CYP2D6 Genotype Research Articles

Genomic study suggests value of genotype‐based dosing

A systematic review and meta‐analysis has identified differences in antidepressant and antipsychotic drug exposure between patients with various levels of genetically associated drug metabolism capacity. These results suggest the basis for using CYP2C19 and CYP2D6 genotyping data to guide dosing recommendations for antidepressants and antipsychotics.

Influence of cytochrome P450 2D6 polymorphism on hippocampal white matter and treatment response in schizophrenia

Cytochrome P450 2D6 (CYP2D6) is expressed at high levels in the brain and plays a considerable role in the biotransformation and neurotransmission of dopamine. This raises the question of whether CYP2D6 variations and its impact on the brain can confer susceptibility to schizophrenia. We investigated the possible links among the CYP2D6 genotype, white matter (WM) integrity of the hippocampus, and the treatment response to antipsychotic drugs in Korean patients with schizophrenia (n = 106). Brain magnetic resonance imaging and genotyping for CYP2D6 were conducted at baseline. The severity of clinical symptoms and the treatment response were assessed using the Positive and Negative Syndrome Scale (PANSS). After genotyping, 43 participants were classified as intermediate metabolizers (IM), and the remainder (n = 63) were classified as extensive metabolizers (EM). IM participants showed significantly higher fractional anisotropy (FA) values in the right hippocampus compared to EM participants. Radial diffusivity (RD) values were significantly lower in the overlapping region of the right hippocampus in the IM group than in the EM group. After 4 weeks of antipsychotic treatment, the EM group showed more improvements in positive symptoms than the IM group. FAs and RDs in the CYP2D6-associated hippocampal WM region were significantly correlated with a reduction in the positive symptom subscale of the PANSS. Greater improvements in positive symptoms were negatively associated with FAs, and positively associated with RDs in the right hippocampal region. The findings suggest that CYP26D-associated hippocampal WM alterations could be a possible endophenotype for schizophrenia that accounts for individual differences in clinical features and treatment responses.

Physiologically based pharmacokinetic modeling of tramadol to inform dose adjustment and drug-drug interactions according to CYP2D6 phenotypes.

The objective of this study was to establish physiologically based pharmacokinetic (PBPK) models of tramadol and its active metabolite O-desmethyltramadol (M1) and to explore the influence of CYP2D6 gene polymorphism on the pharmacokinetics of tramadol and M1. Furthermore, we used PBPK modeling to prospectively predict the extent of drug-drug interactions (DDIs) in the presence of genetic polymorphisms when tramadol was co-administered with the CYP2D6 inhibitors duloxetine and paroxetine. Plasma concentrations of tramadol and M1 were used to adjust the turnover frequency (Kcat ) of CYP2D6 for phenotype populations with different CYP2D6 genotypes. PBPK models were developed to capture the pharmacokinetics between CYP2D6 extensive metabolizers (EMs), intermediate metabolizers (IMs), poor metabolizers (PMs), and ultra-rapid metabolizers (UMs). The validated models were then used to support dose adjustment in different CYP2D6 phenotypes and to predict the extent of CYP2D6-mediated DDIs when tramadol was co-administered with paroxetine or duloxetine. The PBPK models we built accurately describe tramadol and M1 exposure in the population with different CYP2D6 phenotypes. In our prediction, the area under the concentration-time curve (AUCinf-tDlast ) of M1 is 70% lower in PMs than in EMs, 27% lower in IMs, and 15% higher in UMs. Based on the models we built, we suggest that the oral dose of tramadol should be 50% higher for IMs and 25% lower for UMs to achieve an approximately equivalent plasma exposure of M1 as in EMs. When tramadol was co-administered with paroxetine or duloxetine, the magnitude of the inhibitor-substrate interaction was lowest in EMs (0.45), secondary in IMs (0.39), and highest in PMs (0.18) in terms of M1. The current example uses the PBPK model to guide dose adjustment of tramadol and to predict the effect of CYP2D6 genetic polymorphisms on DDIs for rational clinical use of tramadol in the future.

Pharmacogenetics Guidelines: Overview and Comparison of the DPWG, CPIC, CPNDS, and RNPGx Guidelines.

