CYP2D6 Drug Research Articles

The metabolic profiles of endogenous and exogenous substances in a poor metabolizer of humanized CYP2D6 model

Background: Species differences in CYP2D6 drug metabolism complicate the extrapolation of in vivo pharmacokinetic data to humans and impact the prediction of drug responses. This study aimed to develop an in vivo model to predict human responses to CYP2D6 metabolized compounds and to evaluate medication risks and disease development.Methods: We used embryonic stem cell (ES) targeting and CRISPR-Cas9 technology to create a humanized CYP2D6 mouse model by inserting the human wild-type CYP2D6 gene and knocking out the mouse Cyp2d locus. Metoprolol was used as the substrate probe to examine the pharmacokinetic properties of exogenous substances, tissue distribution, and in situ metabolism of CYP2D6. Untargeted and quantitative metabolomics analyses compared endogenous substance metabolism between different species of CYP2D6 enzymes.Results: No significant differences in CYP2D6 homologous protein distribution and expression of primary metabolic organs were found between humanized CYP2D6 mice and wild-type (WT) mice. The activity and metabolic capacity of CYP2D6 in humanized mice were substantially lower than homologous Cyp2d22 of WT mice in metabolizing metoprolol. The levels of several glycerolipids and glycerophospholipid-related metabolites were down-regulated in humanized CYP2D6 mice. Triglyceride TG (14:0_22:6_22:6) was significantly downregulated in male and female humanized mice, suggesting a strong association with reduced CYP2D6 activity.Conclusions: This study established a robust animal model to investigate human CYP2D6-mediated metabolic profiles of exogenous and endogenous compounds, predict medication risks, and explore the potential roles of CYP2D6 in organ-specific toxicity and disease development.

Solanidine Metabolites as Diet-Derived Biomarkers of CYP2D6-Mediated Tamoxifen Metabolism in Breast Cancer Patients.

Tamoxifen is an important antiestrogen for the treatment of hormone receptor-positive breast cancer and undergoes bioactivation by CYP2D6 to its active metabolite endoxifen. Genetic variation in CYP2D6 has been linked to endoxifen levels during tamoxifen therapy. Recent studies have suggested solanidine, a glycoalkaloid phytochemical in potatoes, undergoes CYP2D6-mediated metabolism to 4-OH-solanidine (m/z 414) and 3,4-seco-solanidine-3,4-dioic acid (SSDA; m/z 444). Using a retrospective cohort of 1,032 breast cancer patients on tamoxifen therapy, we examined the association of solanidine metabolites with CYP2D6 activity and its correlation with tamoxifen metabolism. Solanidine, 4-OH-solanidine, or SSDA was detected in 99.7% (N = 1,029) of plasma samples. Decreased solanidine metabolite ratios were found in CYP2D6 intermediate and poor metabolizers (P < 0.0001). Patients on CYP2D6 strong inhibitors had a 77.6% and 94.2% decrease in 4-OH-solandine/solanidine (P < 0.0001) and SSDA/solanidine (P < 0.0001), respectively. The ratio of endoxifen to tamoxifen was highly correlated with both 4-OH-solandine/solanidine (ρ = 0.3207, P < 0.0001) and SSDA/solanidine (ρ = 0.5022, P < 0.0001) ratios. Logistic regression modeling was used to determine that 4-OH-solanidine/solanidine and SSDA/solanidine ratios below 2.1 and 0.8, respectively, predicted endoxifen concentrations of <16 nM. In conclusion, solanidine, 4-OH-solanidine, and SSDA are diet-derived biomarkers of CYP2D6 activity. Moreover, in patients on tamoxifen therapy, 4-OH-solanidine/solanidine and SSDA/solanidine predicted endoxifen levels including the inhibitory effects of concomitantly prescribed CYP2D6-interacting medications. Accordingly, 4-OH-solanidine/solanidine or SSDA/solanidine ratio has the potential to be particularly useful prior to initiation of tamoxifen or for determining the impact of CYP2D6 drug interactions, as well as prior to switching from an aromatase inhibitor to tamoxifen.

A Novel Approach to Improve Accuracy of CYP2D6 Enzyme Activity and Drug Response Predictions.

