Content uploaded by Jesse J Swen
Author content
All content in this area was uploaded by Jesse J Swen on Apr 29, 2016
Content may be subject to copyright.
A preview of the PDF is not available
Challenges in CYP2D6 Phenotype Assignment from Genotype Data: A Critical Assessment and Call for Standardization
Abstract and Figures
The cytochrome P450 2D6 (CYP2D6) enzyme contributes to the metabolism and/or bioactivation of approximately 25% of clinically used drugs. The CYP2D6 gene locus is highly polymorphic and complex, and variants within this gene locus affect CYP2D6 enzymatic function resulting in a wide range of metabolic activity from little to no activity to ultrarapid metabolism. For many of the drugs metabolized by CYP2D6, the variation in metabolic activity is one of the most important factors responsible for interindividual drug response. Therefore, determining an individual's CYP2D6 phenotype, or metabolic status, will help identify individuals that may benefit from a change in drug or drug dosage. Genotype analysis has become the method of choice to predict a person's metabolic status. Numerous reference laboratories now offer CYP2D6 genotyping; however, there can be substantial differences in the number of genetic variants interrogated as well as test interpretation. Furthermore, there is no standardized process of how a CYP2D6 genotype result is translated into a phenotype assignment. This review summarizes the complexity of CYP2D6 genotyping and highlights the major challenges for phenotype classification. We call for the implementation of a universally accepted system for CYP2D6 phenotype assignment to promote consistency of test interpretation among reference laboratories and medical institutions. We propose a system that utilizes the CYP2D6 activity score system to place individuals into a continuum of activity scores - rather than using the traditional poor, intermediate, extensive and ultra-rapid metabolizer categorizations - and directly translating activity scores into clinically actionable recommendations.
Figures - uploaded by Jesse J Swen
Author content
All figure content in this area was uploaded by Jesse J Swen
Content may be subject to copyright.
... Metabolically, PPIs undergo widespread hepatic metabolism usually thru the cytochrome P450 (CYP) enzyme gadget, particularly related to CYP2C19 and CYP3A4 enzymes [11]. Similarly, SSRIs are substrates for diverse CYP enzymes, developing the capability for aggressive inhibition or induction of those enzymes when co-administered with PPIs [12]. For instance, PPIs may also inhibit the metabolism of sure SSRIs, inclusive of citalopram and escitalopram, ensuing in accelerated plasma concentrations and extended removal halflives [13]. ...
... Heightened consciousness of ability signs of drug toxicity or diminished healing efficacy is crucial all through the initiation or adjustment of drugs regimens involving those marketers. The pharmacokinetic interplay among PPIs and SSRIs may also stand up from diverse mechanisms, such as aggressive inhibition or induction of hepatic cytochrome P450 (CYP) enzymes involved in drug metabolism [12]. PPIs, appearing as inhibitors or substrates of CYP enzymes, may disrupt the metabolism of SSRIs, altering their pharmacokinetic profiles [13]. ...
... Previous studies have explored the interaction between PPIs and SSRIs, with evidence suggesting PPIs might also influence the metabolism, absorption, protein binding, and removal of certain SSRIs via mechanisms like CYP450 enzyme inhibition [12,13]. PPIs can also circuitously alter neurotransmitter structures and contribute to pharmacodynamic interactions with SSRIs [15]. ...