Many studies have shown that the efficacy and risk of side effects of drug treatment is influenced by genetic variants. Evidence based guidelines are essential for implementing pharmacogenetic knowledge in daily clinical practice to optimize pharmacotherapy of individual patients. A literature search was performed to select committees developing guidelines with recommendations being published in English. The Dutch Pharmacogenetics Working Group (DPWG), the Clinical Pharmacogenetics Implementation Consortium (CPIC), the Canadian Pharmacogenomics Network for Drug Safety (CPNDS), and the French National Network (Réseau) of Pharmacogenetics (RNPGx) were selected. Their guidelines were compared with regard to the methodology of development, translation of genotypes to predicted phenotypes, pharmacotherapeutic recommendations and recommendations on genotyping. A detailed overview of all recommendations for gene-drug combinations is given. The committees have similar methodologies of guideline development. However, the objectives differed at the start of their projects, which have led to unique profiles and strengths of their guidelines. DPWG and CPIC have a main focus on pharmacotherapeutic recommendations for a large number of drugs in combination with a patient’s genotype or predicted phenotype. DPWG, CPNDS and RNPGx also recommend on performing genetic testing in daily clinical practice, with RNPGx even describing specific clinical settings or medical conditions for which genotyping is recommended. Discordances exist, however committees also initiated harmonizing projects. The outcome of a consensus project was to rename “extensive metabolizer (EM)” to “normal metabolizer (NM)”. It was decided to translate a CYP2D6 genotype with one nonfunctional allele (activity score 1.0) into the predicted phenotype of intermediate metabolizer (IM). Differences in recommendations are the result of the methodologies used, such as assessment of dose adjustments of tricyclic antidepressants. In some cases, indication or dose specific recommendations are given for example for clopidogrel, codeine, irinotecan. The following drugs have recommendations on genetic testing with the highest level: abacavir (HLA), clopidogrel (CYP2C19), fluoropyrimidines (DPYD), thiopurines (TPMT), irinotecan (UGT1A1), codeine (CYP2D6), and cisplatin (TPMT). The guidelines cover many drugs and genes, genotypes, or predicted phenotypes. Because of this and their unique features, considering the totality of guidelines are of added value. In conclusion, many evidence based pharmacogenetics guidelines with clear recommendations are available for clinical decision making by healthcare professionals, patients and other stakeholders.

Cyrius: accurate CYP2D6 genotyping using whole-genome sequencing data

Responsible for the metabolism of ~21% of clinically used drugs, CYP2D6 is a critical component of personalized medicine initiatives. Genotyping CYP2D6 is challenging due to sequence similarity with its pseudogene paralog CYP2D7 and a high number and variety of common structural variants (SVs). Here we describe a novel bioinformatics method, Cyrius, that accurately genotypes CYP2D6 using whole-genome sequencing (WGS) data. We show that Cyrius has superior performance (96.5% concordance with truth genotypes) compared to existing methods (84–86.8%). After implementing the improvements identified from the comparison against the truth data, Cyrius’s accuracy has since been improved to 99.3%. Using Cyrius, we built a haplotype frequency database from 2504 ethnically diverse samples and estimate that SV-containing star alleles are more frequent than previously reported. Cyrius will be an important tool to incorporate pharmacogenomics in WGS-based precision medicine initiatives.

Effect of CYP2C19 genotypes on tamoxifen metabolism and early-breast cancer relapse

CYP2C19*2 and CYP2C19*17 might influence tamoxifen metabolism and clinical outcome. Our aim was to investigate the effect of CYP2C19 genotypes on tamoxifen concentrations and metabolic ratios (MRs) and breast cancer recurrence in a large cohort of Caucasian women. Genetic variants (CYP2D6 and CYP2C19 genotypes), tamoxifen and metabolites concentrations, baseline characteristics, and breast cancer recurrence from the CYPTAM study (NTR1509) were used. CYP2C19*2 and CYP2C19*17 genotypes were evaluated as alleles and as groups based on CYP2D6 genotypes (high, intermediate and low activity). Log-rank test and Kaplan–Meier analysis were used to evaluate differences in recurrence defined as relapse-free survival (RFS). Classification tree analyses (CTAs) were conducted to assess the levels of interactions per polymorphism (CYP2D6 and CYP2C19 genotypes) on endoxifen concentrations. No differences in mean concentrations and MRs were observed when comparing CYP2C19 genotypes (CYP2C19*1/*1; CYP2C19*1/*2; CYP2C19*2/*2; CYP2C19*1/*17; CYP2C19*17/*17; CYP2C19*2/*17). Only significant differences (p value < 0.05) in mean concentrations and MRs were observed when comparing tamoxifen activity groups (high, intermediate and low activity). A log-rank test did not find an association across CYP2C19 genotypes (p value 0.898). CTAs showed a significant relationship between CYP2D6 and endoxifen (p value < 0.0001), but no association with CYP2C19 genotypes was found. CYP2C19 polymorphisms do not have a significant impact on tamoxifen metabolism or breast cancer relapse.