A Novel Approach to Improve Accuracy of CYP2D6 Enzyme Activity and Drug Response Predictions.

Effects of CYP2D6 Genetic Polymorphism and Drug Interaction on the Metabolism of Dacomitinib.

We aim to study the effects of CYP2D6 variants and drug-drug interaction on the metabolism of dacomitinib. CYP2D6 variants were incubated with 25-1000 μM dacomitinib for 40 min at 37 °C, and the reaction was terminated by cooling to -80 °C immediately. For an in vivo experiment, 18 male Sprague-Dawley rats were randomly divided into three groups (n = 6): a single dose of 5 mg/kg dacomitinib (group A), a single dose of 6 mg/kg trazodone (group B), and a combined group (group C). Processed samples were analyzed by ultraperformance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS.) The relative clearance of dacomitinib was reduced for most of the variants. Moreover, the inhibitory potency of classic CYP inhibitors on dacomitinib metabolism was significantly different among the main subtypes of CYP2D6. Interestingly, compared with gefitinib, even the same CYP2D6 variants showed significant differences in metabolic activity, suggesting that the activity of CYP2D6 has strong variability. In addition, the interaction between trazodone and dacomitinib was determined both in vitro and in vivo. When dacomitinib was given in combination with trazodone, the blood exposure to these two drugs increased remarkably. The mechanistic study revealed that the interaction followed the noncompetitive inhibition. We demonstrated that the activity of CYP2D6 variants to metabolize dacomitinib was significantly reduced. In combination with the CYP2D6 inhibitor, the degree of activity inhibition of different variants obviously differed. When trazodone and dacomitinib were used in combination, the body exposure to the two drugs increased significantly. This study provides data for the precise use of dacomitinib in clinical settings.

How to Integrate CYP2D6 Phenoconversion Into Clinical Pharmacogenetics: A Tutorial.

CYP2D6 genotype is increasingly being integrated into practice to guide prescribing of certain medications. The CYP2D6 drug metabolizing enzyme is susceptible to inhibition by concomitant drugs, which can lead to a clinical phenotype that is different from the genotype-based phenotype, a process referred to as phenoconversion. Phenoconversion is highly prevalent but not widely integrated into practice because of either limited experience on how to integrate or lack of knowledge that it has occurred. We built a calculator tool to help clinicians integrate a standardized method of assessing CYP2D6 phenoconversion into practice. During tool-building, we identified several clinical factors that need to be considered when implementing CYP2D6 phenoconversion into clinical practice. This tutorial shares the steps that the University of Florida Health Precision Medicine Program took to build the calculator tool and identified clinical factors to consider when implementing CYP2D6 phenoconversion in clinical practice.

Overactive Bladder Prescribing Considerations: The Role of Polypharmacy, Anticholinergic Burden, and CYP2D6 Drug‒Drug Interactions.

Overactive bladder (OAB) is a common disorder in the general population, and the prevalence increases with age. Adults with OAB typically have a greater number of comorbid conditions, such as hypertension, depression, and dementia, compared with adults without OAB. Subsequent to an increased number of comorbidities, adults with OAB take a greater number of concomitant medications, which may increase the risk of potentially harmful drug‒drug interactions. There are two important considerations for many of the medications approved for the treatment of OAB in the USA: anticholinergic burden and potential for drug‒drug interactions, notably related to cytochrome P450 (CYP) 2D6, which is responsible for the metabolism of approximately 25% of all drugs. A substantial number of drugs used for the treatment of OAB and comorbid conditions (e.g., cardiovascular and neurologic disorders) are CYP2D6 substrates or inhibitors. Furthermore, a substantial number of drugs with CYP2D6 properties also have strong anticholinergic properties. Here, we review polypharmacy associated with OAB and its common comorbidities, identify drugs with reported anticholinergic properties, and provide an overview of clinically relevant drug‒drug interactions in the treatment of OAB as they relate to CYP2D6 metabolism. This review aims to provide clinicians with essential information necessary for making treatment decisions when managing OAB.

