This recommendation was based on their well-established functional effects on CYP2C9 activity and drug response availability of reference materials, and their appreciable allele frequencies in major ethnic groups. Approximately 10 - 20% of Asians are poor metabolizers, as are 2 - 5% of people of Caucasian descent. (e.g. Among them, 3.98% of subjects were predicted to be poor metabolizers. 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). Wood (2001) discussed pointers to genetic differences underlying racial differences in the response to drugs. The wild type is CYP2C9∗1, which is the normal gene encoding CYP2C9 enzyme with normal enzymatic activity. About 30% of Europeans are IMs and 4% are PMs, and the frequencies of these phenotypes are somewhat lower in other populations (Table 3). On the basis of their ability to metabolize CYP2C9 substrates, individuals can be categorized by groups. Homozygous for CYP2C9∗3 are PMs. Poor metabolizers – These patients have little or no working CYP2C9. Other alleles with reduced activities include CYP2C9∗4, CYP2C9∗5, and CYP2C9∗30. [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. More than 55 variants of CYP2C9 have been identified (http://www.cypalleles.ki.se) of which CYP2C9*2 and CYP2C9*3 are the two most common variant alleles that show largely reduced enzymatic activities that lead to poor metabolism. The potential clinical importance of CYP2C9 polymorphism during therapy with NSAID was subject to evaluation in some clinical trails. warfarin or phenytoin), questions about the potential clinical utility of genotyping or phenotyping screening for CYP2C9 polymorphism prior to pharmacotherapy appear to be justified. The largest database is available for tolbutamide (oral antidiabetic agent) supporting its use as a selective in vivo CYP2C9 probe [117]. The following CYP2C9 alleles are recommended for inclusion in tier 2: CYP2C9*12, *13, and *15. In addition, a different set of P450 isoforms metabolize R warfarin. [22] The carriers of the CYP2C9*2 or CYP2C9*3 alleles in a heterozygous state, i.e. CYP2C9 is the principal enzyme responsible for the metabolism of S-warfarin. 9 . Among them, 3.98% of subjects were predicted to be poor metabolizers. Low CYP2D6 activity may decrease the risk of schizophrenia. Table 3. Kalow (1986) stated that the frequency of poor mephenytoin metabolizers was about 5% among 459 Canadians of European extraction. Genetic variation in drug metabolizing enzymes is also used to predict the CYP2D6 activity score . [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. 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. On the other hand, genetic CYP2C19 polymorphism seems not to be relevant for safe therapy with warfarin, although CYP2C19 takes part in biotransformation of R-warfarin [120]. 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]. Clinical Trial Registration Information— 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. 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. Argl44Cys (CYP2C9*2 allele) and Ile359Leu (CYP2C9*3 allele), respectively [114]. 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. [5][6], CYP2C9 is an important cytochrome P450 enzyme, which plays a major role in the oxidation of both xenobiotic and endogenous compounds. [15] At least 20 single nucleotide polymorphisms (SNPs) have been reported to have functional evidence of altered enzyme activity. Prevalence of subjects with two low-activity alleles i.e. 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. [15] CYP2C9*13 prevalence is approximately 1% in the Asian population,[26] but in Caucasians this variant prevalence is almost zero. It likewise metabolizes docosahexaenoic acid to epoxydocosapentaenoic acids (EDPs; primarily 19,20-epoxy-eicosapentaenoic acid isomers [i.e. 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. Drugs that may need to be avoided or have their doses decreased: Celecoxib. CYP2C9 is the main enzyme involved in the metabolic elimination of S warfarin. The importance of CYP2C9 for oxidative biotransformation of numerous nonsteroidal antiinflammatory drugs (e.g. 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. 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). 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]. Increased gene expression due to rs7089580 T allele leads to increased rate of warfarin metabolism and increased warfarin dose requirements. Sufficient number of studies has provided comparable results in general. It was reported that polymorphism of CYP2C9 as well as of CYP2C19 contributes to variability in phenytoin pharmacokinetics. 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. RESULTS: For CYP2C9, allele frequencies of *2 and *3 variant were 14.5% and 7.6%, respectively. It was indicated that the noncompetitive binding site of 6-hydroxyflavone is the reported allosteric binding site of the CYP2C9 enzyme.[38]. 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). Up to 20-30% of Caucasians are fast metabolizers… The phenotypes CYP2C9*2 and CYP2C9*3 are the two most common variations and are associated with reduced enzymatic activity. Furthermore, case reports suggest that CYP2C9 PMs are at increased risk for dose-related phenytoin toxicity. CYP2C9 makes up about 18% of the cytochrome P450 protein in liver microsomes. The carriers of homozygous CYP2C9*1 variant, i.e. Insufficient biotransformation of the phenytoin can result in symptoms of drug intoxication. Neither substitution appears to affect substrate binding. 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). Decreased enzyme activity and clearance of CYP2C9 substrates have been reported with the CYP2C9∗5, ∗6, ∗8 and ∗11 alleles [95–98]. Because many substrates of CYP2C9 are drugs with narrow therapeutic range (e.g. 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). ", "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. The CYP2C9 gene codes for an enzyme that metabolizes quite a few medications in the liver. At least 20 single nucleotide polymorphisms (SNPs) have been reported to have functional evidence of altered enzyme activity. 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. This subfamily includes enzymes that catalize metabolism of xenobiotics, including some proton pump inhibitors and antiepileptic drugs. The CYP2C9∗2 and ∗3 alleles are the most common variant CYP2C9 alleles in Caucasians but are much less prevalent among Asians and African Americans, as shown in Table 6.3. 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 ). 10,11-EDPs]) and eicosapentaenoic acid to epoxyeicosatetraenoic acids (EEQs, primarily 17,18-EEQ and 14,15-EEQ isomers). 