Association of CYP2D6 genotype predicted phenotypes with oxycodone requirements and side effects in children undergoing surgery

Association of CYP2D6 genotype predicted phenotypes with oxycodone requirements and side effects in children undergoing surgery

New opportunities of pharmacogenetics approach to personalized tamoxifen therapy (updated systematic review)

Tamoxifen is the selective modulator of estrogen receptors. Nowadays, it is widely used in the treatment of ER(+) breast cancer and substantially decreases the risks of recurrence and disease progression. However, high interindividual variability in response is observed, calling for a personalized approach to tamoxifen treatment. Tamoxifen is metabolized by cytochrome P450, resulting in the formation of active metabolites, including 4-hydroxy-tamoxifen and endoxifen. The effectiveness and success of treatment depends largely on concentrations of the active tamoxifen metabolites in blood plasma. Polymorphisms in the genes encoding these enzymes are proposed to influence on pharmacokinetics and pharmacodynamics of tamoxifen. Therefore, pharmacogenetic approach may form the basis of personalized treatment of breast cancer. In the updated systematic review, we analyze all current data about the potential use of genotyping of CYP2D6, CYP2С19, CYP3A4/5, CYP2B6 to predict an individual response on tamoxifen treatment.

CYP2D6 Genotype in Relation to Liver Toxicity Due to Tetrabenazine in Iraqi Patients with Hyperkinetic Movement Disorders

Abstract &#x0D; The common types of movement disorders are ; dystonia which is a syndrome of repetitive muscle contractions. While , Huntington disease is autosomal dominant progressive neurodegenerative disorder, which is characterized by involuntary movements (“chorea”).&#x0D; Tetrabenazine therapy has been shown to effectively control this movements compared with placebo.&#x0D; Design the proper dosing approach for patients treated with tetrabenazine with genotype polymorphisms and their hepatic effect on patients.&#x0D; A prospective case controlled study was carried on 50 patients whom divided into 2 groups :first group involved 25 patients who had chorea, and group 2 included patients with dystonia, whom treated with (tetrabenazine) for three months. In addition to control group involved 25 healthy subjects . Blood samples were collected at the beginning and after three months to assess liver function in relation to genetic polymorphism of CYP 450 2D6 enzyme for both groups and measuring the plasma concentration of tetrabenazine , alpha and beta dyhdrotetrabenazine.&#x0D; The results show a significant CYP 450 2D6 enzyme polymorphism. And elevations of liver enzymes in the patient indicate hepatotoxicity of tetrabenazine and its metabolites,&#x0D; Determination a genotype of the CYP 450 2D6 genes in Iraqi patients, in relation to the safety and efficacy of tetrabenazine .

Biochip-based approach for comprehensive pharmacogenetic testing.

Individual sensitivity to many widely used drugs is significantly associated with genetic factors. The purpose of our work was to develop an instrument for simultaneous determination of the most clinically relevant pharmacogenetic markers to allow personalized treatment, mainly in patients with cardiovascular diseases. Multiplex one-step polymerase chain reaction (PCR) followed by hybridization on a low-density biochip was applied to interrogate 15 polymorphisms in the following eight genes: VKORC1-1639G>A, CYP4F2 1297G>A, GGCX 2374C>G, CYP2C9 *2,*3 (430C>T, 1075A>C), CYP2D6 *3,*4, *6, *9, *41 (2549delA, 1846G>A, 1707delT, 2615_2617delAAG, 2988G>A), CYP2C19 *2,*3,*17 (681G>A, 636G>A,-806C>T), ABCB1 (3435C>T), SLCO1B1 *5. Two hundred nineteen patients with cardiovascular diseases (CVD) and 48 female patients with estrogen receptor (ER)-positive breast cancer (BC) were genotyped. Of the 219 CVD patients, 203 (92.7%) carried one or more actionable at-risk genotypes based on VKORC1/CYP2C9, CYP2C9, CYP2C19, SLCO1B1, and CYP2D6 genotypes. Among them, 67 patients (30.6%) carried one, 58 patients (26.5%) carried two, 51 patients (23.3%) carried three, 26 patients (11.9%) carried four, and one patient (0.4%) carried five risk actionable genotypes. In the ER-positive BC group 12 patients (25%) were CYP2D6 intermediate or poor metabolizers. The developed biochip is applicable for rapid and robust genotyping of patients who were taking a wide spectrum of medications to optimize drugs and dosage and avoid adverse drug reactions in cardiology, oncology, psychiatry, rheumatology and gastroenterology.