Combining Antidepressants with β‐Blockers: Evidence of a Clinically Significant CYP2D6 Drug Interaction

The β-blockers and antidepressants are two of the most commonly prescribed drug classes in the United States. Several antidepressants are potent inhibitors of cytochrome P450 2D6 liver enzymes (CYP2D6) and can increase the plasma concentrations of certain β-blockers when administered concomitantly, potentially leading to serious medical consequences such as hypotension, bradycardia, and falls. The primary objective of this investigation was to determine whether initiating an antidepressant in patients receiving β-blockers increased the risk of hemodynamic adverse events. Our primary outcome was time to hospital admissions or emergency department (ED) visits for an International Classification of Diseases-9 diagnosis suggestive of excessive β-blockade. We conducted a survival analysis for adults continuously enrolled in the California Medicaid system (Medi-Cal) between 2004 and 2012. Eligible patients were required to be receiving β-blocker medications that are primarily CYP2D6 substrates (e.g., metoprolol, propranolol, or carvedilol). Univariate and multivariable analyses were performed for patients who concurrently received antidepressants with β-blockers. An additional multivariable analysis analyzed the association of this combination upon hospitalizations or ED visits for all causes. A total of 21,292 beneficiaries met the inclusion criteria, and 4.3% of patients required hospitalization or ED visits within 30days of co-medication. In multivariable analysis, patients receiving antidepressants with moderate to strong CYP2D6 inhibitory potential (fluoxetine, paroxetine, duloxetine, or bupropion) had a greater risk for hospitalization or ED visits for hemodynamic events than those initiated on antidepressants with weak CYP2D6 inhibition for 30days or less when each was compared with patients receiving no antidepressants (hazard ratio [HR] 1.53, 95% confidence interval [CI] 1.03-2.81; p=0.04 vs HR 1.24; 95% CI 0.82-1.88; p=0.30). Other demographic variables associated with increased morbidity included advanced age, male sex, higher β-blocker doses, and African American race or Hispanic ethnicity. Results of this analysis suggest that initiation of certain antidepressants was associated with an increased risk for serious medical sequelae among patients concurrently receiving β-blockers. Greater risk was observed with antidepressants that potently inhibit the CYP2D6 enzyme, implying that increased morbidity may be mediated by a metabolic drug interaction.

Drug Use in Denmark for Drugs Having Pharmacogenomics (PGx) Based Dosing Guidelines from CPIC or DPWG for CYP2D6 and CYP2C19 Drug-Gene Pairs: Perspectives for Introducing PGx Test to Polypharmacy Patients.

Background: The cytochrome P450 drug metabolizing enzymes CYP2D6 and CYP2C19 are the major targets for pharmacogenomics (PGx) testing and determining for drug response. Clinical dosing guidelines for specific drug-gene interactions (DGI) are publicly available through PharmGKB. The aim of this register study was to map the use of drugs in Denmark for drugs having actionable dosing guidelines (AG) i.e., dosing recommendations different from standard dosing for CYP2D6 or CYP2C19 DGI in terms of consumption. Methods: The Danish Register of Medicinal Product Statistics was the source to retrieve consumption in Defined Daily Dose (DDD) i.e., the assumed average maintenance dose per day for a drug used for its main indication in adults and number of users (2017 data). Clinical dosing guidelines were available from the PharmGKB website. Results: Forty-nine drugs have guidelines corresponding to 14.5% of total sales in DDD. Twenty-eight drugs have AG corresponding to 375.2 million DDD. Pantoprazole, lansoprazole, omeprazole, clopidogrel, and metoprolol constituted fifty-eight percent of the consumption in DDD of drugs having AG. The consumption of antidepressant drugs, opioids, and antipsychotic drugs were 157.0 million DDD; with 441,850 users, 48.9 million DDD; with 427,765 users, and 23.7 million DDD; with 128,935 users, respectively. Age distributions of consumption of drugs and drug combinations, e.g., for sertraline redeemed either alone or in combination with metoprolol and tramadol, are presented. Conclusion: This exploratory register study clearly showed that a large fraction of the Danish population, especially the elderly, are exposed to drugs or drug combinations for which there exist AG related to PGx of CYP2D6 or CYP2C19.