5, 8, 13 Individuals are classified as extensive (EM), intermediate (IM), or poor metabolizers (PM) based on their ability to metabolize CYP2C9 … alkene) bonds to form epoxide products that act as signaling molecules. CYP2C9, CYP2C19, CYP2D6, DPYD) ... Poor metabolizer . CYP2C9 polymorphism was shown to result in interindividual differences in oxidation and activation of the drug [126]. 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). This enzyme also assists in metabolizing other drugs such as ibuprofen, which reduces inflammation. The CYP2C9*2 and CYP2C9*3 alleles are much less prevalent among Asians and African-Americans. [18] Other relevant variants are cataloged by PharmVar under consecutive numbers, which are written after an asterisk (star) character to form an allele label. 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). 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]. A wide variation exists in how this gene metabolizes these drugs. Table 6.3. 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. 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). [15], CYP2C9*13 is defined by a missense variant in exon 2 (NM_000771.3:c.269T>C, p.Leu90Pro, rs72558187). Cytochrome P450 2C19 (abbreviated CYP2C19) is an enzyme protein. 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%). 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. 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. Results Larisa H. Cavallari, Kathryn M. Momary, in Pharmacogenomics (Second Edition), 2019. [32][33], Most inhibitors of CYP2C9 are competitive inhibitors. [18], Not all clinically-significant genetic variant alleles have been registered by PharmVar. of the *1/*1 genotype, are designated extensive metabolizers (EM), or normal metabolizers. 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… Enzymes encoded by this gene are involved in drug metabolism as well as synthesis of cholesterol, steroids, and other lipids. About 3% to 5% of Caucasians are poor metabolizers for CYP2C19?that is, they lack functioning genes for the synthesis of CYP2C19. CYP2C9 is ~ 18% of CYP450 protein in liver microsomes. cyp2c9 Both variants of the CYP2C9 enzyme, *2 (c.430C>T) and *3 (c.1075A>C), exhibit impaired function leading to poor metabolism (PM) phenotypes for various drugs. CYP2C9 is involved in the elimination of approximately 10% of the metabolized drugs from the list of top 100 drugs by US sales. Table 4 Clinical histories of participants identified as CYP2D6, CYP2C9, or CYP2C19 poor metabolizers. A difference in allelic frequencies has been well documented in populations with diverse ethnic origins. 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. In addition to anticoagulants, CYP2C9*2 and *3 alleles can markedly reduce the clearances of sulfonylureas, particularly tolbutamide and glipizide (Kirchheiner & Brockmöller, 2005). CYP2C9 also is themajor enzyme involved in the dispositionof warfarin. 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]. Cytochrome P450 2D6 (CYP2D6) is an enzyme that in humans is encoded by the CYP2D6 gene. 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. Probably the best studied CYP2C9 substrate is S warfarin, which undergoes 7-hydroxylation by CYP2C9. [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]. Where classes of agents are listed, there may be exceptions within the class. [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. Despite a large number of studies showing important roles for the CYP2C9*2 and *3 alleles as determinants of warfarin dose requirement in Europeans, there have been fewer studies on other ethnic groups that show lower frequencies for these alleles but may be positive for other CYP2C9 variants that are also associated with decreased activity. Who is a poor metabolizer? Interestingly, both CYP2C9*2 (4–7%) and CYP2C9*3 (4%) are present in Asian-Indians [38]. 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. Balraj Mittal, ... Gaurav Agarwal, in Advances in Clinical Chemistry, 2015. This decrease coincides with about a 20% reduction in warfarin-dose requirements with the CYP2C9∗8 allele [78]. Both variants are mainly present in Caucasians with allele frequencies of 10–15% (*2) and 4–10% (*3). The CYP2C9∗8 allele is one of the most common variant CYP2C9 alleles in African Americans but is virtually absent in other populations [94]. CYP2C9*2 (Arg144Cys) and CYP2C9*3 (Ile359Leu) are the two most widely studied genetic variants. The poor metabolizer phenotype occurred in 7 of 31 Japanese-Canadians and 2 of 39 Chinese-Canadians. Use a reduced dosage. 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). Substrates for CYP2C9 can be found in Table 3.1. 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. In a study published in 2014, the AT genotype showed slightly higher expression than TT, but both much higher than AA. Most published studies have focused on the common variant alleles CYP2C9*2 and *3. 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). 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. As discussed, S warfarin is also subject to metabolism at other positions by other CYP isoforms [6]. A number of specific CYP2C9 variants have been identified that result in enzymatic deficiencies. 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. Population Frequencies of CYP2C9, CYP2C19, and CYP2D6 Phenotypes in Major Populations. 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]. 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). Thus, patients with a CYP2C9 variant allele should be monitored closely for signs and symptoms of bleeding throughout warfarin therapy. Patients heterozygous for CYP2C9*2 demonstrated stronger reduction of diastolic and systolic blood pressure compared to patients homozygous for CYP2C9*1 (wild type). They are the best-studied alleles largely because they are functionally detrimental and globally the most common CYP2C9 variants. 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). The poor metabolizers are carrying two defective alleles, resulting in substantially decreased drug metabolism and, in particular situations, higher levels of drugs … 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). Biotransformation of numerous nonsteroidal antiinflammatory drugs ( e.g plasma concentrations [ 118 ] be found in table 3.1 angiotensin type... ) are more sensitive to adverse events upon administration of drugs metabolized by CYP2C9 arecalled CYP2C9 substrates there are differences. 118 ] heart failure from unanticipated changes in CYP2C9 enzymatic activity of phenytoin accounts about... 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