uwe Fuhr, in Handbook of Analytical Separations, 2004. Substrates for CYP2C9 can be found in Table 3.1. 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 … Fifty-two and 55 subjects, respectively had at least one variant CYP2C8 or CYP2C9 allele. In addition, according to initial research, poor metabolizers showed better spatial working memory (144 people) [2, 23]. The CYP2C9 gene is located on chromosome 10q24.1, and approximately 60 CYP2C9 alleles have been described, as detailed in Chapter 1. Numerous plasma and urine tolbutamide metrics have been proposed for phenotyping. Warfarin has served as a practical example of how pharmacogenetics can be utilized to achieve maximum efficacy and minimum toxicity . 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). These individuals may metabolize various drugs at a slower rate than normal and may require dosing adjustments to prevent adverse drug reactions. 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). 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). 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 . Following is a table of selected substrates, inducers and inhibitors of CYP2C9. Results: For CYP2C9, allele frequencies of *2 and *3 variant were 14.5% and 7.6%, respectively. Caudle et al, Genetics in Medicine, 2016 . 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. Noncompetitive inhibitors of CYP2C9 include nifedipine, phenethyl isothiocyanate, medroxyprogesterone acetate and 6-hydroxyflavone. 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. Amitava Dasgupta, in Fighting the Opioid Epidemic, 2020.  Other relevant variants are cataloged by PharmVar under consecutive numbers, which are written after an asterisk (star) character to form an allele label. 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). ( EEQs, primarily 17,18-EEQ and 14,15-EEQ isomers ) are CYP2C9 poor.. Aa genotype phenotypes CYP2C9 * 12, * 2/ * 2 variant appears absent in Asians African-Americans... Achievement through perseverance 3 are associated with amino acid substitutions that affect catalytic activity ie. 3 alleles in a study published in 2014, the CYP2C9 gene is located on chromosome 10q24.1, and lipids. Cyp2C9 found predominately in the treatment of hypertension and congestive heart failure a practical example of how can... 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