Interethnic Variability in CYP2D6, CYP2C9, and CYP2C19 Genes and Predicted Drug Metabolism Phenotypes Among 6060 Ibero- and Native Americans: RIBEF-CEIBA Consortium Report on Population Pharmacogenomics.

Pharmacogenetic variation in Latin Americans is understudied, which sets a barrier for the goal of global precision medicine. The RIBEF-CEIBA Network Consortium was established to characterize interindividual and between population variations in CYP2D6, CYP2C9, and CYP2C19 drug metabolizing enzyme genotypes, which were subsequently utilized to catalog their "predicted drug metabolism phenotypes" across Native American and Ibero American populations. Importantly, we report in this study, a total of 6060 healthy individuals from Ibero-America who were classified according to their self-reported ancestry: 1395 Native Americans, 2571 Admixed Latin Americans, 96 Afro-Latin Americans, 287 white Latin Americans (from Cuba), 1537 Iberians, and 174 Argentinean Ashkenazi Jews. Moreover, Native Americans were grouped into North-, Central-, and South Amerindians (from Mexico, Costa Rica, and Peru, respectively). All subjects were studied for the most common and functional CYP2D6, CYP2C9, and CYP2C19 allelic variants, and grouped as genotype-predicted poor or ultrarapid metabolizer phenotypes (gPMs and gUMs, respectively). Native Americans showed differences from each ethnic group in at least two alleles of CYP2D6, CYP2C9, and CYP2C19. Native Americans had higher frequencies of wild-type alleles for all genes, and lower frequency of CYP2D6*41, CYP2C9*2, and CYP2C19*17 (p < 0.05). Native Americans also showed less CYP2C19 gUMs than the rest of the population sample. In addition, differences within Native Americans (mostly North vs. South) were also found. The interethnic differences described supports the need for population-specific personalized and precision medicine programs for Native Americans. To the best of our knowledge, this is the largest study carried out in Native Americans and other Ibero-American populations analyzing CYP2D6, CYP2C9, and CYP2C19 genetic polymorphisms. Population pharmacogenomics is a nascent field of global health and warrants further research and education.

CYP450 Genotype/Phenotype Concordance in Mexican Amerindian Indigenous Populations-Where to from Here for Global Precision Medicine?

Global precision medicine demands characterization of drug metabolism and phenotype variation in diverse populations, including the indigenous societies. A related question is the extent to which CYP450 drug metabolizing enzyme genotype and phenotype data are concordant and whether they can be used interchangeably. These issues are increasingly debated as precision medicine continues to expand as a popular research topic worldwide. We report here the first study in clinically relevant CYP450 drug metabolism phenotypes and genotypes in Mexican Amerindian indigenous subjects. In a large sample of 450 unrelated and medication free Mexican Amerindian indigenous healthy persons from four Mexican states (Chihuahua, Durango, Nayarit, and Sonora), we performed multiplexed phenotyping for the CYP1A2, CYP2C9, CYP2C19, CYP2D6, and CYP3A4 drug metabolizing enzymes using the CEIBA cocktail and genotyped the same pathways for functional polymorphic variation. Remarkable interindividual variability was found for the actual drug metabolizing capacity of all the enzymes analyzed, and, more specifically, the metabolic ratios calculated were significantly different across individuals with different number of active alleles for CYP2C9, CYP2C19, and CYP2D6. The drug metabolizing capacity "predicted" from the genotype determined was not in accordance with the actual capacity "measured" by phenotyping in several individuals for CYP2C9, CYP2C19, and CYP2D6. Consequently, a more extensive genotyping of the main CYP enzymes, including rare variants, together with the analysis of the actual drug metabolizing capacity using an appropriate phenotyping approach will add valuable information for accurate drug metabolism studies, especially useful in understudied populations such as Mexican Amerindians. In sum, this study demonstrates that current personalized medicine strategies based on "predicted" phenotype from genotyping of alleles with high frequency in European populations are not adequate for Mestizos and Native American populations.

The effect of rs5758550 on CYP2D6*2 phenotype and formation of endoxifen in breast cancer patients using tamoxifen.