Effects of CYP2D6 Genotypes on Venlafaxine Metabolism in Japanese Psychiatric Patients With Depression.

Venlafaxine (VEN) is primarily metabolized by CYP2D6. Although several studies have reported the significant effects of CYP2D6 on VEN and O-desmethylvenlafaxine (ODV) pharmacokinetics in Whites, limited data are available regarding the effects of the Asian-specific CYP2D6 genotype on VEN metabolism. This study evaluated the effects of the CYP2D6*10 and CYP2D6*5 genotypes on the steady-state plasma concentrations of VEN and ODV in Japanese patients. This study included 75 Japanese patients with depression who were treated with VEN. Steady-state plasma concentrations of VEN and ODV were measured using liquid chromatography. Polymerase chain reaction was used to determine CYP2D6 genotypes. A stepwise multiple regression analysis was performed to analyze the relationship between independent variables (sex, age, smoking habit, and number of mutated alleles, CYP2D6*10 and CYP2D6*5), subject-dependent variables (plasma concentrations of VEN and ODV [all corrected for dose and body weight]), and the ODV/VEN ratio. Significant correlations were observed between the daily dose of VEN (corrected for body weight) and plasma concentrations of VEN (r = 0.498, P < 0.001) and ODV (r = 0.380, P = 0.001); ODV plasma concentrations were approximately 3.2 times higher than VEN plasma concentrations (VEN versus ODV = 18.60 ng/mL versus 59.10 ng/mL). VEN plasma concentrations (corrected for dose and body weight) did not differ with differing numbers of CYP2D6-mutated alleles. However, the ODV/VEN ratio decreased as the number of mutated CYP2D6 alleles increased (P = 0.001). This is the first study to examine the effects of CYP2D6*10 in a clinical setting. Although no effects on the plasma concentrations of VEN or ODV were observed, CYP2D6 polymorphism affects the ODV/VEN ratio. Further studies are needed to confirm the clinical relevance of these findings.

Pitfalls and challenges associated with phenoconversion in forensic toxcicology

PurposeIn recent years, several publications have demonstrated the interest and the usefulness of pharmacogenetics in forensic toxicology. However, this approach remains namely focused on DNA-based phenotype, which may potentially lead to misinterpretation. Other determinants such as co-medication or physiological parameters may also impact the phenotype. This article aims to highlight the importance of considering such determinants in forensic toxicology, through the original case of a heroin-related fatality. MethodEthanol concentration determination and toxicological screening were performed using gas chromatography with flame ionization detection, liquid chromatography with diode array detection and gas chromatography with mass spectrometry detection. CYP2C19 and CYP2D6 genotypes were determined by Taqman® real-time PCR analyses. ResultsFemoral blood analyses revealed the presence of ethanol, morphine, codeine, venlafaxine (VEN), O-desmethylvenlafaxine (ODV) and N-desmethylvenlafaxine (NDV), paroxetine, and risperidone. 6-acetylmorphine was also identified in urine. VEN, paroxetine and risperidone were quantified at supra-therapeutic or toxic blood concentrations. NDV was not quantified. The metabolic ratio of VEN (ODV to VEN) was exceptionally low (about 0.7). Pharmacogenetics testing showed that the patient was heterozygous for the CYP2C19*2 loss-of-function allele, which predict an intermediate metabolism for CYP2C19. None of the deficient CYP2D6 alleles investigated were identified. Those results suggest an extensive CYP2D6-metabolism phenotype. ConclusionA discrepancy was seen between the results of the genomic evaluation and the observed metabolic ratio of VEN. This tends to exclude a genetic origin and lead us to formulate other hypotheses, such as phenoconversion that may have been induced by drug interaction involving patients’ regular medications. Phenoconversion is as a complex phenomenon that leads to genotype-phenotype mismatch without any genetic abnormality particularly described for cytochromes P450 2D6 and 2C19. Although transient, phenoconversion can have a significant impact on the analysis and interpretation of genotype-focused clinical outcomes correlation and in forensic toxicology conclusions.

