Cytochrome P450 2D6 Alleles Research Articles

Cytochrome P450 2D6 profiles and anti-relapse efficacy of tafenoquine against Plasmodium vivax in Australian Defence Force personnel.

Plasmodium vivax infections and relapses remain a major health problem for malaria-endemic countries, deployed military personnel, and travelers. Presumptive anti-relapse therapy and radical cure using the 8-aminoquinoline drugs primaquine and tafenoquine are necessary to prevent relapses. Although it has been demonstrated that the efficacy of primaquine is associated with Cytochrome P450 2D6 (CYP2D6) activity, there is insufficient data on the role of CYP2D6 in the anti-relapse efficacy of tafenoquine. We investigated the relationship between CYP2D6 activity status and tafenoquine efficacy in preventing P. vivax relapses retrospectively using plasma samples collected from Australian Defence Force personnel deployed to Papua New Guinea and Timor-Leste who participated in clinical trials of tafenoquine during 1999-2001. The CYP2D6 gene was amplified from plasma samples and fully sequenced from 92 participant samples, comprised of relapse (n = 31) and non-relapse (n = 61) samples, revealing 14 different alleles. CYP2D6 phenotypes deduced from combinations of CYP2D6 alleles predicted that among 92 participants 67, 15, and 10 were normal, intermediate, and poor metabolizers, respectively. The deduced CYP2D6 phenotype did not correlate with the corresponding participant's plasma tafenoquine concentrations that were determined in the early 2000s by high-performance liquid chromatography or liquid chromatography-mass spectrometry. Furthermore, the deduced CYP2D6 phenotype did not associate with P. vivax relapse outcomes. Our results indicate that CYP2D6 does not affect plasma tafenoquine concentrations and the efficacy of tafenoquine in preventing P. vivax relapses in the assessed Australian Defence Force personnel.

Using population pharmacokinetic analyses of drugs metabolized by CYP2D6 to study the genotype-phenotype translation.

Cytochrome P450 2D6 (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 the evidence, the activity score system may be further refined to better reflect the enzyme function associated with these alleles.

Characterization of CYP2D6 Pharmacogenetic Variation in Sub-Saharan African Populations.

Cytochrome P450 2D6 (CYP2D6) is a key enzyme in drug response owing to its involvement in the metabolism of ~ 25% of clinically prescribed medications. The encoding CYP2D6 gene is highly polymorphic, and many pharmacogenetics studies have been performed worldwide to investigate the distribution of CYP2D6 star alleles (haplotypes); however, African populations have been relatively understudied to date. In this study, the distributions of CYP2D6 star alleles and predicted drug metabolizer phenotypes-derived from activity scores-were examined across multiple sub-Saharan African populations based on bioinformatics analysis of 961 high-depth whole genome sequences. This was followed by characterization of novel star alleles and suballeles in a subset of the participants via targeted high-fidelity Single-Molecule Real-Time resequencing (Pacific Biosciences). This study revealed varying frequencies of known CYP2D6 alleles and predicted phenotypes across different African ethnolinguistic groups. Twenty-seven novel CYP2D6 star alleles were predicted computationally and two of them were further validated. This study highlights the importance of studying variation in key pharmacogenes such as CYP2D6 in the African context to better understand population-specific allele frequencies. This will aid in the development of better genotyping panels and star allele detection approaches with a view toward supporting effective implementation of precision medicine strategies in Africa and across the African diaspora.

Physiologically Based Pharmacokinetic Modeling to Describe the CYP2D6 Activity Score-Dependent Metabolism of Paroxetine, Atomoxetine and Risperidone.