CYP2D6*2 is considered fully active, but it has been suggested that it only happens in the presence of rs5758550. This study aims to elucidate the impact of this enhancer. DNA and blood samples from women enrolled in the CYPTAM study (NTR1509) were analyzed. Fourteen CYP2D6*2 carriers without the enhancer were reclassified. The relationship of CYP2D6 phenotypes and drug levels was studied. After correction for the absence of the enhancer, the correlation between CYP2D6 phenotypes and endoxifen did not improve (R2: 0.290 vs 0.279). No difference was observed in mean concentrations between CYP2D6*2 individuals with and without the enhancer. The rs5758550 enhancer does not lead to improved prediction of endoxifen levels in breast cancer patients.

Integrated safety analysis of rolapitant with coadministered drugs from phase II/III trials: an assessment of CYP2D6 or BCRP inhibition by rolapitant

BackgroundRolapitant, a long-acting neurokinin (NK)1 receptor antagonist (RA), has demonstrated efficacy in prevention of chemotherapy-induced nausea and vomiting in patients administered moderately or highly emetogenic chemotherapy. Unlike other NK1 RAs, rolapitant does not inhibit or induce cytochrome P450 (CYP) 3A4, but it does inhibit CYP2D6 and breast cancer resistance protein (BCRP). To analyze potential drug–drug interactions between rolapitant and concomitant medications, this integrated safety analysis of four double-blind, randomized phase II or III studies of rolapitant examined adverse events (AEs) by use versus non-use of drug substrates of CYP2D6 or BCRP.Patients and methodsPatients were randomized to receive either 180 mg oral rolapitant or placebo ∼1–2 h before chemotherapy in combination with a 5-hydroxytryptamine type 3 RA and dexamethasone. Data for treatment-emergent AEs (TEAEs) and treatment-emergent serious AEs (TESAEs) during cycle 1 were pooled across the four studies and summarized in the overall population and by concomitant use/non-use of CYP2D6 or BCRP substrate drugs.ResultsIn the integrated safety population, 828 of 1294 patients (64%) in the rolapitant group and 840 of 1301 patients (65%) in the control group experienced at least one TEAE. Frequencies of common TEAEs were similar in the rolapitant and control populations. Overall, 53% of patients received CYP2D6 substrate drugs, none of which had a narrow therapeutic index (like thioridazine or pimozide), and 63% received BCRP substrate drugs. When grouped by concomitant use versus non-use of CYP2D6 or BCRP substrate drugs, TEAEs and TESAEs occurred with similar frequency in the rolapitant and control populations.ConclusionsThe results of this study support the safety of rolapitant as part of an antiemetic triple-drug regimen in patients receiving emetogenic chemotherapy, including those administered concomitant medications that are substrates of CYP2D6 or BCRP, such as ondansetron, docetaxel, or irinotecan.

Computational Analysis of Physicochemical Factors Driving CYP2D6 Ligand Interaction.

The metabolic action of CYP2D6 remains a crucial factor influencing the therapeutic outcomes for many drug molecules while others are either only slightly affected or not affected altogether. This study seeks to understand, atomistic resolution, the structural and physicochemical factors influencing CYP2D6 metabolic discrimination. Explicit solvent molecular dynamics simulations in GROMACS were employed to probe the conformational dynamics of CYP2D6 following which the most populated structures were employed for ligand interaction docking studies with AutoDock Vina using selected CYP2D6 drug substrates. Using atomistic treatment at the molecular mechanics level and multiple CYP2D6 conformations for docking, two primary ligand binding subsites (subsites A and B) were identified within an otherwise extensive ligand recognition site. The studied drug molecules were found to display distinct preference for either of the two subsites. Correlation and center-of-mass distribution analysis showed subsite binding preference to depend significantly on CYP2D6 conformation, as well as molecular properties such as molecular size and number of hydrogen bond donor present in the drug molecule. CYP2D6 binding subsite A was found to be relatively selective for small molecular weight with higher polarity compared with subsite B which tends to favor larger molecular weight and relatively hydrophobic molecules such as tamoxifen and imipramine. Our simulations further suggest that the ability of the CYP2D6 binding site residues to sample different conformations may partly account for its ability to metabolize diverse drug classes.