Effects of paroxetine on the pharmacokinetics of atomoxetine and its metabolites in different CYP2D6 genotypes.

The aim of this study was to investigate the effects of paroxetine, a potent inhibitor of CYP2D6, on the pharmacokinetics of atomoxetine and its two metabolites, 4-hydroxyatomoxetine and N-desmethylatomoxetine, in different CYP2D6 genotypes. Twenty-six healthy subjects were recruited and divided into CYP2D6*wt/*wt (*wt=*1 or *2, n = 10), CYP2D6*wt/*10 (n = 9), and CYP2D6*10/*10 groups (n = 7). In atomoxetine phase, all subjects received a single oral dose of atomoxetine (20mg). In paroxetine phase, after administration of a single oral dose of paroxetine (20mg) for six consecutive days, all subjects received a single oral dose of atomoxetine with paroxetine. Plasma concentrations of atomoxetine and its metabolites were determined up to 24 h after dosing. During atomoxetine phase, there were significant differences in Cmax and AUC0-24 of atomoxetine and N-desmethylatomoxetine among three genotype groups, whereas significant differences were not found in relation to CYP2D6*10 allele after administration of paroxetine. AUC ratios of 4-hydroxyatomoxetine and N-desmethylatomoxetine to atomoxetine were significantly different among three genotype groups during atomoxetine phase (all, P < 0.001), but after paroxetine treatment significant differences were not found. After paroxetine treatment, AUC0-24 of atomoxetine was increased by 2.3-, 1.7-, and 1.3-fold, in CYP2D6*wt/*wt, CYP2D6*wt/*10, and CYP2D6*10/*10 groups in comparison to atomoxetine phase, respectively. AUC ratio of 4-hydroxyatomoxetine to atomoxetine in each group was significantly decreased, whereas AUC ratio of N-desmethylatomoxetine to atomoxetine significantly increased after administration of paroxetine. In conclusion, paroxetine coadministration significantly affected pharmacokinetic parameters of atomoxetine and its two metabolites, 4-hydroxyatomoxetine and N-desmethylatomoxetine. When atomoxetine was administered alone, Cmax, AUC0-24 and CL/F of atomoxetine were significantly different among the three CYP2D6 genotype groups. However, after paroxetine coadministration, no significant differences in these pharmacokinetic parameters were observed among the CYP2D6 genotype groups.

Subanalysis of the CYP-GUIDES Trial: CYP2D6 Functional Stratification and Operational Timeline Selection

CYP-GUIDES (Cytochrome Psychotropic Genotyping Under Investigation for Decision Support) was a Randomized Controlled Trial comparing 2 outcomes in hospitalized patients with major depressive disorder treated according to the patient's CYP2D6 genotype and functional status versus standard psychotropic therapy. The primary outcome was hospital Length of Stay (LOS) and the secondary was Re-Admission Rate (RAR) 30 days after discharge. Methodology, total results and database of the trial have been published. Here we present a subanalysis that isolated 3 confounders to assess the impact of CYP2D6 therapeutic guidance on LOS: a single Electronic Medical Record, a minimum 3-day LOS, and CYP2D6 functional stratification of patients.CYP2D6 functional stratification enabled subgrouping patients and comparing outcomes according to CYP2D6 functionality within Group G and Group S. Subfunctional patients evidenced a 2-day shorter LOS in Group G compared to Group S. Drug administration for subfunctional patients in Group S evidenced a higher percentage of CYP2D6 substrate psychotropics being prescribed as well as a greater number of prescriptions than in functional patients.We conclude that there was an effect of pharmacogenetic clinical decision support that reduced LOS in patients with CYP2D6 subfunctional status and reduced prescribing of CYP2D6 substrate dependent drugs.

CYP2D6 Predicts Plasma Donepezil Concentrations in a Cohort of Thai Patients with Mild to Moderate Dementia.

