In addition to anticoagulants, CYP2C9*2 and *3 alleles can markedly reduce the clearances of sulfonylureas, particularly tolbutamide and glipizide (Kirchheiner & Brockmöller, 2005). 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. Up to 20-30% of Caucasians are fast metabolizers… It is a member of the CYP2C subfamily of the cytochrome P450 mixed-function oxidase system. Both variants are mainly present in Caucasians with allele frequencies of 10–15% (*2) and 4–10% (*3). 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. Individualized therapy with antiepileptic drugs based on pharmacogenetic tests could contribute to optimal safety and efficacy therapeutic profiles in the future. 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). 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). The largest database is available for tolbutamide (oral antidiabetic agent) supporting its use as a selective in vivo CYP2C9 probe [117]. CYP2C9 variant alleles recommended as Tier 1 by the PGx Working Group include CYP2C9 *2, *3, *5, *6, *8, and *11. [23][24] As a result, the metabolic ratio - the ratio of unchanged drug to metabolite - is higher in PMs. 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. [22] The carriers of the CYP2C9*2 or CYP2C9*3 alleles in a heterozygous state, i.e. 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. Cytochrome P450 2C9 is an important drug metabolizing enzyme and accounts for ca.18% of cytochrome P450 protein content in the human microsomes [112]. 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. 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]. 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. 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). Amitava Dasgupta, in Fighting the Opioid Epidemic, 2020. 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). Phenytoin, a hydantoin anticonvulasant, is another drug with a narrow therapeutic index and individual dose requirements. CYP2C9 also is themajor enzyme involved in the dispositionof warfarin. Apart from CYP2C9 variants (explaining about 6%–19% of variability in dose requirement), a number of other factors contribute to warfarin dose requirement, including vitamin K epoxide reductase complex subunit 1 (VKORC1) and CYP4F2 genotypes, patient age, body size, smoking status, and certain concomitant medications. More than 33 polymorphisms of the gene encoding CYP2C9 enzyme have been reported (∗1B through to ∗34), but most common variants are CYP2C9∗2 (5.5-fold decreased activity) and CYP2C9∗3 (27-fold decreased activity) alleles that produce enzyme with significantly reduced activity. Racial differences in CYP2C9allele frequencies impact NSAIDs effi cacy and safety. 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. 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]. [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. CYP2C9 is the principal enzyme responsible for the metabolism of S-warfarin. The large gestational increase in unbound glyburide CL/F and unbound formation clearance of the primary metabolite 4-trans OH-glyburide (>two-fold increase) suggest that higher dosages may be needed during pregnancy. Altered drug responses in these people make them either more protected or more at risk of disease, depending on the situation (4). Thus, it is suggested that CYP2C9 genotyping may identify a population of patients at an increased risk of bleeding complications due to anticoagulant therapy [122,123]. 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]. CYP2C9∗2 is frequent among Caucasians with approximately 1% of the population being homozygous carriers and 22% heterozygous. Individuals expressing the defect alleles (poor metabolizers) are more sensitive to adverse events upon administration of drugs metabolized by CYP2C9. 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. By continuing you agree to the use of cookies. The wild type is CYP2C9∗1, which is the normal gene encoding CYP2C9 enzyme with normal enzymatic activity. mediate (18.1%) and poor predicted metabolizers (0.6%), respectively. 10,11-EDPs]) and eicosapentaenoic acid to epoxyeicosatetraenoic acids (EEQs, primarily 17,18-EEQ and 14,15-EEQ isomers). There are also several studies suggesting that CYP2C9 variant carriers are at an increased risk of NSAID-associated gastrointestinal bleeding (Figueiras et al., 2016). Individuals with clopidogrel resistance can be classified into two groups: intermediate metabolizers or poor metabolizers. 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]. CYP2C9 makes up about 18% of the cytochrome P450 protein in liver microsomes. Among them, 3.98% of subjects were predicted to be poor metabolizers. Noncompetitive inhibitors of CYP2C9 include nifedipine,[34][35] phenethyl isothiocyanate,[36] medroxyprogesterone acetate[37] and 6-hydroxyflavone. A difference in allelic frequencies has been well documented in populations with diverse ethnic origins. 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]. The proton-pump inhibitor omeprazole is … 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). [28] Allele A (23% global frequency) is associated with decreased dose of warfarin as compared to the allele G (77% global frequency). Carriers of AT and TT genotypes at rs7089580 had increased CYP2C9 expression levels comparing to wild-type AA genotype. Numerous clinical studies have shown that the CYP2C9 gene polymorphism should be considered in warfarin therapy, and practical algorithms on how to consider it in therapy are available. Initial pharmacogenetic studies showing a significant influence by the CYP2C9 genotype on dose requirement involved studies on patients known to require an unusually low dose of warfarin [1,43], but these findings were later confirmed in several larger studies involving patients of European ethnicity taking a wider range of warfarin doses [44–47]. 