Pharmacogenetics of Antidepressants, A Review of Significant Genetic Variants in Different Populations

Major depressive disorder is a highly prevalent disease that is challenging to treat, often requiring medication and dose adjustments. Genetic factors play an important role in psychotropic medication responses. However, the translation of pharmacogenetics findings to clinical recommendations with regards to antidepressant responses is still in its early stages. We reviewed recent primary research articles, meta-analyses, and reviews on the pharmacogenetics of antidepressant treatment for major depressive disorder in different populations. We identified eight genes with likely associations with treatment responses and summarized genetic variants most likely to influence treatment responses. We determined the frequency of these variants in Caucasian, Asian, Hispanic, and African American populations. The genes are related to functions in drug metabolism, transport, signalling, stress response, and neuroplasticity. Clinical recommendations already exist for CYP2D6 and CYP2C19 cytochrome P450 drug metabolism genes. The other genes are: ABCB1 with single nucleotide polymorphisms (SNPs) rs2032583 and rs2235015; FKBP5 with SNPs rs1360780, rs3800373, and rs4713916; GNB3 with SNP rs5443; BDNF with SNP rs6265; HTR2A with SNPs rs7997012 and rs6313; and SLC6A4 with polymorphisms 5-HTTLPR and STin2. There is significant variability of the frequencies of these polymorphisms in the different populations we reviewed. There is also variability in the antidepressant responses between populations carrying the same polymorphism in some cases, indicating a likely polygenic influence. Future studies in the pharmacogenetics of antidepressants would benefit from including more subjects from underrepresented ethnic groups and stratifying results.

Pharmacogenetic comparison of CYP2D6 predictive and measured phenotypes in a South African cohort.

The relationship between genetic variation in CYP2D6 and variable drug response represents a potentially powerful pharmacogenetic tool. However, little is known regarding this relationship in the genetically diverse South African population. The aim was therefore to evaluate the relationship between predicted and measured CYP2D6 phenotype. An XL-PCR+Sequencing approach was used to determine CYP2D6 genotype in 100 healthy volunteers and phenotype was predicted using activity scores. With dextromethorphan as the probe drug, metabolic ratios served as a surrogate measure of in vivo CYP2D6 activity. Three-hour plasma metabolic ratios of dextrorphan/dextromethorphan were measured simultaneously using semi-automated online solid phase extraction coupled with tandem mass spectrometry. Partial adaptation of the activity score system demonstrated a strong association between genotype and phenotype, as illustrated by a kappa value of 0.792, inter-rater discrepancy of 0.051 and sensitivity of 72.7%. Predicted phenotype frequencies using the modified activity score were 1.3% for poor metabolisers (PM), 7.6% for intermediate metabolisers (IM) and 87.3% for extensive metabolisers (EM). Measured phenotype frequencies were 1.3% for PM, 13.9% for IM and 84.8% for EM. Comprehensive CYP2D6 genotyping reliably predicts CYP2D6 activity in this South African cohort and can be utilised as a valuable pharmacogenetic tool.

Limited predictive value of achieving beneficial plasma (Z)-endoxifen threshold level by CYP2D6 genotyping in tamoxifen-treated Polish women with breast cancer.