Selective Serotonin Reuptake Inhibitors (SSRIs) are used in many psychiatrist issues, no longer confined to tension and despair. While Proton Pump Inhibitors (PPIs) are generally used to treat gastroesophageal reflux disorder and peptic ulcers. PPIs have been mentioned to interact with several medicinal drugs due to their impact on gastric pH and hepatic enzyme pastime. SSRIs are administered through prescriptions whilst most of the PPIs are considered OTC medications, which causes a primary difficulty for those who take the SSRI's and use over-the-counter medications along with PPIs. Pharmacokinetic interactions among PPIs and SSRIs involve changes in drug metabolism and absorption. PPIs majorly work by way of inhibiting cytochrome P450 enzymes, mainly CYP2C19, which may additionally influence the metabolism of positive SSRIs that results in modifications inside the plasma concentrations and the half-lifestyles. More in particular PPIs can modulate gastric pH, probably influencing the dissolution and bioavailability of SSRIs, whilst the medical importance of this interplay remains doubtful. On the pharmacodynam-ic side, serotonin syndrome, a potentially lifestyles-threatening condition characterized with the aid of excessive serotonergic activity that's a subject with concurrent use of SSRIs and PPIs. PPIs can also enhance the hazard of serotonin syndrome by way of inhibiting the metabolism of SSRIs, main to accelerated serotonin ranges. Clinicians must be vigilant in monitoring sufferers for signs and symptoms of serotonin syndrome when those medicinal drugs are co-administered. While there's proof suggesting capability interactions among PPIs and SSRIs at both pharmaco-kinetic and pharmacodynamic stages, in addition studies are warranted to explain the clinical importance and most effective control strategies of those interactions. Healthcare providers should remember person patient elements, which includes concomitant medicinal drugs and comorbidities, while prescribing SSRIs and PPIs concurrently, to reduce the risk of negative consequences and ensure premier therapeutic results.
... Multiple CYP2D6-2D7 hybrid gene structures, full CYP2D6 gene duplications and deletions with variable and often poorly defined breakpoints are routinely found. These CNVs and SVs occur with varying frequencies across populations and may not be included in, or can interfere with, testing platforms (Gaedigk et al., 1991;Steijns and Van Der Weide, 1998;Gaedigk, 2013;Hicks et al., 2014;Scantamburlo et al., 2017;Del Tredici et al., 2018;Gaedigk et al., 2018;Nofziger and Paulmichl, 2018;Nofziger et al., 2020). Additionally, SNPs, particularly those in the CYP2D7 pseudogene, can also interfere with CYP2D6 genotyping (Gaedigk et al., 2015;Numanagić et al., 2015;Riffel et al., 2015). ...
... The genetic analysis of the clinically relevant CYP2D6 gene is often complex and has presented substantial challenges to the testing community (Gaedigk, 2013;Hicks et al., 2014;Gaedigk et al., 2015;Riffel et al., 2015;Nofziger and Paulmichl, 2018;Nofziger et al., 2020). This has resulted in the potential of incorrect phenotype assignment, particularly in samples with less common haplotypes, SV/CNV, or from populations which have not been well characterized (Wang et al., 2022). ...
Complex regions in the human genome such as repeat motifs, pseudogenes and structural (SVs) and copy number variations (CNVs) present ongoing challenges to accurate genetic analysis, particularly for short-read Next-Generation-Sequencing (NGS) technologies. One such region is the highly polymorphic CYP2D loci, containing CYP2D6, a clinically relevant pharmacogene contributing to the metabolism of >20% of common drugs, and two highly similar pseudogenes, CYP2D7 and CYP2D8. Multiple complex SVs, including CYP2D6/CYP2D7-derived hybrid genes are known to occur in different configurations and frequencies across populations and are difficult to detect and characterize accurately. This can lead to incorrect enzyme activity assignment and impact drug dosing recommendations, often disproportionally affecting underrepresented populations. To improve CYP2D6 genotyping accuracy, we developed a PCR-free CRISPR-Cas9 based enrichment method for targeted long-read sequencing that fully characterizes the entire CYP2D6-CYP2D7-CYP2D8 loci. Clinically relevant sample types, including blood, saliva, and liver tissue were sequenced, generating high coverage sets of continuous single molecule reads spanning the entire targeted region of up to 52 kb, regardless of SV present (n = 9). This allowed for fully phased dissection of the entire loci structure, including breakpoints, to accurately resolve complex CYP2D6 diplotypes with a single assay. Additionally, we identified three novel CYP2D6 suballeles, and fully characterized 17 CYP2D7 and 18 CYP2D8 unique haplotypes. This method for CYP2D6 genotyping has the potential to significantly improve accurate clinical phenotyping to inform drug therapy and can be adapted to overcome testing limitations of other clinically challenging genomic regions.
... The human cytochrome P450 (CYP) drug-metabolising enzymes (DMEs), such as CYP2D6, CYP2C9, CYP2C19, and CYP2B6, are subject to genetic polymorphism, which gives rise to individual genotypes with the correspondent genotype-predicted phenotypes classified in poor (gPM), intermediate (gIM), normal (gNM), and ultrarapid metabolisers (gUM) [1][2][3][4]. This inter-genotypic variability accounts for the variability in drug response, particularly drug efficacy and/or safety [5]. ...