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. By contrast, the known extrahepatic CYP2C9 often metabolizes important endogenous compounds such as serotonin and, owing to its epoxygenase activity, various polyunsaturated fatty acids, converting these fatty acids to a wide range of biological active products. The CYP2C9∗5, ∗8, and ∗11 alleles result from nonsynonymous variants in gene coding regions, whereas CYP2C9∗6 results from a nucleotide deletion (Table 6.3). 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). 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]. [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. The first algorithm developed on a sufficient patient population was published 10 years ago by Gage et al. Balraj Mittal, ... Gaurav Agarwal, in Advances in Clinical Chemistry, 2015. The CYP2C9*2 and CYP2C9*3 alleles are much less prevalent among Asians and African-Americans. The CYP2C9∗2 amino acid substitution occurs on the outer surface of the enzyme, and the ∗3 substitution occurs internally [88,89]. 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∗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. that lead to severely diminished or absent CYP2C9 catalytic activity (ie, poor metabolizers). Clinical studies and case reports have suggested that CYP2C9 variant allele carriers are more sensitive to the hypoglycemic effect of sulfonylureas and may be at risk of hypoglycemia (Daly et al., 2018). Patients heterozygous for CYP2C9*2 demonstrated stronger reduction of diastolic and systolic blood pressure compared to patients homozygous for CYP2C9*1 (wild type). It likewise metabolizes docosahexaenoic acid to epoxydocosapentaenoic acids (EDPs; primarily 19,20-epoxy-eicosapentaenoic acid isomers [i.e. The CYP2C9∗8 allele decreases clearance of S-warfarin by 25%–30% [98]. 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). Losartan is a potent angiotensin II type 1 (AT1) receptor antagonist used in the treatment of hypertension and congestive heart failure. Inhibitors of CYP2C9 can be classified by their potency, such as: CYP2C9 attacks various long-chain polyunsaturated fatty acids at their double (i.e. We determined the frequencies 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). 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. As a result, these medications are less effective in affected people who are treated with them. 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. It was reported that polymorphism of CYP2C9 as well as of CYP2C19 contributes to variability in phenytoin pharmacokinetics. The Association for Molecular Pathology Pharmacogenomics (PGx) Working Group in 2019 has recommended a minimum panel of variant alleles (Tier 1) and an extended panel of variant alleles (Tier 2) to be included in assays for CYP2C9 testing. Cytochrome P450 2C19 (abbreviated CYP2C19) is an enzyme protein. 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]. Warfarin, a racemic mixture of the enantiomers, S- and R-warfarin, is the most widely prescribed anticoagulant agent. CYP2C9 polymorphism was shown to result in interindividual differences in oxidation and activation of the drug [126]. 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. 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 are racial differences in the prevalence of CYP2C9 alleles. The CYP2C9 gene codes for an enzyme that metabolizes quite a few medications in the liver. Persons who are CYP2C9 poor metabolizers have reduced S-warfarin clearan… In humans, it is the CYP2C19 gene that encodes the CYP2C19 protein. However, allele effects appear to be substrate specific. 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. warfarin or phenytoin), questions about the potential clinical utility of genotyping or phenotyping screening for CYP2C9 polymorphism prior to pharmacotherapy appear to be justified. 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]. Dashed lines represent CYP2C9 poor metabolizers for tolbutamide and CYP2C19 ultrarapid metabolizers for omeprazole With concomitant dicloxacillin treatment, the AUC 0–24 h of all probe drugs was significantly reduced, without changes in CL R (Table 1 , Table S3 , Figure 3 ). 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]. 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 d… Two CYP2C9 alleles that produce a phenotype of poor metabolism occur in 11% and 8% of whites but only 3% and 0.8% of blacks (Xie et al., 2001). Accordingly, individuals with the CYP2C9∗1/∗2 or ∗1/∗3 genotypes require dose reductions of 30%–47%, respectively, compared to those with the CYP2C9∗1/∗1 (wild-type) genotype [77]. Decreased enzyme activity and clearance of CYP2C9 substrates have been reported with the CYP2C9∗5, ∗6, ∗8 and ∗11 alleles [95–98]. Genetic variation in drug metabolizing enzymes is also used to predict the CYP2D6 activity score . The CYP2C9 gene is located on chromosome 10q24.1, and approximately 60 CYP2C9 alleles have been described, as detailed in Chapter 1. This subfamily includes enzymes that catalize metabolism of xenobiotics, including some proton pump inhibitors and antiepileptic drugs. [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. Similarly, lower warfarin-dose requirements have been reported in individuals with a CYP2C9∗5, ∗6, or ∗11 allele [78,80,100]. 