The cytochrome P450 2D6 (CYP2D6) genotype is the single most important determinant of CYP2D6 activity as well as interindividual and interpopulation variability in CYP2D6 activity. Here, the CYP2D6 activity score provides an established tool to categorize the large number of CYP2D6 alleles by activity and facilitates the process of genotype-to-phenotype translation. Compared to the broad traditional phenotype categories, the CYP2D6 activity score additionally serves as a superior scale of CYP2D6 activity due to its finer graduation. Physiologically based pharmacokinetic (PBPK) models have been successfully used to describe and predict the activity score-dependent metabolism of CYP2D6 substrates. This study aimed to describe CYP2D6 drug–gene interactions (DGIs) of important CYP2D6 substrates paroxetine, atomoxetine and risperidone by developing a substrate-independent approach to model their activity score-dependent metabolism. The models were developed in PK-Sim®, using a total of 57 plasma concentration–time profiles, and showed good performance, especially in DGI scenarios where 10/12, 5/5 and 7/7 of DGI AUClast ratios and 9/12, 5/5 and 7/7 of DGI Cmax ratios were within the prediction success limits. Finally, the models were used to predict their compound’s exposure for different CYP2D6 activity scores during steady state. Here, predicted DGI AUCss ratios were 3.4, 13.6 and 2.0 (poor metabolizers; activity score = 0) and 0.2, 0.5 and 0.95 (ultrarapid metabolizers; activity score = 3) for paroxetine, atomoxetine and risperidone active moiety (risperidone + 9-hydroxyrisperidone), respectively.

Acute pharmacogenetic dystonic reactions in a family with the CYP2D6 *41 allele: a case report

BackgroundDystonia is a known neurological complication of certain medications; however, the mechanism behind such effects is often undetermined. Similarly, the clinical pharmacogenomic effects associated with various alleles of the cytochrome P450 family of proteins, and their role in acute dystonic reactions, are also presently unknown.Case presentationWe describe a woman presenting with acute dystonic reactions to ondansetron, prochlorperazine, and metoclopramide followed by persistent focal dystonia. A similar family history was reported in her siblings and her father to prochlorperazine, drugs all metabolized by the cytochrome P450 2D6 (CYP2D6) enzyme. Pharmacogenomic testing indicated the patient was heterozygous for the intermediate metabolizer *41 allele (CYP2D6 2988G>A, NM_000106.6:c.985+39G>A, rs28371725). Her father was homozygous for this CYP2D6 *41 allele, and consequently, her siblings were obligate carriers.ConclusionsThe metabolism of ondansetron, metoclopramide, or prochlorperazine in patients with the *41 CYP2D6 allele has not been studied. In this family, clinical evidence implicates the *41 CYP2D6 allele as causing extrapyramidal adverse pharmacologic reactions. Patients with a family history of medication-induced dystonia involving these medications should be considered for pharmacogenomic testing, and patients carrying the *41 CYP2D6 allele should consider reduction or avoidance of CYP2D6-mediated medications to minimize the potential risk of adverse extrapyramidal effects.

Clinical Trial: CYP2D6 Related Dose Escalation of Tamoxifen in Breast Cancer Patients With Iranian Ethnic Background Resulted in Increased Concentrations of Tamoxifen and Its Metabolites.

