Among the CYP enzymes, CYP2D6 stands out for its relative inability to be induced by xenobiotic exposure. CYP2D6 represents less than 5% of the CYP liver content, but is responsible for the metabolism of up to 25% of common drugs, mainly antidepressants, antipsychotics, beta-blockers, antiretroviral agents, antiarrhythmics, morphine derivatives, and tamoxifen, many of which have a narrow therapeutic window [51,52]. AU - Sato, Yuji. The extensive metabolizers have two normal alleles and normal metabolism; intermediate metabolizers have one defective allele and may have slower drug metabolism; the ultrafast metabolizers have gene duplications and have increased drug metabolism. Metabolism by CYP3A4 results in the inactive N-demethylated metabolites norhydrocodone and noroxycodone, respectively. Compounds of clinical interest include several antidepressants (amitriptyline, clomipramine, desipramine, imipramine, paroxetine), antipsychotics (haloperidol, risperidone, thioridazine), β-blockers (timolol, S-metoprolol), codeine, dextromethorphan, duloxetine, tramadol, and tamoxifen. It is inhibited by celecoxib, cinacalcet, quinidine, several SSRIs (paroxetine and fluoxetine), and terbinafine [51]. This GeneFocus provides a comprehensive overview and summary of CYP2D6 genetic variation and describes how the information provided by PharmVar is utilized by the Pharmacogenomics These authors also identified novel CYP450 CNV alleles (CYP2B6∗30 and CYP2E1∗1Cx2) [48]. The CYP3A5∗3 allele (6986A > G) is the most frequently occurring allele of CYP3A5 that results in a splicing defect that abolishes enzyme activity. These six include: CYP1A2, CYP2C9, CYP2D6, CYP2C19, CYP3A4 and CYP3A5. Targeted CYP2D6 genotyping will not detect any alleles that are not directly interrogated so the wild-type CYP2D6*1 allele is typically assigned in the absence of other detected variants. Drugs metabolized by CYP2D6 arecalled CYP2D6 substrates (see Table 2 at right). There is a tremendous variability in liver CYP2D6 content where in some individuals no protein is present (Zanger et al., 2001). Where there has been significant interest in CYP2D6 pharmacogenetics has been in the use of the estrogen receptor blocker, tamoxifen, in the adjuvant treatment of postmenopausal breast cancer (Brauch et al., 2013) as the active metabolite, endoxifen, is formed by two-step processes involving CYP2D6 (Dehal and Kupfer, 1997). Interestingly, CYP2D6 is not an inducible enzyme by known, classic mechanisms for enzyme induction. William C. Schaffenburg, ... Cynthia M.C. Overall, PMs and, to a lesser extent, IMs are prone to exaggerated side effects from drugs metabolized by CYP2D6, whereas normal doses of the same drugs tend to be ineffectual for UMs6,9. These findings suggest no clinically meaningful drug-drug interactions between clobazam and drugs metabolized by CYP3A4, CYP2C19, CYP1A2, or CYP2C9. Such complex CYP2D6 genotype–phenotype relationships among various populations have rendered a personalized medicine approach to tailoring pharmacotherapy of CYP2D6 substrate drugs rather than a challenging one (Gaedigk et al., 2008). Pharmacogenomics of antidepressant drug response: the genomewide association study approach Psychotropic medications belong to the most frequently prescribed drugs with more than 100Mio daily drug doses in Germany in long-term therapies [1]. Many other psychotherapeutic drugs are substrates for or inhibitors of CYP2D6, so this enzyme is of particular interest for patients on such drugs. copies of CYP2D6, although some haplotypes (e.g. As such, determining which CYP2D6 allele is duplicated is important for proper interpretation when a gene duplication is identified in conjunction with a heterozygous genotype [53]. CYP2D6 is one of the most polymorphic CYP genes in humans among the CYPs, accounting for around 80 different allelic variants and 130 genetic variations described [50]. Both single-nucleotide polymorphisms (SNPs) and CNVs can affect CYP450 activity by altering gene expression. Characteristics: The cytochrome P450 (CYP) isozyme 2D6 is involved in the metabolism of many drugs. CYP2C19 catalyzes the metabolism of many commonly used drugs, including phenytoin, omeprazole, and benzodiazepines. Q3.7 With over 90 documented allelic variants reported, CYP2D6 displays remarkable polymorphism, sometimes with whole gene duplication. 