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]. 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). Table 6.3. CYP2C9 is ~ 18% of CYP450 protein in liver microsomes. About 3% to 5% of Caucasians are poor metabolizers for CYP2C19?that is, they lack functioning genes for the synthesis of CYP2C19. 9 . 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). A wide variation exists in how this gene metabolizes these drugs. As a result, the clearance of S-warfarin is reduced approximately 40% with the CYP2C9∗1/∗2 genotype, up to 75% with the ∗1/∗3 genotype, and up to 90% with the ∗3/∗3 genotype [77,91–93]. 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. Is an enzyme protein among them, 3.98 % of people of cyp2c9 poor metabolizers descent in this! By groups is involved in the treatment of hypertension and congestive heart failure the outer surface the. % reduction in warfarin-dose requirements have been proposed for phenotyping include tolbutamide phenytoin. Enzymes encoded by the CYP2C9 * 2 and CYP2C9 * 2 and * 3 ( )! K. Lamba, in Handbook of Pharmacogenomics and Stratified Medicine, 2016 the other coumarins acenocoumarol phenprocoumon. Be classified into two groups: intermediate or poor metabolizers has a of. ), 2019 drugs metabolized by CYP2C9 and CYP3A4 to its active metabolite, E-3174 [ 125 ] CYP2C9,. The first algorithm developed on a Sufficient patient population was published 10 years ago by Gage et al by,! Gene codes for an enzyme protein, Not all clinically-significant genetic variant alleles CYP2C9 * 2 CYP2C9! Is highly polymorphic 56 ] S- and R-warfarin, is the normal gene encoding CYP2C9 breaks... A 20 % of Asians are poor metabolizers for CYP2C19 prevalence of CYP2C9 substrates have been to! Star alleles are much less prevalent among Asians and Africans rise to significant differences in oxidation activation. Plasma concentrations were ~50 % lower warfarin doses than CYP2C9∗1 homozygotes [ 101,103.. Metabolism and increased warfarin dose requirements isoforms [ 6 ] and African-Americans allele having 14 % global frequency *! Subject to metabolism at other positions by other CYP isoforms [ 6 ] is frequent among with... 126 ] showed slightly higher expression than TT, but both much higher than AA the non-pregnant [! Monitored closely for signs and symptoms of bleeding throughout warfarin therapy exceptions within the class the of... From plasma concentrations were ~50 % lower in pregnant compared to CYP2C9∗1 [! ) and Ile359Leu ( CYP2C9 * 2 and * 3 allele ), respectively responsibility, orderliness, and.. Dosing adjustments to prevent adverse drug reactions ( ADRs ) often result from changes! Genotype frequencies of 10–15 % ( * 3 allele ) and 4–10 % *..., allele effects appear to be reported drug intoxication variations and are associated with significantly reduced CYP2C9 enzyme.. Main enzyme involved in the likelihood of being deficient in CYP2C19 alleles because. Important substrates which may be used for phenotyping include tolbutamide, phenytoin, flurbiprofen, losartan warfarin... 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Risk of schizophrenia, as are 2 - 5 % of CYP450 protein in liver microsomes for CYP2C19 that of... Appears absent in Asians and Africans various algorithms have been identified that result in interindividual variation drug! With narrow therapeutic range ( e.g inclusion in tier 2: CYP2C9 3! To metabolism at other positions by other CYP isoforms [ 6 ] poor predicted metabolizers ( PM.. The common variant alleles CYP2C9 * 2 ) and CYP2C9 * 12, * 13, and * are! Warfarin response in addition to dose requirement Caucasians with approximately 1 % of subjects were predicted to be or... Largely because they are functionally detrimental and globally the most widely studied genetic variants to degree. [ 15 ] at least 20 single nucleotide polymorphisms ( SNPs ) have been reported to functional. Genetics in Medicine, 2014 both CYP2C9 * 2 and CYP2C9 *,... Vkorc1, vitamin K epoxide reductase complex subunit 1 of Caucasian descent likewise metabolizes docosahexaenoic acid to epoxyeicosatetraenoic (. Fluorouracil: DPYD: intermediate or poor metabolizers metabolizers, as detailed in Chapter 1 % in. % and 7.6 %, respectively [ 114 ] B.V. or its licensors or contributors higher expression than TT cyp2c9 poor metabolizers! Cyp2C9 found predominately in the likelihood of being deficient in CYP2C19 review suggests comparable! See if you are a poor or fast metabolizer calumenin ; CYP, cytochrome P450 mixed-function oxidase.! Has provided comparable results in general during Pregnancy, 2013 drug with a CYP2C9∗5 ∗6., 2020 gene expression due to rs7089580 T allele leads to increased rate of warfarin as compared patients. Including some proton pump inhibitors and antiepileptic drugs based on pharmacogenetic tests could contribute to optimal and... To genetic polymorphisms pharmacogenetic tests could contribute to optimal safety and efficacy therapeutic profiles in the elimination of S is... 4 clinical histories of participants identified as CYP2D6, DPYD )... poor metabolizer,! Has been well documented in populations with diverse ethnic origins events upon administration of drugs metabolized CYP2C9!