Introduction: The polymorphic enzyme cytochrome P450 2D6 (CYP2D6) catalyzes a major step in the bioactivation of tamoxifen. Genotyping of clinically relevant CYP2D6 alleles and subsequent dose adjustment is a promising approach to individualize breast cancer therapy. The aim of this study was to investigate the relationship between the plasma levels of tamoxifen and its metabolites and different CYP2D6 genotypes under standard (20 mg/day) and dose-adjusted therapy (Registration ID in Iranian Registry of Clinical Trials: IRCT2015082323734N1).Materials and Methods: Using TaqMan® assays common alleles of CYP2D6 (∗1, ∗2, ∗4, ∗5, ∗6, ∗10, ∗17, and ∗41) and gene duplication were identified in 134 breast cancer patients. Based on CYP2D6 genotypes patients with an activity score 1 (n = 15) and 0–0.5 (n = 2) were treated with tamoxifen adjusted dosage of 30 and 40 mg/day, respectively. The concentration of tamoxifen and its metabolites before and after 4 and 8 months of dose adjustment were measured using LC-MS/MS technology.Results: At baseline, (Z)-endoxifen plasma concentrations (33 ± 15.5, 28.1 ± 14, 26.6 ± 23.4, 14.3 ± 8.6, and 10.7 ± 5.5 nmol/l for EM/EM, EM/IM, EM/PM, IM/IM and PM/PM, respectively) and the metabolic ratio (Z)-Endoxifen/N-desmethyltamoxifen (0.0558 ± 0.02, 0.0396 ± 0.0111, 0.0332 ± 0.0222, 0.0149 ± 0.0026, and 0.0169 ± 0.0177 for EM/EM, EM/IM, EM/PM, IM/IM, and PM/PM, respectively) correlated with CYP2D6 genotype (Kruskal–Wallis p = 0.013 and p < 0.0001, respectively). Dose escalation to 30 and 40 mg/day in patients with a CYP2D6 activity score of 1 (n = 15) and 0–0.5 (n = 2) resulted in a significant increase in (Z)-endoxifen plasma levels (22.17 ± 24.42, 34.43 ± 26.54, and 35.77 ± 28.89 nmol/l at baseline, after 4 and 8 months, respectively, Friedman p = 0.0388) along with the plasma concentrations of tamoxifen and its other metabolites. No severe side effects were recorded during dose escalation.Conclusion: For the first time, we show the feasibility of dose escalation of tamoxifen in breast cancer patients with compromised CYP2D6 activity and Iranian ethnic background to increase the plasma concentrations of (Z)-endoxifen.

Cytochrome P450 2D6 profiles and their relationship with outcomes of primaquine anti-relapse therapy in Australian Defence Force personnel deployed to Papua New Guinea and East Timor

BackgroundPrimaquine, an 8-aminoquinoline with anti-hypnozoite activity against Plasmodium vivax, is metabolized by human cytochrome P450 2D6 (CYP2D6) to its active metabolite. Human CYP2D6 activities may influence the metabolism of primaquine and the risk of experiencing Plasmodium relapses following primaquine anti-relapse therapies (PART). In this study, the CYP2D6 profile and its relationship with outcomes of PART in Australian Defence Force (ADF) personnel is retrospectively investigated.MethodsGenomic DNA was isolated from stored and de-identified serum or blood samples from ADF personnel deployed on peacekeeping duties to Papua New Guinea (PNG) (1999) and East Timor (1999–2000) who received PART before returning to Australia and after experiencing relapses. CYP2D6 allelic type was determined by PCR and Sanger sequencing. CYP2D6 allele frequency, predicted phenotypes and activity scores were compared among personnel who did not experience P. vivax (ADF-NR, n = 48) and those who experience at least one (ADF-R, n = 109) relapse, as well as between those who experienced 1 (n = 79), 2 (n = 21) and 3–5 (n = 9) relapses within the ADF-R group.Results16 CYP2D6 alleles were observed in 157 ADF personnel. Alleles *1, *4, *2 and *41 were major alleles (> 5%). The CYP2D6 allele frequency profile in the ADF-NR group matched that of a European population. There was an increased proportion of non-functional CYP2D6 alleles in the ADF-R group compared to the European population and ADF-NR group. However, frequencies of predicted CYP2D6 phenotype and activity score were not different between the ADF-R and ADF-NR groups, nor among sub-groups experiencing multiple relapses within the ADF-R group.ConclusionsCYP2D6 phenotype or activity score based on the allele classification was not a major contributor to P. vivax relapse in this ADF cohort. Other factors such as adherence and/or parasite tolerance to primaquine are likely contributing factors to P. vivax relapses in this cohort.

Distribution of CYP2D6 polymorphism in the Middle Eastern region.