PurposeDonepezil, a drug frequently used to treat dementia, is mainly metabolized by cytochrome P450 2D6 (CYP2D6). This study investigated the relationships between CYP2D6 genotype and activity scores as well as predicted phenotype of plasma donepezil concentrations in 86 Thai dementia participants.Materials and MethodsCYP2D6 was genotyped using bead-chip technology (Luminex xTAG® v.3). Steady-state trough plasma donepezil concentrations were measured using high-performance liquid chromatography.ResultsSixteen genotypes were found but the most frequent genotypes detected among our participants were CYP2D6*10/*10 (27.9%) and *1/*10 (26.7%). One-third of the participants had an activity score of 1.25 which predicted that they were normal metabolizers. The overall median (interquartile range) of plasma donepezil concentration was 51.20 (32.59–87.24) ng/mL. Normal metabolizers (NMs) had lower plasma donepezil concentrations compared to intermediate metabolizers (IMs) (41.15 (28.44–67.65) ng/mL vs 61.95 (35.25–97.00) ng/mL). Multivariate analysis showed that CYP2D6 activity score (r2 = 0.50) and the predicted phenotype (independent of dose) could predict the plasma donepezil concentration (r2 = 0.49).ConclusionPlasma donepezil concentration in NMs was lower compared to IMs. Additional studies with larger sample size and use of next-generation sequencing as well as its outcomes are warranted to confirm the benefit of using pharmacogenetic-guided treatment for donepezil.

Effects of CYP2D6 genetic polymorphism on the pharmacokinetics of metoclopramide.

Metoclopramide inhibits the central and peripheral D2 receptors and is frequently prescribed in adults and children as an antiemetic or a prokinetic drug to control symptoms of upper gastrointestinal motor disorders. Metoclopramide is predominantly metabolized via N-dealkylation and it is primarily mediated by CYP2D6 which is highly polymorphic. Thus, the effects of CYP2D6 genetic polymorphism on the pharmacokinetics of metoclopramide were evaluated in this study. All volunteers were genotyped for CYP2D6 and divided into four different genotype groups (CYP2D6*wt/*wt [*wt = *1 or *2], CYP2D6*wt/*10, CYP2D6*10/*10, and CYP2D6*5/*10). Each subject received a single oral dose of metoclopramide 10mg. Plasma concentrations of metoclopramide were measured by using HPLC-UV. Compared to CYP2D6*wt/*wt, AUCinf of CYP2D6*wt/*10, CYP2D6*10/*10, and CYP2D6*5/*10 significantly increased by 1.5-, 2.3-, and 2.5-fold, respectively. Cmax also increased significantly in comparison to CYP2D6*wt/*wt across all genotype groups, with 1.5-, 1.7-, and 1.7-fold increases seen in CYP2D6*wt/*10, CYP2D6*10/*10, and CYP2D6*5/*10 groups, respectively. The CL/F of metoclopramide decreased in CYP2D6 genotype groups with decreased function alleles, as decreases of 37%, 56% and 61% were observed in CYP2D6*wt/10, *10/10, and *5/*10 genotype groups in comparison to the CYP2D6*wt/*wt group. In conclusion, the genetic polymorphisms of CYP2D6 significantly affected metoclopramide pharmacokinetics.

A Review of the Important Role of CYP2D6 in Pharmacogenomics.

Cytochrome P450 2D6 (CYP2D6) is a critical pharmacogene involved in the metabolism of ~20% of commonly used drugs across a broad spectrum of medical disciplines including psychiatry, pain management, oncology and cardiology. Nevertheless, CYP2D6 is highly polymorphic with single-nucleotide polymorphisms, small insertions/deletions and larger structural variants including multiplications, deletions, tandem arrangements, and hybridisations with non-functional CYP2D7 pseudogenes. The frequency of these variants differs across populations, and they significantly influence the drug-metabolising enzymatic function of CYP2D6. Importantly, altered CYP2D6 function has been associated with both adverse drug reactions and reduced drug efficacy, and there is growing recognition of the clinical and economic burdens associated with suboptimal drug utilisation. To date, pharmacogenomic clinical guidelines for at least 48 CYP2D6-substrate drugs have been developed by prominent pharmacogenomics societies, which contain therapeutic recommendations based on CYP2D6-predicted categories of metaboliser phenotype. Novel algorithms to interpret CYP2D6 function from sequencing data that consider structural variants, and machine learning approaches to characterise the functional impact of novel variants, are being developed. However, CYP2D6 genotyping is yet to be implemented broadly into clinical practice, and so further effort and initiatives are required to overcome the implementation challenges and deliver the potential benefits to the bedside.

High prevalence of CYP2D6 ultrarapid metabolizers in a mestizo Colombian population in relation to Hispanic mestizo populations.