... For CYP2B6 and CYP2C19, the AS method could not be applied, thus, the attribution to phenotypes was based on tables available on PHARMGKB, and consensus standardized terms for phenotypes were used [34,35]. Considering the method used by Hicks et al. for CYP2D6 [1] to assign the activity prediction based on genotype test, we propose the use of "g-phenotype", which includes gPM, gIM, gNM, and gUM, for all the analysed CYPs. ...
In toxicogenetics, an integrative approach including the prediction of phenotype based on post-mortem genotyping of drug-metabolising enzymes might help explain the cause of death (CoD) and manner of death (MoD). The use of concomitant drugs, however, might lead to phenoconversion, a mismatch between the phenotype based on the genotype and the metabolic profile actually observed after phenoconversion. The aim of our study was to evaluate the phenoconversion of CYP2D6, CYP2C9, CYP2C19, and CYP2B6 drug-metabolising enzymes in a series of autopsy cases tested positive for drugs that are substrates, inducers, or inhibitors of these enzymes. Our results showed a high rate of phenoconversion for all enzymes and a statistically significant higher frequency of poor and intermediate metabolisers for CYP2D6, CYP2C9, and CYP2C19 after phenoconversion. No association was found between phenotypes and CoD or MoD, suggesting that, although phenoconversion might be useful for a forensic toxicogenetics approach, more research is needed to overcome the challenges arising from the post-mortem setting.
... CYP2D6*10 is characterized by a combination of missense substitutions in exon 1, which lead to a key substitution of cytosine-to-thymine c.100C>T p. (Pro34Ser), c. 408G>C (no change), and a nonspecified modification c.1457G>Cp.(Ser486Thr) (Hicks et al., 2014). The populationspecific reported allele frequency in European populations is <2%, 4%-6% in African populations, and 9%-44% in Asian populations, with c.100C>T p.(Pro34Ser) as the predominant substitution (Bagheri et al., 2015;Fedorinov et al., 2018). ...
Cytochrome P450 2D6 (CYP2D6) is responsible for the metabolism of up to 20% of small-molecule drugs and therefore, may impact the safety and efficacy of medicines in broad therapeutic areas. CYP2D6 is highly polymorphic, and the frequency of variants can differ across racial and ethnic populations, significantly affecting enzymatic function and drug metabolism. However, rare variants of CYP2D6 present a unique challenge for academia, industry, and regulatory agencies alike due to the lack of feasibility of characterizing their clinical relevance in clinical trials, particularly in variants that exhibit population-specific frequencies in racial and ethnic groups that are poorly represented in clinical trials. Despite significant advancement in pharmacogenomics, the substrate specificity and related clinical relevance of these CYP2D6 rare variants remain largely unclear, and further efforts are warranted to characterize the burden of these variants on adverse drug reactions and drug efficacy. Thus, cell-based in vitro systems can be used to inform substrate-specific effects and the overall relevance of a rare variant. Liver microsomes, cell-based expression systems, ex vivo primary samples, and purified variant protein have all been used with various substrates to potentially predict the clinical impact of new substrates. In this review, we identify rare variants of CYP2D6 that demonstrate differences across races in prevalence and thus are often unassessed in clinical trials. Accordingly, we examine current pharmacogenomic in vitro models used to analyze the functional impact of these rare variants in a substrate-specific manner. SIGNIFICANCE STATEMENT: Variants of CYP2D6 play a clinically relevant role in drug metabolism, leading to potential safety and efficacy concerns. Although the influence of prevalent variants is often well characterized, rare variants are traditionally not included in clinical trials. This review captures the clinical relevance of rare variants in CYP2D6 by highlighting in vitro models that analyze their impact on the metabolism of CYP2D6 substrates.
... Thus, the disparities in MAF between our cohort and the Caucasian reference may be attributed to the differences in ethnicity and the relatively smaller sample size in our study compared with the reference dataset. Another factor contributing to the higher incidence of CYP2D6*2 and lower incidence of CYP2D6*41 could be the presence of two shared SNPs (rs16947 and rs1135840) in both alleles, posing challenges in distinguishing between them in some cases (Hicks et al., 2014). We further assessed CYP2D6 protein and activity levels across various CYP2D6 phenotype metabolizers. ...