Cytochrome P450 2D6 (CYP2D6) is an important drug-metabolizing enzyme involved in the pharmacokinetic metabolism of drugs. CYP2D6 gene is highly polymorphic, and the combination of its different alleles yields different phenotypes including extensive metabolizer (EM), intermediate metabolizer (IM), poor metabolizer (PM), and ultrarapid metabolizer (UM). Genotyping of the important alleles for this gene in different ethnicities is of particular importance for assessing the efficacy of various drugs. In this study, we reviewed the CYP2D6 allele and phenotype frequencies predicted from the genotypes of CYP2D6 in the Middle East area. Regardless of different ethnicities, the CYP2D6*41 allele frequency was shown to be higher than that of other reduced functional alleles. In addition, CYP2D6*4 was the most frequent nonfunctional allele in all studied populations in the Middle East. Taken together, our findings illustrated that the frequencies of PM or IM alleles and different genotypes harboring these alleles are relatively high in the Middle Eastern countries. Therefore, the study of CYP2D6 alleles for each patient to detect those that are at risk is of great importance to prevent adverse drug reactions through individualization therapy.

Association between cytochrome P450 2D6 polymorphisms and body fluid methamphetamine concentrations in Japanese forensic autopsy cases

Methamphetamine (MA) is an illicit stimulant that affects the central nervous system. Cytochrome P450 2D6 (CYP2D6) plays an important role in MA metabolism. Numerous allelic variants confer substantial variation in CYP2D6 activity among individuals. In the present study, we examined the frequencies of CYP2D6 alleles, including CYP2D6*1, *2, *4, *5, *10, *14A, *14B, *18, and *36, and multiplication, in 82 forensic autopsy cases of MA abusers and 567 autopsy cases in which MA was not detected (controls). Ultrarapid metabolizer (UM), extensive metabolizer (EM), intermediate metabolizer (IM), and poor metabolizer (PM) phenotypes were predicted from CYP2D6 genotypes. Of MA abusers, 64 subjects were predicted to be EM, 17 were IM, and 1 was UM. No MA abuser had the predicted PM phenotype. No significant differences in CYP2D6 phenotype frequencies were found between MA abusers and controls. MA and amphetamine (AMP) concentrations were measured in the right heart blood, left heart blood, peripheral external iliac blood, urine, pericardial fluid, and bone marrow of MA abusers. MA concentrations in urine and bone marrow were significantly higher in IM than in EM. AMP concentration was not associated with CYP2D6 phenotype in any body fluid. These results suggest that the MA concentration in body fluids is influenced by CYP2D6 phenotypes in the Japanese population.

Functional characterization of wild-type and 24 CYP2D6 allelic variants on gefitinib metabolism in vitro

BackgroundCytochrome P450 2D6 (CYP2D6), a member of the CYP450 enzyme super family, is a polymorphic enzyme that metabolizes ~25% of therapeutic drugs. CYP2D6 exhibits significant genetic polymorphisms which might cause adverse effects and therapeutic failures of some drugs.ObjectiveThe purpose of this study was to evaluate the catalytic activities of 22 novel CYP2D6 alleles (CYP2D6*87, *88, *89, *90, *91, *92, *93, *94, *95, *96, *97, *98, R25Q, F164L, E215K, F219S, V327M, D336N, V342M, R344Q, R440C, R497C) on the metabolism of gefitinib in vitro.Methods and resultsCYP2D6 variants were incubated with 1–100 μM gefitinib for 60 min at 37°C and the reaction was terminated by cooling to −80°C immediately. Gefitinib and its metabolite O-desmethyl gefitinib were analyzed by an ultra-performance liquid chromatography-tandem mass spectrometry system. Compared to CYP2D6.1, most CYP2D6 variants exhibited significantly decreased relative clearance values (from 3.11% to 79.35%), whereas CYP2D6.92 and CYP2D6.96 displayed no detectable enzyme activity. Only CYP2D6.94 exhibited a markedly increased intrinsic clearance value, and eight variants (CYP2D6.88, CYP2D6.89, CYP2D6.91, CYP2D6.97, V342M, R344Q, F219S, and F164L) showed no significant difference. In addition, 23 CYP2D6 allelic isoforms exhibited substrate inhibition trend toward gefitinib.ConclusionAs the first study of all the aforementioned alleles for gefitinib metabolism, these comprehensive data may help in the clinical assessment of the metabolism of gefitinib, and may also offer a reference for personalized treatment with gefitinib in clinical settings.