Background: Interethnic differences in CYP2D6 allele frequency have been demonstrated across Latin-American countries. Only one previous study describing CYP2D6 genotypes in Colombian population has been performed. Thus, this study aimed to evaluate the CYP2D6 genetic variability in a mestizo Colombian population, as well as the similarities and differences concerning other Hispanic mestizo (HM) populations. Methodology: Two hundred and twelve unrelated healthy Colombian subjects were studied, in which different CYP2D6 polymorphisms were analyzed by extra long-PCR and real-time PCR. Results &discussion: A high percentage of ultrarapid metabolizers (18.4%) was found, representing the highest frequency calculated within the HM populations studied. However, the percentage of poor metabolizers (4.7%) was similar to those previously reported in HM populations.

Impact of Plasmodium vivax malaria and antimalarial treatment on cytochrome P450 activity in Brazilian patients.

To investigate the impact of Plasmodium vivax malaria and chloroquine-primaquine chemotherapy on CYP2D6 and CYP2C19 activity in patients from the Brazilian Amazon. Adult patients (n = 30) were given subtherapeutic doses of CYP2D6 and CYP2C19 phenotypic probes metoprolol (10 mg) and omeprazole (2 mg) in three different stages of vivax malaria illness: acute disease (study phase 1), post chemotherapy (phase 2) and convalescence (stage 3). Plasma concentrations of probes and CYP-hydroxylated metabolites (α-OH metoprolol and 5-OH omeprazole) were measured using LC/MS/MS. Two pharmacokinetic metrics were used to estimate CYP activity: (a) ratio of plasma concentrations of probe/metabolite at 240 minutes after administration of the probes and (b) ratio of areas under the time-concentration curves for probe/metabolite (AUC0-12h ). For statistical analysis, the pharmacokinetic metrics were normalized to the respective values in phase 3. Taqman assays were used for CYP2D6 and CYP2C19 genotyping. Cytokines levels were measured using cytometric bead array. Both pharmacokinetic metrics for metoprolol and omeprazole, and plasma concentrations of cytokines IL-6, IL-8 and IL-10 varied significantly across the three study phases (ANOVA P < 0.0001). Post hoc tests showed greater metoprolol:α-OH metoprolol ratios in phases 1 and 2 compared to phase 3, larger omeprazole:5-OH omeprazole ratios in phase 1 than in phases 2 and 3, and higher circulating IL-6, IL-8 and IL-10 in phase 1 than in phases 2 and 3. P. vivax malaria and treatment altered CYP2D6 and CYP2C19 metabolic phenotypes. CYP2C19 inhibition is attributed to a higher level of circulating proinflammatory cytokines, while suppression of CYP2D6 is ascribed mainly to chloroquine exposure.

Simplified phenotyping of CYP2D6 for tamoxifen treatment using the N-desmethyl-tamoxifen/ endoxifen ratio

IntroductionCYP2D6 protein activity can be inferred from the ratio of N-desmethyl-tamoxifen (NDMT) to endoxifen (E). CYP2D6 polymorphisms are common and can affect CYP2D6 protein activity and E level. Some retrospective studies indicate that E < 16 nM may relate to worse outcome. Materials and methodsA target NDMT/E ratio was defined as associated with an E level of 15 nM in the 161 patient Test cohort of tamoxifen-treated patients, dichotomizing them into ‘Normal’ (NM) and ‘Slow’ (SM) CYP2D6 metabolizer groups. This ratio was then tested on a validation cohort of 52 patients. Patients were phenotyped based on the standard method (ultrarapid/extensive, intermediate or poor metabolizers; UM/EM, IM, PM) or a simplified system based on whether any variant allele (V) vs wildtype (wt) was present (wt/wt, wt/V, V/V). Comprehensive CYP2D6 genotyping was undertaken on germline DNA. ResultsA target NDMT/E ratio of 35 correlated with the 15 nM E level, dichotomizing patients into NM (<35; N = 117) and SM (>35; N = 44) groups. The ratio was independently validated by a validation cohort. The simplified system was better in predicting patients without slow metabolism, with specificity and sensitivity of 96% and 44% respectively, compared with the standard method - sensitivity 81% and specificity 83%. ConclusionsThe simplified classification system based on whether any variant was present better identified patients who were truly not CYP2D6 slow metabolizers more accurately than the current system. However, as CYP2D6 genotype is not the only determinant of endoxifen level, we recommend that direct measurement of endoxifen should also be considered.