1 The CYP2D6 gene is highly polymorphic and genetic variations may give rise to reduced, normal or increased activity of the CYP2D6 enzyme. CYP2D6 is expressed mainly in liver, and although this enzyme represents ∼3% of the hepatic CYP content, it metabolizes ∼20% of drugs. Keep in mind that many drugs are metabolized by more than one CYP450 enzyme, and CYP2D6 may represent only one pathway. The poor metabolizers are carrying two defective alleles, resulting in substantially decreased drug metabolism and, in particular situations, higher levels of drugs and increased risk for adverse drug reactions [43]. Metabolized mainly by CYP2D6 and to a lesser extent by CYP3A4. Individuals with at least one allele of 6986A, designated as CYP3A5∗1, are classified as CYP3A5 expressers [43]. CYP2D6 is one of the most abundantly expressed hepatic cytochrome P450 enzymes. Related Journals of Drug metabolised by CYP2D6 Other CYP2D6 substrates have also been studied during pregnancy. Research has also gone into CYP2D6 and its effects on estrogen-responsive breast cancer treatment with tamoxifen, with conclusions still being contested as to clinical significance.26, V.M. Cytochrome P450 2D6 (CYP2D6) is the major human autoantigen in type 2 AIH. Interestingly, the increase in CYP2D6 activity during pregnancy is so great that the major pathway for elimination for clonidine switched from primarily renal to primarily metabolic. In total, 416 drugs metabolized by CYP2D6 were prescribed, with 257 (62%) of these classified as an antidepressant (Anatomical and Therapeutic Chemical [ATC] category N06A) or antipsychotic (ATC N05A). The authoritative source for defining alleles is the CYP Allele Nomenclature Committee 's CYP2D6 Allele Nomenclature page, which has now been merged into the PharmVar CYP2D6 page. The use of CYP2D6‐inhibiting drugs can result in increased blood concentrations of tramadol 37 as less tramadol is metabolized via CYP2D6 to the active metabolite O‐desmethyltramadol 23, 25. Classification of Recommendation Ultra-rapid metabolizer : Citalopram and escitalopram . This enzyme also metabolizes several endogenous substances such as hydroxytryptamines and neurosteroids. Their discoveries have been based on phenotypic changes after a long process of identification [49]. T1 - Effects of the CYP2D6*10 alleles and co-medication with CYP2D6-dependent drugs on risperidone metabolism in patientswith schizophrenia. The most convincing evidence of altered CYP2D6-mediated metabolism in CKD is from an FDA analysis that systematically and quantitatively evaluated the pharmacokinetics of numerous CYP2D6 substrates reported in CKD studies.59 This work demonstrated a decrease in CYP2D6-mediated clearance and that drug clearance decreases as kidney disease progresses. Tod M(1), Goutelle S, Gagnieu MC; Genophar II Working Group. Collaborators: Bleyzac N, Bourguignon L, Castellan C, Charpiat B, Guyeffier F, Kassaï B, Nony P. AU - Yagihashi, Tatsuhiko. The CYP genes are highly polymorphic in humans, with hundreds of SNPs, insertions and deletions, and CNVs described to date [43]. Owing to current NGS-based projects, new knowledge regarding the intron sequence variability among the CYP genes should be revealed and new alleles could be recognized explaining yet unidentified genetic backgrounds of individual differences in drug metabolism [49]. Drugs Affecting Hepatic Microsomal Enzymes. It is responsible for the metabolism and elimination of approximately 25% of clinically used drugs, in a process referred to as O-demethylation. Pratt, S.A. Scott, in Diagnostic Molecular Pathology, 2017. The mean apparent oral clearance of clonidine is approximately 80% higher in pregnant women compared with the non-pregnant population. Moreover, CYP2D6∗17 (decreased activity, nonsynonymous polymorphism) is present in 30% of Africans. Cytochrome P450 enzymes can be inhibited or induced by drugs, resulting in clinicall… Collectively, these data suggest that CYP2D6 activity is decreased in CKD and that HD restores CYP2D6 activity, potentially by removing uremic inhibitors of metabolism. Cytochrome P450 enzymes are essential for the metabolism of many medications. CYP2C9 also is themajor enzyme involved in the dispositionof warfarin. Copyright © 2021 Elsevier B.V. or its licensors or contributors. These polymorphisms are designated CYP2D6*(gene variant)XN, where XN refers to the number of gene copies. Rommel G. Tirona, Richard B. Kim, in Clinical and Translational Science (Second Edition), 2017. Antidepressants, antiarrhythmics, beta-blockers, and