Effect of 22 CYP2D6 variants found in the Chinese population on tolterodine metabolism in vitro

Cytochrome P450 2D6 (CYP2D6) is an important member of the cytochrome P450 enzyme superfamily. We recently identified 22 novel variants in the Chinese population using PCR and bidirectional sequencing methods. The aim of this study is to characterize the enzymatic activity of these variants and their effects on the metabolism of the antimuscarinic drug tolterodine in vitro. A baculovirus-mediated expression system was used to express wild-type CYP2D6 and 24 variants (CYP2D6*2, CYP2D6*10, and 22 novel CYP2D6 variants) at high levels. The insect microsomes expressing CYP2D6 proteins were incubated with 0.1–50 μM tolterodine at 37 °C for 30 min and the metabolites were analyzed by high-performance liquid chromatography–tandem mass spectrometry system. Of the 24 CYP2D6 variants tested, 2 variants (CYP2D6*92 and CYP2D6*96) were found to be catalytically inactive, 4 variants (CYP2D6*94, F164L, F219S and D336N) exhibited markedly increased intrinsic clearance values (Vmax/Km) compared with the wild-type (from 66.34 to 99.79%), whereas 4 variants (CYP2D6*10, *93, *95 and E215K) exhibited significantly decreased values (from 49.02 to 98.50%). This is the first report of all these rare alleles for tolterodine metabolism and these findings suggest that more attention should be paid to subjects carrying these infrequent CYP2D6 alleles when administering tolterodine in the clinic.

CYP2D6 allele distribution in Macedonians, Albanians and Romanies in the Republic of Macedonia.

Cytochrome P450 2D6 (CYP2D6) is an enzyme of great importance for the metabolism of clinically used drugs. More than 100 variants of the CYP2D6 gene have been identified so far. The aim of this study was to investigate the allele distribution of CYP2D6 gene variants in 100 individuals of each of the Macedonian, Albanian and Romany population, by genotyping using long range polymerase chain reaction (PCR) and a multiplex single base extension method. The most frequent variants and almost equally distributed in the three groups were the fully functional alleles *1 and *2. The most common non functional allele in all groups was *4 that was found in 22.5% of the Albanians. The most common allele with decreased activity was *41 which was found in 23.0% of the Romany ethnic group, in 11.0% of the Macedonians and in 10.5% of the Albanians. Seven percent of the Albanians, 6.0% of the Romani and 4.0% of the Macedonians were poor metabolizers, while 5.0% of the Macedonians, 1.0% of Albanians and 1.0% of the Romanies were ultrarapid metabolizers. We concluded that the CYP2D6 gene locus is highly heterogeneous in these groups and that the prevalence of the CYP2D6 allele variants and genotypes in the Republic of Macedonia is in accordance with that of other European populations.

Novel +90G>A Intronic Polymorphism of CYP2D6.

CYP2D6, an enzyme, metabolizes a large number of commonly prescribed drugs. Variations in CYP2D6 gene encoding this enzyme have been associated with individual differences in drug metabolism rates. The purpose of our study was to identify some allelic variants of CYP2D6 gene and to detect defective CYP2D6 alleles, as part of a pharmacogenetic screening program. A prospective study was done on 120 participants referred to Royan Institute in 2013. Allele and genotype frequencies for polymorphism of CYP2D6 gene in exons 1 and 4 were determined by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) analysis and sequencing on PCR products, respectively. We identified a novel variant of the gene encoding cytochrome P450 2D6 (CYP2D6) at position +90 of intron 4 by sequencing method. This novel polymorphism of CYP2D6 has been deposited in GeneBank(®) under the accession number KF225465 in Jun 2013. In the current study, we identified novel polymorphism in intron 4. This single nucleotide polymorphism (SNP) is known as +90G>A in the fourth intron.

The CYP4502D6 *4 and *6 alleles are the molecular genetic markers for drug response: implications in colchicine non-responder FMF patients.