BackgroundTamoxifen, the most frequently used drug for treating estrogen receptor-positive breast cancer, must be converted into active metabolites to exert its therapeutic efficacy, mainly through CYP2D6 enzymes. The objective of this study was to investigate the impact of CYP2D6 polymorphisms on (Z)-endoxifen-directed tamoxifen metabolism and to assess the usefulness of CYP2D6 genotyping for identifying patients who are likely to have insufficient (Z)-endoxifen concentrations to benefit from standard therapy.MethodsBlood samples from 279 Polish women with breast cancer receiving tamoxifen 20 mg daily were analyzed for CYP2D6 genotype and drug metabolite concentration. Steady-state plasma levels of tamoxifen and its 14 metabolites were measured by using the ultra-performance liquid chromatography tandem mass spectrometry (UPLC-MS/MS) method.ResultsIn nearly 60 % of patients, including over 30 % of patients with fully functional CYP2D6, (Z)-endoxifen concentration was below the predefined threshold of therapeutic efficacy. The most frequently observed CYP2D6 genotype was EM/PM (34.8 %), among which 83.5 % of patients had a combination of wild-type and *4 alleles. Plasma concentration of five metabolites was significantly correlated with CYP2D6 genotype. For the first time, we identified an association between decreased (E/Z)-4-OH-N-desmethyl-tamoxifen-β-D-glucuronide levels (r2 = 0.23; p < 10−16) and increased CYP2D6 functional impairment. The strongest correlation was observed for (Z)-endoxifen, whose concentration was significantly lower in groups of patients carrying at least one CYP2D6 null allele, compared with EM/EM patients. The CYP2D6 genotype accounted for plasma level variability of (Z)-endoxifen by 27 % (p < 10−16) and for the variability of metabolic ratio indicating (Z)-endoxifen-directed metabolism of tamoxifen by 51 % (p < 10−43).ConclusionsThe majority of breast cancer patients in Poland may not achieve a therapeutic level of (Z)-endoxifen upon receiving a standard dose of tamoxifen. This finding emphasizes the limited value of CYP2D6 genotyping in routine clinical practice for identifying patients who might not benefit from the therapy. In its place, direct monitoring of plasma steady-state (Z)-endoxifen concentration should be performed to personalize and optimize the treatment.Electronic supplementary materialThe online version of this article (doi:10.1186/s12885-015-1575-4) contains supplementary material, which is available to authorized users.

Characterization of the CYP2D6 drug metabolizing phenotypes of the Chilean mestizo population through polymorphism analyses

We tested the influence of four polymorphisms and gene duplication in CYP2D6 on in vivo enzyme activity in a Chilean mestizo population in order to identify the most relevant genetic profiles that account for observed phenotypes in this ethnic group.CYP2D6*2 (2850C>T), *3 (2549A>del), *4 (1846G>A), *17 (1023C>T) and gene duplication were determined by PCR-RFLP or PCRL in a group of 321 healthy volunteers. Individuals with different variant alleles were phenotyped by determining debrisoquine 4-hydroxylase activity as a metabolic ratio (MR) using a validated HPLC assay.Minor allele frequencies were 0.41, 0.01, 0.12 and 0.00 for CYP2D6*2, *3, *4 and *17 variants, respectively, and the duplication frequency was 0.003. Genotype analysis correlated with phenotypes in 18 of 23 subjects (78.3%). 11 subjects were extensive metabolizers (EM), 8 were intermediate metabolizers (IM), 2 were poor metabolizers (PM) and 2 were ultra-rapid metabolizers (UM) which is fairly coincident with expected phenotypes metabolic ratios ranged from 0.11 to 126.41. The influence of CYP2D6*3 was particularly notable, although only heterozygote carriers were present in our population. Individuals homozygous for *4 were always PM. As expected, the only subject with gene duplication was UM.In conclusion, there was a clear effect of genotype on observed CYP2D6 activity. Classification of EM, PM and UM through genotyping was useful to characterize CYP2D6 phenotype in the Chilean mestizo population.

The influences of CYP2D6 genotypes and drug interactions on the pharmacokinetics of venlafaxine: exploring predictive biomarkers for treatment outcomes.