opioid analgesics are typical substrates of CYP2D6. In a small study, oral metoprolol AUC was reported to be two- to four-fold lower during pregnancy than in the non-pregnant population [1, 2]. The activity of CYP2D6, based on genetic testing, can and should ideally be taken into account when administering a number of drugs. From: Pharmacogenomics (Second Edition), 2019, Raj Vuppalanchi MD, in Practical Hepatic Pathology, 2011, CYP2D6 constitutes up to 2% of hepatic CYP content and is responsible for the metabolism of up to 20% of drugs that undergo biotransformation. Moreover targeted sequence screening projects have been performed to search for nonsynonymous mutations. Keywords: antidepressant drugs, CYP2C19, CYP2D6, drug metabolism, pharmacogenetics. Other genes that are highly polymorphic in this gene family are CYP2C9 and CYP2C19, while other genes with important functional polymorphisms are CYP1A2, CYP1B1, CYP2A6, CYP2A13, CYP2B6, CYP2C8, CYP2J2, CYP2R1, CYP2W1, CYP3A4, CYP3A5, CYP3A7, CYP4A22, CYP4B1, CYP4F2, CYP5A1, CYP8A1, CYP19A1, CYP21A2, and CYP26A1[43]. It metabolizes approximately 20% of the most commonly prescribed medications.13 The CYP2D6 gene is highly polymorphic, and many genetic variations (e.g. The initial interpretation of the study suggested that CYP2D6 activity was not altered by kidney disease.53 These data were subsequently reanalyzed using kinetic modeling, and the authors found that CYP2D6 activity was decreased in CKD.54 There is other support for decreased CYP2D6 in kidney disease. 1 In patients … Cytochrome P450 2D6 (CYP2D6) is an enzyme that in humans is encoded by the CYP2D6 gene. Although this class has more than 50 enzymes, six of them metabolize 90 percent of drugs, with the two most significant enzymes being CYP3A4 and CYP2D6. AU - Chino, Bun. Repeated gene duplications have subsequently given rise to one of the largest and most complex of multigene families. Multiple tricyclic antidepressants, β blockers, haloperidol, sertraline, paroxetine, and thioridazine are among the common drugs metabolized by CYP2D6. CYP2D6 is an important and complex pharmacogene, the aforementioned technologies enhance characterization and the ability to associate variation with drug-associated phenotypes. It is metabolized by CYP2D6 into the metabolites 2-dehydrosparteine and 5-dehydrosparteine. In Asians, CYP2D6∗10 (decreased activity, nonsynonymous polymorphism) and CYP2D6∗41 (decreased expression, intronic SNP causing aberrant splicing) are found in up to 50% and 10% of this population, respectively. Utilizing dextromethorphan as a CYP2D6 probe, Tracy et al. Many drugs metabolized by CYP2D6 are antidepressants or antipsychotics, making the isoenzyme a potentially im-portant factor in psychiatric practice. It is evident that thousands of mutations are localized in introns and gene-flanking regions that are not present in the databases [49]. AU - Sakuma, Kei. CYP2D6: Breaking down medications. about 1% in Thai, Chinese and Japanese populations and up to 4.8% in Indians versus 5-10% in Caucasians), the increased prevalence of the CYP2D6*10 allele in Asians does have an impact on drugs metabolized by CYP2D6. Most CYP2D6 polymorphisms result in an allele that lacks metabolic activity. Sparteine is a sodium-channel blocker and class 1a antiarrhythmic agent used as an in vivo probe of CYP2D6. CYP2D6 is a particularly challenging enzyme to understand and study because of its genetic polymorphism. CYP2D6 is located within a large CYP2 gene cluster on the long arm of chromosome 19 [5]. Drugs that Induce CYP2D6; May Reduce Gleevec levels. The cytochrome P450 (CYP)1 enzyme debrisoquine 4-hydroxylase known as CYP2D6 is involved in the oxidative metabolism of many different classes of commonly used drugs, including neuroleptics, tricyclic antidepressants, selective serotonin reuptake inhibitors, β-adrenoceptor blockers, and antiarrhythmics (1)(2). More than 20 CYP3A4 variants have been identified; however, important functional alterations have not been found [43,49]. CYP450s comprise an archaic superfamily of hemoproteins originating from an old gene that existed in very primitive organisms [43,44]. The CYP2D6∗4 allele was the first defective CYP2D6 variant allele to be identified (in 1990) and constitutes the main explanation for the poor metabolizer (PM) phenotype among Caucasians [49]. Drugs that inhibit CYP1A2 will predictably increase the plasma concentrations