Cytochrome P450 2D6 (CYP2D6) is a critical hepatic drug-metabolizing enzyme in humans, responsible for metabolizing approximately 20-25% of commonly used medications, such as codeine, desipramine, fluvoxamine, paroxetine, and tamoxifen. The CYP2D6 gene is highly polymorphic, resulting in substantial interindividual variability in its catalytic function and the pharmacokinetics and therapeutic outcomes of its substrate drugs. Though many functional CYP2D6 variants have been discovered and validated, a significant portion of the variability in the expression and activity of CYP2D6 remains unexplained. In this study, we performed a genome-wide association study (GWAS) to identify novel variants associated with CYP2D6 protein expression in individual human livers, followed by a conditional analysis to control for the effect of functional CYP2D6 star alleles. We also examined their impact on hepatic CYP2D6 activity. Genotyping on a genome-wide scale was achieved using the Illumina Multi-Ethnic Genotyping Array (MEGA). A Data Independent Acquisition (DIA)-based proteomics method was utilized to quantify CYP2D6 protein concentrations. CYP2D6 activity was determined by measuring the Dextromethorphan O-demethylation in individual human liver s9 fractions. The GWAS identified 44 SNPs that are significantly associated with CYP2D6 protein expressions with a p-value threshold of 5.0×10-7 Following the conditional analysis, five SNPs, including the cis-variants rs1807493 and rs1062753, and the trans-variants rs4073010, rs729559, and rs80274432, emerged as independent variants significantly correlated with hepatic CYP2D6 protein expressions. Notably, four of these SNPs, except for rs80274432, also exhibited a significant association with CYP2D6 activities in human livers, suggesting their potential as novel and independent cis- and trans-variants regulating CYP2D6. Significance Statement We identified four novel cis- and trans- pQTLs/aQTLs of CYP2D6 using individual human livers, which are independent from known functional CYP2D6 star alleles. This study connects the CYP2D6 gene, expression and activity, enhancing our understanding into the genetic variants associated with CYP2D6 protein expression and activity, potentially advancing our insight of the interindividual variability in CYP2D6 substrate medication response.
... 108 Pharmacogenomics Analyze genetic variations and drug response data to predict individual drug responses and identify potential adverse reactions, enabling personalized medicine approaches. 109 Pharmacokinetic modeling Enhance pharmacokinetic modeling, which involves studying how drugs are absorbed, distributed, metabolized, and excreted by the body. Machine learning models can predict drug concentrations in different tissues and optimize dosing regimens. ...
Artificial intelligence (AI) and machine learning (ML) represent significant advancements in computing, building on technologies that humanity has developed over millions of years—from the abacus to quantum computers. These tools have reached a pivotal moment in their development. In 2021 alone, the U.S. Food and Drug Administration (FDA) received over 100 product registration submissions that heavily relied on AI/ML for applications such as monitoring and improving human performance in compiling dossiers. To ensure the safe and effective use of AI/ML in drug discovery and manufacturing, the FDA and numerous other U.S. federal agencies have issued continuously updated, stringent guidelines. Intriguingly, these guidelines are often generated or updated with the aid of AI/ML tools themselves. The overarching goal is to expedite drug discovery, enhance the safety profiles of existing drugs, introduce novel treatment modalities, and improve manufacturing compliance and robustness. Recent FDA publications offer an encouraging outlook on the potential of these tools, emphasizing the need for their careful deployment. This has expanded market opportunities for retraining personnel handling these technologies and enabled innovative applications in emerging therapies such as gene editing, CRISPR-Cas9, CAR-T cells, mRNA-based treatments, and personalized medicine. In summary, the maturation of AI/ML technologies is a testament to human ingenuity. Far from being autonomous entities, these are tools created by and for humans designed to solve complex problems now and in the future. This paper aims to present the status of these technologies, along with examples of their present and future applications.