The cytochrome P450 2D6 (CYP2D6) is a cytochrome P450 enzyme involved in the oxidative biotransformation of the xenobiotics, carcinogens and various clinically important drugs. Patients are evaluated in three sub-groups of extensive (EM), intermediate (IM) and poor metabolizer (PM) phenotypes due to their drug-metabolising ability for the target CYP2D6 gene. Colchicine non-responsive FMF patients were prospectively genotyped for the major CYP2D6 alleles in the current study. Major CYP2D6 alleles of *1, *3, *4, *5, and *6 were genotyped for 30 responsive and 60 non-responsive FMF patients by multiplex PCR-based reverse-hybridization StripAssay and real-time PCR methods. DNA banks isolated from blood-EDTA were retrospectively used in the current patients and results were compared statistically. Increased CYP2D6 *4 and *6 allele frequencies were highly detected in the colchicine non-responsive FMF patients when compared to the responsive group. Results showed the frequencies of major CYP2D6 *1(wild), *3(2637A>delA), *4(G1934A), *5(total gene deletion) and *6(1707T del) alleles in 0.550, 0.042, 0.158, 0.025 and 0.225 for non-responder and 0.880 and 0.120 (CYP2D6*1 and *4) for the responder groups, respectively. Despite small sample size, this study suggests that there is an association between CYP2D6*4 and CYP2D6*6 alleles and drug intoxicants in colchicine non-responder FMF patients.

Response to CYP2D6 substrate antidepressants is predicted by a CYP2D6 composite phenotype based on genotype and comedications with CYP2D6 inhibitors.

The cytochrome P450 2D6 (CYP2D6) is involved in the metabolism of most antidepressants. Comedication with a potent CYP2D6 inhibitor can convert patients with extensive metabolizer (EM) or ultra-rapid metabolizer (UM) genotypes into poor metabolizer (PM) phenotypes. Since comedication is frequent in depressed patients treated with antidepressants, we investigated the effect of the CYP2D6 composite phenotype on antidepressant efficacy, taking into account both the CYP2D6 genotype and comedication with CYP2D6 inhibitors. 87 Caucasian in patients with a major depressive episode were prospectively treated with flexible doses of antidepressant monotherapy as well as comedications and genotyped for the major CYP2D6 alleles (CYP2D6*3 rs35742686, *4 rs3892097, *5 del, *6 rs5030655, and *2xN). They were classified for CYP2D6 composite phenotype and assessed for antidepressant response after 4weeks. In terms of genotypes (g), 6 subjects were UMg, 6 PMg, and 75 EMg. Ten patients were coprescribed a CYP2D6 inhibitor, resulting in the following composite phenotypes (cp): 5 UMcp, 16 PMcp, and 66 EMcp. Whereas none of the CYP2D6 genotypes were significantly associated with antidepressant response, UMcp had a lower antidepressant response than PMcp or EMcp (respectively: 39.0±17.9, 50.0±26.0, and 61.6±23.4, p=0.02). Despite small sample size, this study suggests that a CYP2D6 composite phenotype, taking into account both genotype and comedications with CYP2D6 inhibitors, could predict CYP2D6 substrate antidepressants response. Thus, to optimize antidepressant response, CYP2D6 genotype could be performed and comedications with CYP2D6 inhibitors should be avoided, when prescribing CYP2D6 substrate antidepressants.

CYP2D6 Genotype Should Not Be Used to Determine Endocrine Therapy in Postmenopausal Breast Cancer Patients

The antiestrogen tamoxifen is an effective treatment for all stages of estrogen receptor (ER)-positive breast cancer.1 Tamoxifen blocks estrogen-dependent breast cancer growth by competing with estrogen for binding to its receptor. Tamoxifen itself has antiestrogenic properties, but it is metabolized by a number of cytochrome P450 enzymes into many different metabolites that have varying degrees of antiestrogenic activity. Studies have consistently shown that cytochrome P450 2D6 (CYP2D6), a highly polymorphic drug-metabolizing enzyme, is the enzyme primarily responsible for the production of one of the most potent metabolites, endoxifen (4-hydroxy-N-desmethyl-tamoxifen). Preclinical studies of estrogen-dependent breast cancer have shown that endoxifen is an approximately 100-fold more potent antiestrogen than tamoxifen or the major tamoxifen metabolite, N-desmethyl-tamoxifen. Patients who are homozygous for two null CYP2D6 alleles, and are therefore poor metabolizers (PMs), as well as patients who are taking medications that are CYP2D6 inhibitors, have lower serum endoxifen concentrations as compared with patients who have one or more wild-type CYP2D6 alleles (intermediate metabolizers (IMs) and extensive metabolizers (EMs), respectively) (reviewed by Hertz et al.2).