of the medications or decrease in clearance of substrates. PY - 2009/9/17. Hence, the fact that individual response to the … CYP2D6 is responsible for the metabolism of the second highest number of drugs metabolized by P450 enzymes. Overall, 20% to 30% of drugs are metabolized through this pathway, with more than 50 drug substrates known (see Table 3.2).2,8,11 Because of these important issues, CYP2D6 has been extensively studied.25 In contrast to CYP2C9, CYP2D6 alleles that alter enzymatic activity are common. The CYP450 group consists of 57 CYP genes, which are categorized into 18 families and 44 subfamilies coding more than 50 isoenzymes located primarily in liver [5]. drugs metabolized by CYP2D6. Genotype-based quantitative prediction of drug exposure for drugs metabolized by CYP2D6. The CYP2A6, CYP2B6, and CYP2E1 combined deletion/duplication allele frequencies ranged from 2 to 10%. Forsome CYP2D6 substrat… A noteworthy attribute of CYP2D6 is that it is not inducible; rather, it is highly polymorphic with more than 100 variant alleles and ∼200-fold variability in the metabolism of at least 100 drugs [58–61]. Approximately 1% to 3% of African American and Asian patients and 5% to 10% of Caucasians lack this enzyme, placing them at risk for increased toxicity from medications that are metabolized by CYP2D6.32 A subpopulation with higher than usual activity also has been described (“extensive and ultrarapid metabolizers”).25,26,33, Mary F. Hebert, in Clinical Pharmacology During Pregnancy, 2013. As with type 2 AIH patients, Ad-2D6–infected mice generated type 1 liver kidney microsomal-like antibodies that recognized the immunodominant epitope of CYP2D6. CYP2D6 also metabolizes several cardiac drugs from antiarrhythmic classes as well as beta blockers; some antifungals; and the antiestrogen tamoxifen. CONCLUSIONS: Several patient populations (eg, psychiatric, psychogeriatric, geriatric) have a high prevalence of patients treated with at least one drug metabolized by CYP2D6. The CYP2D6 enzyme metabolizes (breaks down) about 25% of pharmaceutical drugs including SSRIs, opioids, tamoxifen, dextromethorphan, and beta-blockers. Potent CYP2D6 inhibitors: Increased AUC of pitolisant. For example, CYP2D6*1X2 represents two copies of CYP2D6*1. A number of polymorphisms have been identified and the frequency of these alleles differ with the specific population examined.37 The majority of poor metabolizers have the CYP2D6*3, CYP2D6*4, CYP2D6*5, and CYP2D6*6 genotypes, whereas ultrarapid metabolizers have multiple copies of CYP2D6*1, CYP2D6*2, or CYP2D6*35 genotypes.38, Urszula Demkow, in Clinical Applications for Next-Generation Sequencing, 2016. Interestingly, the conversion of codeine to the active form, morphine, is catalyzed by CYP2D6; patients with low CYP2D6 activity demonstrate a poor analgesic response to codeine.32 There are no significant inducers of this activity. CYP2C9 is involved in the metabolism of many clinically important drugs, including tolbutamide, glipizide, phenytoin, warfarin, and certain nonsteroidal anti-inflammatory drugs. CYP2D6 activity was assessed in 12 CKD patients and 12 healthy controls by administering 100 mg of sparteine and 40 mg of dextromethorphan on separate days. However, only 36% of the clonidine was excreted unchanged in the urine in pregnancy compared with 59% in the non-pregnant population [32–35]. In addition to the CYPs, NADPH cytochrome P450 reductase, the electron donor for CYP enzymes, has been shown to have important polymorphic alterations, and the second electron donor, cytochrome b5, has also been shown to exhibit functionally actionable polymorphisms, although functionally variant alleles are rare [5,43,49]. May result in above normal levels of Gleevec; May be more of a concern for higher doses of Gleevec; CYP2D6 inhibitors • Amiodarone � High-resolution microarray-based comparative genomic hybridization and DNA sequencing localized CYP2A6, CYP2B6, and CYP2E1 break points to directly oriented low-copy repeats resulting in the CYP2B6∗29 partial deletion allele and novel CYP2B6/2B7P1 duplicated fusion allele (CYP2B6∗30) [48]. *35) have been associated with ultrametabolism independent of gene duplication6,14. examined the role of CYP450 CNVs in selected CYP450 pharmacogenes using multiplex ligation-dependent probe amplification and quantitative polymerase chain reaction [48]. CYP450s catalyze oxygenation of lipophilic drugs and other xenobiotics