... Reports of interethnic differences in CYP2D6 activity have led leading researchers in the field to warrant further investigation into the contribution of ethnicity on CYP2D6 genotype-phenotype relationships. [3][4][5] However, investigations of interethnic differences in CYP2D6 activity within CYP2D6 genotypes are often hampered by varying allele frequencies across ethnicities making clinical studies of adequate sample size difficult to conduct. 6 For example, the decreased function allele CYP2D6*10 occurs at a frequency of ~43% in Asian populations, whereas the allele frequency in other populations is only ~2%-7%. 2 Similarly, the decreased function allele CYP2D6*17 is very common in individuals of African ancestry (allele frequency ~18%-20%), whereas other ethnic groups only carry the allele at a frequency of 0%-3%. 2 As the majority of pharmacogenetic studies are limited to specific geographic regions and thus only represent one or a few ethnic groups, interethnic comparisons are often underpowered due to inadequate sample sizes. ...
Polymorphism of the CYP2D6 gene leads to substantial interindividual variability in CYP2D6 enzyme activity. Despite improvements in prediction of CYP2D6 activity based on genotype information, large interindividual variability within CYP2D6 genotypes remains and ethnicity could be a contributing factor. The aim of this study was to investigate interethnic differences in CYP2D6 activity using clinical datasets of three CYP2D6 substrates: (i) brexpiprazole (N=476), (ii) tedatioxetine (N=500) and (iii) vortioxetine (N=1,073). The CYP2D6 activity of all individuals in the dataset was estimated through population pharmacokinetic analyses as previously reported. Individuals were assigned a CYP2D6 phenotype and CYP2D6 genotype group based on their CYP2D6 genotype and interethnic differences were investigated within each group. Among individuals categorized as CYP2D6 normal metabolizers, African Americans had a lower CYP2D6 activity compared to Asians (P<0.01) and in the tedatioxetine and vortioxetine analyses also compared to Caucasians (P<0.01). Among CYP2D6 intermediate metabolizers, interethnic differences were also observed, but the findings were not consistent across the substrates. Asian carriers of CYP2D6 decreased function alleles tended to exhibit higher CYP2D6 activity compared to Caucasians and African Americans. The observed interethnic differences within the CYP2D6 phenotype and genotype groups appeared to be driven by differences in CYP2D6 allele frequencies across ethnicities rather than interethnic differences in enzyme activity for individuals carrying identical CYP2D6 genotypes.
CYP2D6 is an important drug metabolizing enzyme exhibiting extensive interindividual variability predominantly caused by genetic polymorphism. Predicting CYP2D6 function based on genotype may be used to personalize pharmacotherapy, but the process of translating CYP2D6 genotype into predicted phenotype is complex and has suffered from a lack of consensus. The Clinical Pharmacogenetics Implementation Consortium and Dutch Pharmacogenetics Working Group have proposed a standardized translation scheme based on the activity score system aiming to facilitate more consistent CYP2D6 genotype-phenotype translation. However, this system remains suboptimal particularly with regards to decreased function alleles and substrate-specific behaviour. This review summarizes the process and challenges for functional assignment of CYP2D6 alleles. We discuss population pharmacokinetics (popPK) as a tool for estimating CYP2D6 function and present findings from three popPK meta-analyses quantifying the impact of individual CYP2D6 alleles in the metabolism of vortioxetine, tedatioxetine and brexpiprazole. Findings from these analyses indicate that the activity values currently assigned to decreased function alleles CYP2D6*9, *17 and *41 overestimate their function. Moreover, the CYP2D6*2 allele exhibited reduced activity in the metabolism of brexpiprazole indicating substrate-specific behaviour. Considering the totality of evidence, the activity score system may be further refined to better reflect the enzyme function associated with these alleles.