Two biomarkers: concentration ratio of O-desmethylvenlafaxine/venlafaxine and concentration sum of venlafaxine + O-desmethylvenlafaxine were adopted to indicate venlafaxine responses, but neither is validated. To evaluate the ability of two biomarkers in reflecting venlafaxine pharmacokinetic variations, and to further examine their relationship with venlafaxine treatment outcomes. Two well-defined influencing factors: CYP2D6 genotypes and drug interactions were enriched into a three-period crossover study to produce venlafaxine pharmacokinetic variations: In each period, healthy CYP2D6 extensive metabolizers (EM group; n = 12) and CYP2D6*10/*10 intermediate metabolizers (IM group; n = 12) were pretreated with clarithromycin (CYP3A4 inhibitor), or nothing (control), or clarithromycin + paroxetine (CYP3A4 + CYP2D6 inhibitors), before administration of a single-dose of 75mg venlafaxine. Both biomarkers were evaluated (1) for their relationship with the influencing factors in healthy volunteers and (2) for their relationships with the venlafaxine responses/adverse events reported in two patient studies. Significant venlafaxine pharmacokinetic variations were observed between the EM and IM groups (geometric mean ratio [95% CI] of area under the curve, 3.0 [1.8-5.1] in the control period), and between the control and clarithromycin + paroxetine periods (4.1 [3.5-4.7] and 2.0 [1.7-2.4] in the EM and IM group, respectively). O-Desmethylvenlafaxine/venlafaxine was superior to venlafaxine + O-desmethylvenlafaxine to reflect the influencing factors. In the patient studies, O-desmethylvenlafaxine/venlafaxine > 4 showed high precision in predicting venlafaxine responders/partial-responders (92%) and patients without venlafaxine-related adverse events (88%); the O-desmethylvenlafaxine/venlafaxine < 4 and venlafaxine + O-desmethylvenlafaxine > 400ng/ml combination showed higher precision (100%) than O-desmethylvenlafaxine/venlafaxine < 4 alone (65%) in predicting venlafaxine non-responders. We propose using O-desmethylvenlafaxine/venlafaxine for CYP2D6 phenotyping, and O-desmethylvenlafaxine/venlafaxine with venlafaxine + O-desmethylvenlafaxine for predicting venlafaxine treatment outcomes in future prospective studies.

The effect of CYP2D6 drug-drug interactions on hydrocodone effectiveness.

The hepatic cytochrome 2D6 (CYP2D6) is a saturable enzyme responsible for metabolism of approximately 25% of known pharmaceuticals. CYP interactions can alter the efficacy of prescribed medications. Hydrocodone is largely dependent on CYP2D6 metabolism for analgesia, ondansetron is inactivated by CYP2D6, and oxycodone analgesia is largely independent of CYP2D6. The objective was to determine if CYP2D6 medication coingestion decreases the effectiveness of hydrocodone. This was a prospective observational study conducted in an academic U.S. emergency department (ED). Subjects were included if they had self-reported pain or nausea and were excluded if they were unable to speak English, were less than 18 years of age, had liver or renal failure, or carried diagnoses of chronic pain or cyclic vomiting. Detailed drug ingestion histories for the preceding 48 hours prior to the ED visit were obtained. The patient's pain and nausea were quantified using a 100-mm visual analog scale (VAS) at baseline prior to drug administration and following doses of hydrocodone, oxycodone, or ondansetron. We used a mixed model with random subject effect to determine the interaction between CYP2D6 drug ingestion and study drug effectiveness. Odds ratios (ORs) were calculated to compare clinically significant VAS changes between CYP2D6 users and nonusers. A total of 250 (49.8%) of the 502 subjects enrolled had taken at least one CYP2D6 substrate, inhibitor, or inducing pharmaceutical, supplement, or illicit drug in the 48 hours prior to ED presentation. CYP2D6 drug users were one-third as likely to respond to hydrocodone (OR = 0.33, 95% confidence interval [CI] = 0.1 to 0.8) and more than three times as likely as nonusers to respond to ondansetron (OR = 3.4, 95% CI = 1.3 to 9.1). There was no significant difference in oxycodone effectiveness between CYP2D6 users and nonusers (OR = 0.53, 95% CI = 0.3 to 1.1). CYP2D6 drug-drug interactions appear to change effectiveness of commonly prescribed drugs in the ED. Drug-drug interaction should be considered prior to prescribing CYP2D6 drugs.

PP138—Analysis of CYP2D6 genetic polymorphisms in mexican mestizos, lacandones and tzeltales

More than 80 allelic variants have been described for CYP2D6 that result in poor (PM), efficient or extensive (EM) and ultrarapid (UM) metabolizers of CYP2D6 drug substrates. The distribution of PMs, Ems, and UMs varies markedly among human populations; however, it has been particularly difficult to determine in countries with wide ethnic diversity. Currently, the Mexican population is composed of Mestizos (≈90%) and >85 different ethno linguistic indigenous populations (Mexican-Amerindians). Lacandones and Tzeltales are Mexican indigenous individuals that inhabit the state of Chiapas.