to give rise to more hydrophilic metabolites suitable for their elimination in the urine or for further metabolism by other enzymes [45,46]. Consequently, when *1 is reported by targeted genotyping, a rare CYP2D6 star (*) allele not included in the genotyping panel would not be detected, which can only be identified by gene sequencing. A more recent study investigated the effect of CKD and HD on nebivolol pharmacokinetics.58 Nebivolol is a beta blocker supplied as a racemic mixture of the enantiomers d-nebivolol and l-nebivolol and is metabolized by CYP2D6-mediated hydroxylation and glucuronidation. … Forty-five Puerto Rican mental health patients were identified by their mental health providers and referred to the study in 2008. Conversely, an ultra-rapid metabolizer would likely suffer side effects from a normal dose Genetic polymorphisms play a significant role in determining CYP2D6 activity. ScienceDirect ® is a registered trademark of Elsevier B.V. ScienceDirect ® is a registered trademark of Elsevier B.V. URL: https://www.sciencedirect.com/science/article/pii/B9780443068034000046, URL: https://www.sciencedirect.com/science/article/pii/B9780128017395000118, URL: https://www.sciencedirect.com/science/article/pii/B978012802101900020X, URL: https://www.sciencedirect.com/science/article/pii/B9780128158760000632, URL: https://www.sciencedirect.com/science/article/pii/B9780123868824000165, URL: https://www.sciencedirect.com/science/article/pii/B9780128094686000139, URL: https://www.sciencedirect.com/science/article/pii/B9780721606934500104, URL: https://www.sciencedirect.com/science/article/pii/B9780123860071000039, URL: https://www.sciencedirect.com/science/article/pii/B9780323612111000036, URL: https://www.sciencedirect.com/science/article/pii/B978012800886700039X, Next Generation Sequencing in Pharmacogenomics, Clinical Applications for Next-Generation Sequencing, Clinical and Translational Science (Second Edition), Distlerath et al., 1985; Gonzalez et al., 1988, Drug Metabolism in Chronic Kidney Disease, Handbook of Pharmacogenomics and Stratified Medicine, Animal Models for the Study of Human Disease (Second Edition), Haddad and Winchester's Clinical Management of Poisoning and Drug Overdose (Fourth Edition), Impact of Pregnancy on Maternal Pharmacokinetics of Medications, William C. Schaffenburg, ... Cynthia M.C. Concomitant use of drugs metabolized by CYP2D6 may require dosage adjustment. Although laboratory guidelines for CYP2D6 genotyping in relation to tamoxifen therapy have been reported [54], no current professional guidelines detail which alleles should be included in clinical CYP2D6 assays. Here is a partial list of drugs metabolized by CYP2D6: dextromethorphan (cough syrup) hydrocodone; methadone; tamoxifen (breast cancer, estrogen blocker) Marked interethnic variations in the frequency of various alleles have been reported [53] and are available in various online databases (dbSNP [54], ALFRED [55], 1000 Genomes [25,50]). Bradley L. Urquhart, Thomas D. Nolin, in Chronic Renal Disease (Second Edition), 2020. Joseph McGraw, in Handbook of Pharmacogenomics and Stratified Medicine, 2014. Four potential CYP2D6 phenotypic subgroups exist. Drugs metabolized by CYP1A2 are called CYP1A2 substrates. A major group of drug-metabolizing enzymes is the microsomal cytochrome P450 (CYP450) family [44]. A number of other drugs which are metabolized by CYP1A2 may inhibit : or induce the action of the enzyme. The enzymatic activity can vary up to 1000-fold between allele types.11 Clinically this translates to at least a 50-fold difference in drug doses tolerated between various individuals; this principle is illustrated by the wide dosing range of the CYP2D6 substrate doxepin and various β-blockers. Drugs metabolised by CYP2D6. Moreover, the bioactivation of codeine to morphine requires CYP2D6 leading to reports of genetic influence of drug safety (Koren et al., 2006). 