Background: People who take statins respond differently to them due to genetic differences. One of the most significant enzymes involved in drug metabolism is cytochrome P450 2D6 (CYP2D6) enzyme, coded by the CYP2D6 gene. Individuals who carry two non-functional alleles in this gene are considered as poor metabolizers. Recognizing poor metabolizers may help prevent adverse effects of drugs. Objective: This study aims to assess the association of CYP2D6*4, as the most frequent non-functional allele of CYP2D6 gene, and response to atorvastatin in patients with high low-density lipoprotein (LDL) level in northern Iran. Methods: A total of 180 patients with high LDL level underwent treatment with atorvastatin for 8 weeks to assess their response. They were assessed in terms of CYP2D6*4 polymorphism using the amplification-refractory mutation system/polymerase chain reaction method and the results were validated by the sanger sequencing method. At the end, the association between CYP2D6*4 allele and response to atorvastatin was assessed. Results: In patients, the percentage of the CYP2D6*4 variant was 7%. This allele was not observed in homozygous patients. There was no significant association between CYP2D6*4 polymorphism and response to atorvastatin, which might be due to low frequency of CYP2D6*4 in patients. The observed allelic frequency was close to the frequency reported in previous studies for healthy Iranian people. Conclusion: It seems that CYP2D6*4 polymorphism is not the cause of poor metabolism in poor metabolizers in northern Iran. Therefore, to diagnose poor metabolizers in this region, further studies on other genes are recommended.
The pace of discovery of potentially actionable pharmacogenetic variants has increased dramatically in recent years. However, the implementation of this new knowledge for individualized patient care has been slow. The Pharmacogenomics Research Network (PGRN) Translational Pharmacogenetics Program seeks to identify barriers and develop real-world solutions to implementation of evidence-based pharmacogenetic tests in diverse health-care settings. Dissemination of the resulting toolbox of "implementation best practices" will prove useful to a broad audience.
Polymorphisms in CYP2D6 and CYP2C19 affect the efficacy and safety of tricyclics, with some drugs being affected by CYP2D6 only, and others by both polymorphic enzymes. Amitriptyline, clomipramine, doxepin, imipramine, and trimipramine are demethylated by CYP2C19 to pharmacologically active metabolites. These drugs and their metabolites, along with desipramine and nortriptyline, undergo hydroxylation by CYP2D6 to less active metabolites. Evidence from published literature is presented for CYP2D6 and CYP2C19 genotype-directed dosing of tricyclic antidepressants.Clinical Pharmacology & Therapeutics (2013); advance online publication 13 March 2013. doi:10.1038/clpt.2013.2.
Abstract Cytochrome P450 2D6 (CYP2D6) plays an important role in the metabolism and bioactivation of about 25% of clinically used drugs including many antidepressants, antipsychotics and opioids. CYP2D6 activity is highly variably ranging from no activity in so-called poor metabolizers to ultrarapid metabolism at the other end of the extreme of the activity distribution. A large portion of this variability can be explained by the highly polymorphic nature of the CYP2D6 gene locus for which > 100 variants and subvariants identified to date. Allele frequencies vary markedly between ethnic groups; some have exclusively or predominantly only been observed in certain populations. Pharmacogenetic testing holds the promise of individualizing drug therapy by identifying patients with CYP2D6 diplotypes that puts them at an increased risk of experiencing dose-related adverse events or therapeutic failure. Inferring a patient's CYP2D6 metabolic capacity, or phenotype, however, is a challenging task due to the complexity of the CYP2D6 gene locus. Allelic variation includes SNPs, small insertions and deletions, gene copy number variation and rearrangements with CYP2D7, a highly related non-functional gene. This review provides a summary of the intricacies of CYP2D6 variation and genotype analysis, knowledge that is invaluable for the translation of genotype into clinically useful information.
Codeine is an analgesic drug acting on μ-opioid receptors predominantly via its metabolite morphine formed almost exclusively by CYP2D6. Genetic polymorphisms in CYP2D6 are associated with diminished pain relief and/or severe opioid side effects. In Chinese individuals, CYP2D6*10 is the most common allele with reduced enzyme activity. In this study, we investigated the effect of this allele on the pharmacokinetics of codeine and its metabolites.
A blood sample was collected from healthy Mongolian volunteers for CYP2D6 genotyping using a PCR-RFLP assay. A pharmacokinetic study was then carried out in three groups with CYP2D6*1/*1 (n = 10), CYP2D6*1/*10 (n = 10) and CYP2D6*10/*10 (n = 9) genotypes by collecting serial blood samples for determination of plasma levels of codeine and its metabolites, morphine, morphine 3-glucuronide (M3G) and morphine 6-glucuronide (M6G) before and after a single 30-mg oral dose of codeine phosphate. Codeine and its metabolites were measured by LC-MS/MS.