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Wither codeine?

Laboratory testing of CYP2D6 alleles in relation to tamoxifen therapy

Tamoxifen, a widely prescribed drug for the treatment and prevention of breast cancer, is metabolized to more potent metabolites by the cytochrome P450 2D6 (CYP2D6) enzyme. Variants in the CYP2D6 gene can cause patients to be either intermediate or poor metabolizers, thereby rendering tamoxifen treatment less effective. Testing for CYP2D6 gene variants is available in Clinical Laboratory Improvement Amendments-certified clinical laboratories; however, the biological complexity of the variants makes result interpretation and phenotype prediction challenging. This article describes the clinical significance of variants as well as important analytical, interpretative, and reporting issues. It is designed to be a guideline for clinical laboratory professionals in performing tests and interpreting results with respect to CYP2D6 genetic variants.

Tamoxifen and CYP2D6: A Contradiction of Data

Tamoxifen is an effective antiestrogen used in the treatment of hormone receptor-positive breast cancer. Bioconversion of tamoxifen to endoxifen, its most abundant active metabolite, is primarily dependent on the activity of cytochrome P450 2D6 (CYP2D6), which is highly polymorphic. Over 20 published studies have reported on the potential association between CYP2D6 polymorphism and tamoxifen treatment outcome, with highly inconsistent results. The purpose of this review is to explore differences among 17 independent studies to identify factors that may have contributed to the discrepant findings. This report discusses six putative factors that are grouped into two categories: (a) clinical management criteria: hormone receptor classification, menopausal status, and tamoxifen combination therapy; (b) pharmacologic criteria: genotyping comprehensiveness, CYP2D6 inhibitor coadministration, and tamoxifen adherence. Comparison of these factors between the positive and negative studies suggests that tamoxifen combination therapy, genotyping comprehensiveness, and CYP2D6 inhibitor coadministration may account for some of the contradictory results. Future association studies on the link between CYP2D6 genotype and tamoxifen treatment efficacy should account for combination therapy and CYP2D6 inhibition, and interrogate as many CYP2D6 alleles as possible.

CYP2D6 genotyping in breast cancer patients by liquid chromatography-electrospray ionization mass spectrometry

The application of cytochrome P450 2D6 (CYP2D6) genotyping to allow a personalized treatment approach for breast cancer patients undergoing endocrine therapy has been repeatedly discussed. However, the actual clinical relevance of the CYP2D6 genotype in the endocrine treatment of breast cancer still remains to be elucidated. A major prerequisite for the successful and valid evaluation of the CYP2D6 genotype with regard to its pharmacokinetic and clinical relevance is the availability of a comprehensive, accurate and cost-effective CYP2D6 genotyping strategy. Herein we present a CYP2D6 genotyping assay employing polymerase chain reaction (PCR)-ion pair reversed-phase high-performance liquid chromatography-electrospray ionization time-of-flight mass spectrometry (ICEMS). The genotyping strategy involves the simultaneous amplification of nine variable regions within the CYP2D6 gene by a two-step PCR protocol and the direct analysis of the generated PCR amplicons by ICEMS. The nucleotide composition profiles generated by ICEMS enable the differentiation of 37 of the 80 reported CYP2D6 alleles. The assay was applied to type the CYP2D6 gene in 199 Austrian individuals including 106 breast cancer patients undergoing tamoxifen treatment. The developed method turned out to be a highly applicable, robust and cost-effective approach, enabling an economical CYP2D6 testing for large patient cohorts.