1 In patients receiving potent CYP2D6 inhibitors, initiate pitolisant at dosage of 8.9 mg once daily; increase after 7 days to maximum dosage of 17.8 mg once daily. Samples from 542 individuals from various ethnic groups were tested. Other drug classes and medications that affect the CNS include acetylcholinesterase inhibitors (donepezil, galantamine); antihistamines (chlorpheniramine); muscle … Therefore, different laboratories may include different CYP2D6 alleles in their testing panels, which can result in conflicting CYP2D6 genotypes and predicted phenotypes between laboratories and studies. Although the CYP2D6 poor metabolizer phenotype is less frequent in Asian than in Western populations (e.g. In fact, almost 25% of all drugs are metabolized by CYP2D6, including dextromethorphan (a key ingredient in products such as Nyquil), beta-blockers, antiarrhythmics, and antidepressants. It is metabolized by CYP2D6 into dextrorphan, an active metabolite. The CYP2D6 function may be described as one of the following [43]: little or no CYP2D6 function—poor metabolizers; a rate of metabolism between the poor and the extensive metabolizers—intermediate metabolizers; normal CYP2D6 function—extensive metabolizers; high CYP2D6 function—ultrarapid metabolizers, subjects with multiple copies of the CYP2D6 gene expressed. AU - Mizuno, Masafumi. For example, most tricyclic antidepressants undergo CYP2D6 metabolism, but other CYP450 enzymes also may be involved. The CYP2D6*1XN, *2XN, and *35XN alleles confer enhanced metabolic phenotype, while CYP2D6*17XN and CYP2D6*41XN show decreased activity and CYP2D6*4XN alleles show none. A CYP2D6 gene deletion (CYP2D6∗5) is present in 5% of all populations. More than 30 variants of CYP2C9 have been identified [43]. The cytochrome P450 2D6 (CYP2D6) is an enzyme of great historical importance for pharmacogenetics and is now thought to be involved in the metabolism of up to 25% of the drugs that are in common use in the clinic [Article: 18001838 ]. CYP2C19 Citalopram, Escitalopram, and Sertraline Phenotype . Indeed, the pharmacogenetics of CYP2D6 has a long history dating from the 1960s with the description of genetic control of nortriptyline plasma levels (Alexanderson et al., 1969) and the discoveries of hereditary deficiencies in the metabolism of debrisoquine and sparteine and the eventual identification of the molecular mechanisms (Distlerath et al., 1985; Gonzalez et al., 1988). AU - Takao, Takahashi. CYP2D6 gene duplications (up to 13 copies) have been described for functional and nonfunctional alleles with ultrarapid metabolizer phenotype being particularly common in Africans. CYP2D6 variants have been shown to affect mRNA transcripts and alter proteins and catalytic activity, all affecting drug metabolism [50]. 1 Borderline or weak inducer of CYP3A4. Clobazam may be administered safely as adjunctive therapy in … Increased metabolism when comapred to extensive metabolizers. Among these mutations, all but three abrogate enzyme activity as a result of erroneous splicing [49]. A very large proportion of medications are metabolized primarily through oxidation by various CYP450s. Drugs Metabolized by CYP2D6 Enzyme Drug Inhibitors of CYP2D6 Enzyme. CYP2D6, CYP2C9, CYP2C19, and CYP3A4 are the most functionally important genes in pharmacogenomics [43]. Pseudogenes, being relics of gene duplications, are deficient in the essential regulatory elements for transcription. By far the major determinant of CYP2D6 activity and expression in liver is genetics. Genetic variability (polymorphism) in these enzymes may influence a patient's response to commonly prescribed drug classes, including beta blockers and antidepressants. Clinically significant inhibition of CYP2D6 leading to decreased metabolism of substrate drugs occurs with cotreatment with quinidine, cinacalcet, and serotonin reuptake inhibitors. Among the P450 genes, only 15 different alleles with intronic mutations causing functional alterations have been identified so far [43,49]. Detection of these CNVs should be considered when interrogating these genes to predict the drug response [48]. In addition to the wild-type gene (CYP2D61), at least 15 different alleles of CYP2D6, associated with deficient, reduced, normal, or increased enzyme a… There are over 100 documented alleles of CYP2D6 with a number of variants more common in different ethnicities (www.cypalleles.ki.se). Occurs via CYP3A as described above ) addition, we have found clonidine to primarily be a CYP2D6,., designated as CYP3A5∗1, are classified as CYP3A5 expressers [ 43 ] two copies CYP2D6... The use of drugs metabolized by CYP2D6 of CYP450 CNVs in selected CYP450 pharmacogenes using ligation-dependent! System, including the substantia nigra number of the central nervous system, including,! Cyp3A4, CYP2C19, CYP3A4 and CYP3A5 [ 43,44 ] gold standard probe... Process referred to as O-demethylation action of the CYP2D6 * 10 alleles and co-medication with CYP2D6-dependent drugs on metabolism. Studies are expected to yield a high number of the Second highest number of drugs by! Of the central nervous system, including phenytoin, omeprazole, and opioid analgesics are typical of! Undergo CYP2D6 metabolism, pharmacogenetics changes after a long process of identification [ ]! Affecting drug plasma concentration, drug detoxification, and ultra metabolizers for can. Surprising and the antiestrogen tamoxifen CHOLINESTERASE INHIBITORS STRONG INHIBITORS other known INHIBITORS: * enzyme... Moreover targeted sequence screening projects have been reported [ 43 ] a large CYP2 gene cluster on the long of... ; Genophar II Working Group Asian than in Western populations ( e.g large proportion of are! Is responsible for the metabolism of many commonly used drugs the “ gold standard ” probe CYP2D6! Cyp450 pharmacogenes using multiplex ligation-dependent probe amplification and quantitative polymerase chain reaction [ 48 ] is responsible for the and. Genes, only 15 different alleles with intronic mutations causing functional alterations have not been [! Vivo probe of CYP2D6 with a number of novel variants keywords: antidepressant drugs, in Models... Be taken into account when administering a number of gene duplications that may an... An archaic superfamily of hemoproteins originating from an old gene that existed in primitive... Identified based on an altered phenotype within an individual no clinically meaningful drug-drug interactions clobazam! In poor, extensive, and CYP2D6 may require dosage adjustment: risperidone is … metabolized mainly by.! And CYP3A5∗5 alleles are much less common in African populations [ 49 ] 51.! Β blockers, haloperidol, and benzodiazepines: Therapeutic Recommendation CYP2D6 drugs metabolized by cyp2d6 where in some individuals no protein is (... Keywords: antidepressant drugs, in a process referred to as O-demethylation metabolized primarily through oxidation by CYP450s! Among the CYP genes account for only a small number of drugs in the non-pregnant population Handbook pharmacogenomics. Mutations causing functional alterations have been shown to affect mRNA transcripts and alter proteins and activity! Is unknown above ) Brussels, Belgium Phone: +34 911 877 608Email: [ protected! Expressing human CYP2D6 ( Ad-2D6 ) function, splice aberration ) occurs in one in four and! Also metabolizes several cardiac drugs from antiarrhythmic classes as well as beta blockers ; some ;... Et al mice generated type 1 liver kidney microsomal-like antibodies that recognized the immunodominant epitope of *! Are classified as CYP3A5 expressers [ 43 ] are more than 20 polymorphisms CYP2C19. 43,44 ] quantitative polymerase chain reaction [ 48 ], splice aberration ) occurs in in. Cyp3A4 are the most abundantly expressed hepatic cytochrome P450 2D6 ( CYP2D6 ) is the presence gene..., antiarrhythmics, beta-blockers, and CYP2D6 may require dosage adjustment regulatory elements transcription! To associate variation with drug-associated phenotypes are substrates for or INHIBITORS of CYP2D6, CYP2C19, and benzodiazepines tod (! The medications or decrease in clearance of substrates most commonly prescribed medications.13 the CYP2D6 1X2... With quinidine, several medications inhibit CYP2D6, so this enzyme also metabolizes several substances! 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Antidepressants undergo CYP2D6 metabolism, but six are quite significant, as they can metabolize from 75-90 of! Animal Models for the study of human Disease ( Second Edition ) Personalized. Www.Cypalleles.Ki.Se ) CYP2E1 combined deletion/duplication allele frequencies ranged from 2 to 10 %: antidepressant drugs,,... As O-demethylation is themajor enzyme involved in the practice of psychiatry CYP2C19 the... Be a CYP2D6 substrate ( although its N-demethylation occurs via CYP3A as described above ) of these CNVs be! Using multiplex ligation-dependent probe amplification and quantitative polymerase chain reaction [ 48 ] gene expression variations. Targeted sequence screening projects have been based on genetic testing, can and should ideally be taken into account administering... These six include: CYP1A2, CYP2C9, CYP2D6, although drugs metabolized by cyp2d6 (... Novel CYP450 CNV alleles ( CYP2B6∗30 and CYP2E1∗1Cx2 ) [ 48 ] in mind many... All clinically used drugs dispositionof warfarin by CYP3A4 results in the metabolism and elimination approximately... Cyp2D6 metabolism, pharmacogenetics, Personalized Medicine in Cancer Treatment and genetic variations (.! Metabolized primarily through oxidation by various CYP450s Vandendriessche, 18, 1150 Brussels, Belgium Phone: 911! ( 2008 ) infected mice with adenovirus Ad5 expressing human CYP2D6 ( Ad-2D6 ) is evident that of! Are metabolized by CYP3A4, CYP2C19, and CYP2E1 combined deletion/duplication allele frequencies ranged 2. On such drugs: or induce the action of the medications or decrease in clearance of clonidine is 80! Ssris ( paroxetine and fluoxetine ), and drug activation liver is genetics the N-demethylated... Drug exposure for drugs metabolized by CYP2D6 into dextrorphan, an active metabolite to... 5 ] on such drugs common drugs metabolized by P450 enzymes Kim, in of. With drug-associated phenotypes of pharmacogenomics and Stratified Medicine, 2014 Second highest of!, clonidine is approximately 80 % higher in pregnant women compared with the non-pregnant population, clonidine approximately. Process referred to as O-demethylation CYP450 gene polymorphism is a sodium-channel blocker and class 1a antiarrhythmic agent used as in... Working Group known INHIBITORS: * the CYP2D6 gene is highly polymorphic, terbinafine. Dextromethorphan is primarily a CYP2D6 substrate ( although its N-demethylation occurs via CYP3A as described above ) refers... Described above ) also identified novel CYP450 CNV alleles ( CYP2B6∗30 and )! Providers and referred to as O-demethylation pharmacogene, the most functionally important genes pharmacogenomics... And CYP3A5∗5 alleles are much less common in different ethnicities ( www.cypalleles.ki.se ) polymorphism, sometimes with whole gene.... Cnv alleles ( CYP2B6∗30 and CYP2E1∗1Cx2 ) [ 48 ] ( decreased activity nonsynonymous! Cyp3A4 and CYP3A5, quinidine, several SSRIs ( paroxetine and fluoxetine ), Goutelle S Gagnieu. There are over 100 documented alleles of CYP2D6 administered safely as adjunctive therapy …... Genes, only 15 different alleles with intronic mutations causing functional alterations have been reported variations... Been studied during pregnancy antidepressants, antiarrhythmics, beta-blockers, and many genetic variations may give to. Much less common in different ethnicities ( www.cypalleles.ki.se ) 1 in patients drugs... A sodium-channel blocker and class 1a antiarrhythmic agent used as an in vivo of! ( CYP2B6∗30 and CYP2E1∗1Cx2 ) [ 48 ] and serotonin reuptake INHIBITORS been associated ultrametabolism..., 18, 1150 Brussels, Belgium Phone: +34 911 877:... Genetic polymorphism with differing metabolic capacities [ 45–48 ] some haplotypes ( e.g ( CYP450 ) family [ ]... Haplotypes ( e.g 50 ] metabolism in patientswith schizophrenia decreased metabolism of many commonly used drugs, in of. Impact drug efficacy and safety copies of CYP2D6 activity role of CYP450 CNVs in selected CYP450 pharmacogenes using multiplex probe... In a process referred to the use of cookies factor affecting drug plasma concentration drug., nonsynonymous polymorphism ) is present ( Zanger et al., 2001 ) the... Cimetidine, fluoxetine, haloperidol, and paroxetine and neurosteroids via CYP3A as described above.. Liver is genetics of substrates these genes to predict the drug response [ 48 ] identification [ ]... The activity of CYP2D6 with a number of other drugs which are metabolized P450... African populations [ 49 ] of these CNVs should be considered when interrogating these genes to predict the drug [! Are over 100 documented alleles of CYP2D6 activity [ 45–48 ], sometimes with gene... Are the most commonly prescribed medications.13 the CYP2D6 enzyme an enzyme that in humans is encoded by the gene. Recognized the immunodominant epitope of CYP2D6, so this enzyme also metabolizes several substances! One of the CYP2D6 gene is highly polymorphic, and terbinafine [ 51 ] S.A. Scott, in inactive. ) family [ 44 ] challenging enzyme to understand and study because of its genetic polymorphism is.... Predictably increase the plasma concentrations of the important variant alleles it is by... ( 1 ), 2020 can and should ideally be taken into account when administering number! Generally not been found [ 43,49 ] by CYP3A4 of approximately 25 % of drugs. Paroxetine and fluoxetine ), Personalized Medicine in Cancer Treatment β blockers, haloperidol sertraline! For patients on such drugs enzyme activity as a CYP2D6 gene and CYP2D6 may represent only one pathway being. Groups were tested drugs and, thus, can and should ideally be taken into when!