No significant differences were observed in the pharmacokinetic parameters of codeine in the three genotype groups. However, the C max and AUC0-∞ of morphine, M3G and M6G were significantly different between the study groups (P < 0.05). Compared with the *1/*1 group, the AUC0-∞ for morphine in the *1/*10 and *10/*10 groups decreased by ratios (95 % CI) of 0.93 (0.26-1.59) and 0.494 (0.135-0.853) respectively. Corresponding ratios for M3G were 0.791 (0.294-1.288) and 0.615 (0.412-0.818) and for M6G were 0.643 (0.39-0.957) and 0.423 (0.267-0.579).
This study demonstrates that the CYP2D6*10 allele plays an important role in the pharmacokinetics of the O-demethylated metabolites of codeine after oral administration.
Clinical medicine is about to embark on an exciting, although harrowing, period of innovation, the result of astonishing advances in genomic science. The current workforce-physicians, nurses, pharmacists, and others-will soon need to adapt to substantial change, driven by genomics, in diagnostic and therapeutic strategies. If errors of omission and commission are to be prevented, sustained efforts in workforce education will be needed on the part of medical schools, training programs, and professional societies.
Tricyclic antidepressant (TCA) clinical pharmacogenetic implementation guidelines for CYP2D6 and CYP2C19 genotypes highlight the importance of both genes. However, studies of the combined impact of the two genes are sparse, limiting the ability to make strong recommendations based on both genes. The warfarin pharmacogenetics literature highlights the strength of a multigenic approach for discovery and clinical implementation. For optimal impact and interpretation, investigators are encouraged to conduct studies in the context of previously well-defined pharmacogenetics markers.
Background:
The highly polymorphic CYP2D6 gene has extensively been studied in many populations, but there is a void of knowledge regarding CYP2D6 pharmacogenetics and activity in populations with unique ancestries and admixture, such as those residing in Trinidad and Tobago.
Materials & methods:
167 healthy Indo- and 103 Afro-Trinidadians were phenotyped with dextromethorphan and extensively genotyped. Gene resequencing was performed to resolve cases with genotype/phenotype discordance.
Results:
CYP2D6 activity did not differ between the Indo-Trinidadians and Afro-Trinidadians. Poor metabolizers were, however, more frequent in the Indo-Trinidadians (4.19 vs 1.94%), and unique allele frequency patterns were observed. Two novel nonfunctional allelic variants were found among the Indo-Trinidadians in two discordant cases. CYP2D6*100 is characterized by a single nucleotide deletion and CYP2D6*101 by a 19-bp deletion; both cause frameshifts.
Conclusion:
Our study underscores the importance of thoroughly characterizing the genetic make up of unique populations when considering pharmacogenetic testing for individualized therapy.
Background
The CYP2D6*10 (*10) allele that causes decreased CYP2D6 activity is present in Asians with a high frequency of about 50%. In this study we studied the effects of the *10 allele on the steady-state plasma concentrations (Css) of haloperidol and reduced haloperidol.Methods
The subjects were 67 Japanese inpatients with schizophrenia who had only the wild-type or *10 alleles. Thirty-four patients were homozygous for the wild-type allele, and 26 were heterozygous and 7 were homozygous for the *10 allele. All patients had been receiving 12 mg/day haloperidol for at least 2 weeks. Plasma concentrations of haloperidol and reduced haloperidol were measured by HPLC.ResultsThe mean ± SD values of haloperidol Css in the patients with 0, 1, and 2 *10 alleles were 22.8 ± 11.0, 30.1 ± 10.6, and 31.2 ± 21.2 nmol/L, respectively, and those values for reduced haloperidol were 6.1 ± 2.9, 9.5 ± 3.7, and 9.9 ± 6.2 nmol/L, respectively. The mean haloperidol Css was significantly (P < .05) higher in the patients with 1 *10 allele than in those with no *10 alleles. The mean Css of reduced haloperidol was significantly (P < .05) higher in the patients with 1 and 2 *10 alleles than in those with no *10 alleles.Conclusion
This study suggests that the *10 allele plays an important role in controlling the Css of both haloperidol and reduced haloperidol, especially in Asian subjects.Clinical Pharmacology & Therapeutics (1999) 65, 291-294; doi: