Polymorphisms Of Cytochrome P450 Enzymes Research Articles

Association of Polymorphic Cytochrome P450 Enzyme Pathways with Falls in Multimedicated Older Adults

ObjectivesDose exposure is considered relevant for drug-associated falls in older adults, pointing to an importance of drug metabolism. Aim was to analyze individual factors altering drug metabolism such as enzyme saturation by drug exposure and pharmacogenetics in the context of drug-associated falls. DesignProspective population-based study (ActiFE-Ulm study). Setting and ParticipantsCommunity-dwelling older adults. MethodsFocus was laid on the metabolism by polymorphic cytochrome P450 (CYP) enzymes CYP2C19, 2C9, and 2D6. Relevant variants of pharmacogenes were analyzed. Logistic binary regression analysis was used to calculate odds ratios (ORs) and 95% CIs for falls observed prospectively over a 1-year period with drug metabolism characteristics. ResultsIn total, 1377 participants were included in the analysis. Although the phenotype predicted by the genotype was not, the use of drugs metabolized by CYP2C19 was associated with falls. Drugs not known as fall risk–increasing drugs (FRIDs; ie, non-FRIDs), but metabolized by CYP2C19, showed an OR of 1.46 (1.11-1.93) in adjusted analysis. Significant effect modification was observed for a reduced CYP2C19 activity phenotype with non-FRIDs metabolized by CYP2C19. Conclusions and ImplicationsThis study suggests an association between the occurrence of falls in older adults and the metabolic capacity of CYP2C19. Thus, an important step toward prevention of falls might be to personalize dosage and treatment length of the main drug classes known to be CYP2C19 substrates, such as many antidepressants, opioids, and sedatives, but also proton pump inhibitors in particular in poor and intermediate metabolizers.

Assessment of Substrate Status of Drugs Metabolized by Polymorphic Cytochrome P450 (CYP) 2 Enzymes: An Analysis of a Large-Scale Dataset.

The analysis of substrates of polymorphic cytochrome P450 (CYP) enzymes is important information to enable drug-drug interactions (DDIs) analysis and the relevance of pharmacogenetics in this context in large datasets. Our aim was to compare different approaches to assess the substrate properties of drugs for certain polymorphic CYP2 enzymes. A standardized manual method and an automatic method were developed and compared to assess the substrate properties for the metabolism of drugs by CYP2D6, 2C9, and 2C19. The automatic method used a matching approach to three freely available resources. We applied the manual and automatic methods to a large real-world dataset deriving from a prospective multicenter study collecting adverse drug reactions in emergency departments in Germany (ADRED). In total, 23,878 medication entries relating to 895 different drugs were analyzed in the real-world dataset. The manual method was able to assess 12.2% (n = 109) of drugs, and the automatic method between 12.1% (n = 109) and 88.9% (n = 796), depending on the resource used. The CYP substrate classifications demonstrated moderate to almost perfect agreements for CYP2D6 and CYP2C19 (Cohen's Kappa (κ) 0.48-0.90) and fair to moderate agreements for CYP2C9 (κ 0.20-0.48). A closer look at different classifications between methods revealed that both methods are prone to error in different ways. While the automated method excels in time efficiency, completeness, and actuality, the manual method might be better able to identify CYP2 substrates with clinical relevance.

Effect of genetic polymorphisms on the pharmacokinetics of gefitinib in healthy Chinese volunteers

Gefitinib is the first-generation drug of epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) metabolised by the cytochrome P450 and transported by P-glycoprotein (ABCB1) and breast cancer resistance protein (ABCG2). In the present study, the pharmacokinetics of gefitinib in healthy Chinese volunteers was investigated and the effect of genetic polymorphisms on its variability was evaluted. Forty-five healthy volunteers were administered a single dose of gefitinib and the blood samples were used for quantifying the concentration of gefitinib and genotyping fifteen single-nucleotide polymorphisms of cytochrome P450 enzymes (CYP3A4, CYP3A5, CYP2D6, CYP2C9 and CYP2C19) and drug transporters (ABCB1 and ABCG2). CYP3A5*3 (rs776746) polymorphism showed a significant influence, with higher gefitinib AUC0-t in carrier of CC genotype than in CT/TT genotype (BH-adjusted p value <0.05). For CYP2C9*3 (rs1057910), significant differences in pharmacokinetics of gefitinib were detected between carriers of AA and AC genotypes, with higher AUC0-t, AUC0-∞ and Cmax in carrier of AC genotype than in AA gen-otype (BH-adjusted p value <0.05). No associations were found between SNPs in CYP3A4, CYP2D6, CYP2C19, ABCB1, ABCG2 and the pharmacokinetics of gefitinib. The SNPs in CYP3A5*3 (rs776746) and CYP2C9*3 (rs1057910) were found to be associated with altered gefitinib pharmacokinetics in healthy Chinese volunteers.

Whole blood hydroxychloroquine: Does genetic polymorphism of cytochrome P450 enzymes have a role?

Systemic lupus erythematosus (SLE) is a chronic autoimmune disease with a wide range of clinical manifestations and multifactorial etiologies ranging from environmental to genetic. SLE is associated with dysregulated immunological reactions, with increased immune complex formation leading to end-organ damages such as lupus nephritis, cutaneous lupus, and musculoskeletal disorders. Lupus treatment aims to reduce disease activity, prevent organ damage, and improve long-term patient survival and quality of life. Antimalarial, hydroxychloroquine (HCQ) is used as a first-line systemic treatment for lupus. It has shown profound efficacy in lupus and its associated conditions. However, wide variation in terms of clinical response to this drug has been observed among this group of patients. This variability has limited the potential of HCQ to achieve absolute clinical benefits. Several factors, including genetic polymorphisms of cytochrome P450 enzymes, have been stipulated as key entities leading to this inter-individual variation. Thus, there is a need for more studies to understand the role of genetic polymorphisms in CYP450 enzymes in the clinical response to HCQ. Focusing on the role of genetic polymorphism on whole blood HCQ in lupus disorder, this review aims to highlight up-to-date pathophysiology of SLE, the mechanism of action of HCQ, and finally the role of genetic polymorphism of CYP450 enzymes on whole blood HCQ level as well as clinical response in lupus.

Utilization of Pharmacogenomics in Assessment of Tolerability and Efficacy of BTK Inhibitors

Background: Oral inhibitors of Bruton's tyrosine kinase (BTKi) are used for a number of B-cell malignancies, including chronic lymphocytic leukemia (CLL), mantle cell lymphoma (MCL), marginal zone lymphoma (MZL) and Waldenstrom's macroglobulinemia/lymphoplasmacytic lymphoma (WM/LPL). Despite excellent hematologic responses often seen with this class of medications, discontinuation may occur due to progression or intolerable side effects. It is not fully understood why some patients develop adverse events and discontinue BTKi therapy. A previous study suggested and association between intolerance to BTKi or phosphoinositide 3-kinase (PI3K) inhibitors in CLL patients with genetic polymorphisms in cytochrome P450 enzymes. Polymorphisms in CYP3A and CYP2D6 affect the metabolism of these agents and may lead to higher-than-expected plasma levels, leading to more adverse events. We therefore evaluated the results of pharmacogenomic testing in Veterans treated with BTKi to determine the extent to which pharmacogenomics polymorphisms are associated with response and intolerance to BTKi therapy. Methods: We identified Veterans receiving care through the Veterans Administration (VA) who were prescribed a BTKi and had undergone pharmacogenetic testing through the Pharmacogenomic Testing for Veterans (PHASER) program, currently offered to veterans at 22 sites across the United States. We retrospectively analyzed clinical factors including time on BTKi, reasons for temporary or permanent discontinuation or dose changes, medical comorbidities, and grade of pertinent side effects associated with BTKi (arrhythmia, hypertension, bleeding, fatigue, arthralgias, rash, diarrhea) as well as use of concomitant medications known to interact with CYP3A or CYP2D6. Results: A total of 61 Veterans were identified, of which 97% (59) were male and 72% (44) were diagnosed with CLL. Of the remaining patients, three were diagnosed with MCL, three with WM/LPL, two with refractory diffuse large B cell lymphoma (DLBCL), one with MZL, and one with monoclonal gammopathy and cold agglutinin disease. Forty-three patients (70.5%) were prescribed ibrutinib, while eight were prescribed acalabrutinib and two zanubrutinib. Twelve patients (20%) permanently discontinued therapy due to intolerance and eight patients (13%) progressed. Another 10 patients temporarily discontinued therapy due to side effects or infection. Median time treated with BTKi was 6.7 months for patients discontinuing for intolerance, 30.1 months for those discontinuing for progression, and 32.9 months for those not requiring discontinuation. The majority of patients who either temporarily or permanently discontinued therapy did so due to new arrhythmia (10 patients), while other complications included infection, pancytopenia, arthralgias, and fatigue. Nearly half of patients were concurrently taking another medication also metabolized through the CYP3A or CYP2D6. Of the 20 patients who progressed or were intolerant of BTKi, 14 (70%) were identified as CYP3A5 poor metabolizers, while 6 (30%) exhibited CYP2D6 intermediate metabolizing function. In comparison, of patients who did not discontinue BTKi, 31 patients (76%) were CYP3A5 poor metabolizers and 11 patients (27%) were CYP2D6 intermediate metabolizers. Conclusions: In our cohort of patients with B cell malignancies who were prescribed BTKi, we identified those who discontinued either due to intolerable side effects or progression at a rate lower than previously reported in the Veteran population. We identified patient with pharmacogenomics polymorphisms that can affect plasma drug levels and are evaluating concurrent use of medication with can affect BTKi metabolism, as well as their effect on time to therapy discontinuation and adverse events. These results will inform the personalized selection of BTKi therapy for patients with B cell malignancies.

Pharmacogenetic and drug interaction aspects on ketamine safety in its use as antidepressant ‐ implications for precision dosing in a global perspective

Ketamine and its enantiomer S-ketamine (esketamine) are known to produce rapid-onset antidepressant effects in major depression. Intranasal esketamine has recently come onto the market as an antidepressant. Besides experience from short-term use in anaesthesia and analgesia, the experience with ketamine as long-term medication is rather low. The use of ketamine and esketamine is limited due to potential neurotoxicity, psychotomimetic side effects, potential abuse and interindividual variability in treatment response including cessation of therapy. Therefore, taking a look at individual patient risks and potential underlying variability in pharmacokinetics may improve safety and dosing of these new antidepressant drugs in clinical practice. Differential drug metabolism due to polymorphic cytochrome P450 (CYP) enzymes and gene-drug interactions are known to influence the efficacy and safety of many drugs. Ketamine and esketamine are metabolized by polymorphic CYP enzymes including CYP2B6, CYP3A4, CYP2C9 and CYP2A6. In antidepressant drug therapy, usually multiple drugs are administered which are substrates of CYP enzymes, increasing the risk for drug-drug interactions. We reviewed the potential impact of polymorphic CYP variants and common drug-drug interactions in antidepressant drug therapy affecting ketamine pharmacokinetics, and the role for dose optimization. The use of ketamine or intranasal esketamine as antidepressants demands a better understanding of the factors that may impact its metabolism and efficacy in long-term use. In addition to other clinical and environmental confounders, prior information on the pharmacodynamic and pharmacokinetic determinants of response variability to ketamine and esketamine may inform on dose optimization and identification of individuals at risk of adverse drug reactions.

Association between genetic polymorphisms in cytochrome P450 enzymes and survivals in women with breast cancer receiving adjuvant endocrine therapy: a systematic review and meta-analysis.

Tamoxifen is commonly prescribed for preventing recurrence in patients with breast cancer. However, the responses of the patients on tamoxifen treatment are variable. Cytochrome P450 genetic variants have been reported to have a significant impact on the clinical outcomes of tamoxifen treatment but no tangible conclusion can be made up till now. The present review attempts to provide a comprehensive review on the associative relationship between genetic polymorphisms in cytochrome P450 enzymes and survival in breast cancer patients on adjuvant tamoxifen therapy. The literature search was conducted using five databases, resulting in the inclusion of 58 studies in the review. An appraisal of the reporting quality of the included studies was conducted using the assessment tool from the Effective Public Health Practice Project (EPHPP). Meta-analyses were performed on CYP2D6 studies using Review Manager 5.3 software. For other studies, descriptive analyses were performed. The results of meta-analyses demonstrated that shorter overall survival, disease-free survival and relapse-free survival were found in the patients with decreased metabolisers when compared to normal metabolisers. The findings also showed that varying and conflicting results were reported by the included studies. The possible explanations for the variable results are discussed in this review.

Effect of Genetic Variation in CYP450 on Gonadal Impairment in a European Cohort of Female Childhood Cancer Survivors, Based on a Candidate Gene Approach: Results from the PanCareLIFE Study.

Simple SummaryChildhood cancer patients receiving treatment containing alkylating agents are at risk of infertility, yet inter-individual variability in treatment-related ovarian damage is observed. Alkylating agents are metabolized by cytochrome P450 (CYP450) enzymes and polymorphisms in these CYP450 enzymes may explain this variability in ovarian damage. This study on genetic variation in CYP450 enzymes of chemotherapy-induced gonadotoxicity, using anti-Müllerian hormone (AMH) levels as a proxy for ovarian reserve, in female childhood cancer survivors (CCSs) may identify patients at risk of infertility. This unique global collaboration of two large CCS studies shows the significant gonadotoxic effect of enzyme CYP3A4*3 and significant protective effect of CYP2B6*2 on gonadal function in CCSs receiving alkylating agents. Genetic variation in CYP3A4 and CYP2B6 have previously been associated with gonadotoxicity after cancer treatment. These findings could guide risk prediction models determining patients at risk of chemotherapy-induced gonadal impairment.Background: Female childhood cancer survivors (CCSs) carry a risk of therapy-related gonadal dysfunction. Alkylating agents (AA) are well-established risk factors, yet inter-individual variability in ovarian function is observed. Polymorphisms in CYP450 enzymes may explain this variability in AA-induced ovarian damage. We aimed to evaluate associations between previously identified genetic polymorphisms in CYP450 enzymes and AA-related ovarian function among adult CCSs. Methods: Anti-Müllerian hormone (AMH) levels served as a proxy for ovarian function in a discovery cohort of adult female CCSs, from the pan-European PanCareLIFE cohort (n = 743; age (years): median 25.8, interquartile range (IQR) 22.1–30.6). Using two additive genetic models in linear and logistic regression, nine genetic variants in three CYP450 enzymes were analyzed in relation to cyclophosphamide equivalent dose (CED) score and their impact on AMH levels. The main model evaluated the effect of the variant on AMH and the interaction model evaluated the modifying effect of the variant on the impact of CED score on log-transformed AMH levels. Results were validated, and meta-analysis performed, using the USA-based St. Jude Lifetime Cohort (n = 391; age (years): median 31.3, IQR 26.6–37.4). Results: CYP3A4*3 was significantly associated with AMH levels in the discovery and replication cohort. Meta-analysis revealed a significant main deleterious effect (Beta (95% CI): −0.706 (−1.11–−0.298), p-value = 7 × 10−4) of CYP3A4*3 (rs4986910) on log-transformed AMH levels. CYP2B6*2 (rs8192709) showed a significant protective interaction effect (Beta (95% CI): 0.527 (0.126–0.928), p-value = 0.01) on log-transformed AMH levels in CCSs receiving more than 8000 mg/m2 CED. Conclusions: Female CCSs CYP3A4*3 carriers had significantly lower AMH levels, and CYP2B6*2 may have a protective effect on AMH levels. Identification of risk-contributing variants may improve individualized counselling regarding the treatment-related risk of infertility and fertility preservation options.

Polymorphisms at CYP enzymes, NR1I2 and NR1I3 in association with virologic response to antiretroviral therapy in Brazilian HIV-positive individuals.

Virologic failure of antiretroviral therapy (ART) may be explained by single nucleotide polymorphisms (SNPs) in drug absorption and metabolism genes. Here, we characterized the associations between polymorphisms in cytochrome P450 enzymes' genes CYP2B6 and CYP3A4/A5, nuclear receptor genes NR1I2/3, and initial ART efficacy among 203 HIV-positive individuals from Rio de Janeiro. Association between SNPs and virologic control was evaluated after 6 and 12 months of follow-up using Cox regression models. The SNP rs2307424 (NR1I3) was associated with increased virologic response after 12 months of treatment, while rs1523127 (NR1I2), rs3003596, and rs2502815 (NR1I3) were associated with decreased response. Increased virologic response after 12 months (adjHR = 1.54; p = 0.02) was also observed among carriers of the NR1I3 haplotype rs2502815G-rs3003596A-rs2307424A versus the reference haplotype G-A-G. Our results suggest that NR1I2 and NR1I3 variants are associated with virologic responses to ART among Brazilians.

Tapentadol Versus Tramadol: A Narrative and Comparative Review of Their Pharmacological, Efficacy and Safety Profiles in Adult Patients.

We conducted a narrative review of the literature to compare the pharmacological, efficacy and safety profiles of tapentadol and tramadol, and to assess the clinical interest of tapentadol in adult patients. Tapentadol and tramadol share a mixed mechanism of action, including both mu-agonist and monoaminergic properties. Tapentadol is approximately two to three times more potent than tramadol and two to three times less potent than morphine. It has no identified analgesically active metabolite and is not significantly metabolised by cytochrome P450 enzymes, thus overcoming some limitations of tramadol, including the potential for pharmacokinetic drug-drug interactions and interindividual variability due to genetic polymorphisms of cytochrome P450 enzymes. The toxicity profiles of tramadol and tapentadol are similar; however tapentadol is likely to result in less exposure to serotoninergic adverse effects (nausea, vomiting, hypoglycaemia) but cause more opioid adverse effects (constipation, respiratory depression, abuse) than tramadol. The safety of tapentadol in real-world conditions remains poorly documented, particularly in at-risk patient subgroups and also in the ability to assess the risk associated with its residual serotonergic activity (serotonin syndrome, seizures). Because of an earlier market introduction, more real-world safety data are available for tramadol, including data from at-risk patient subgroups. The level of evidence on the efficacy of both tramadol and tapentadol for the treatment of chronic pain is globally low. The trials published to date show overall that tapentadol does not provide a clinically significant analgesic improvement compared to existing treatments, for which the safety profile is much better known. In conclusion, tapentadol is not a first-line opioid but represents an additional analgesic in the therapeutic choices, which some patients may benefit from after careful examination of their clinical situation, co-morbidities and co-medications.

Validation of a Population Pharmacokinetic Model of Vortioxetine Using Therapeutic Drug Monitoring Data.

IntroductionVortioxetine is an antidepressant primarily metabolized by the polymorphic enzyme cytochrome P450 (CYP) 2D6. A population pharmacokinetic (popPK) model of vortioxetine and its CYP2D6-dependent metabolite was recently published.ObjectiveThe aim of the current study was to assess the predictive performance of the popPK model using vortioxetine concentration measurements from a clinical setting. Furthermore, the study aimed to evaluate the ability of different CYP2D6 phenotype classification systems to provide accurate concentration predictions.MethodsOverall, 1388 patients receiving vortioxetine treatment were identified from a therapeutic drug monitoring (TDM) database in Oslo, Norway; 334 CYP2D6-genotyped patients with 502 serum concentrations of vortioxetine, analysed by a validated ultra-high-performance liquid chromatography–high-resolution mass spectrometry (UHPLC-HRMS) method, were retrospectively included. The performance of the vortioxetine popPK model was tested on the clinical data from the TDM database.ResultsOverall, the model had a good ability to predict vortioxetine concentrations measured in clinical practice, with a slight tendency to overpredict concentrations. Using simulation-based diagnostics, 76% of the prediction-corrected TDM concentrations were within the 90% prediction interval based on 1000 simulated data sets. Prediction-based diagnostics showed the best performance for CYP2D6 poor and ultrarapid metabolizers, with a median prediction error (MDPE) of 12% and 23%, respectively, while the poorest performance was observed for normal metabolizers, with an MDPE of 66%. In the comparison of different CYP2D6 phenotype classification systems, the use of differentiated activity scores for decreased function alleles did not improve the concentration predictions. Grouping the CYP2D6 genotypes into the four conventional phenotype groups provided predictions closest to the TDM measured concentrations.ConclusionTDM data provide a unique insight into real-world clinical practice with vortioxetine. The tendency of the popPK model to overpredict vortioxetine concentrations measured in TDM may be attributed to several factors, including poor treatment compliance for some patients and, to a lesser extent, lack of information on patient characteristics and misspecified CYP2D6 alleles. To optimize personalized therapy with vortioxetine, real-world clinical data sets originating from different ethnicities need to be studied in the future.Supplementary InformationThe online version contains supplementary material available at 10.1007/s40262-021-01029-7.

Association of single nucleotide polymorphisms of cytochrome P450 enzymes with experience of vasomotor, vaginal and musculoskeletal symptoms among breast cancer patients: a systematic review

BackgroundAdjuvant endocrine therapies are known to induce undesirable adverse effects such as vasomotor, vaginal and musculoskeletal symptoms among breast cancer patients. Drugs used in these therapies are often metabolised by cytochrome P450 (CYP) enzymes, in which their metabolising activities can be modified by single nucleotide polymorphisms (SNP) in CYP genes and CYP genotypes. This review aims to explore whether SNPs or genotypes of CYP are associated with the occurrence, frequency and severity of vasomotor, vaginal and musculoskeletal symptoms in breast cancer patients on adjuvant endocrine therapies.MethodsA literature review was conducted using five electronic databases, resulting in the inclusion of 14 eligible studies, and their findings were presented narratively. Selected items from the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) checklist were used for critical appraisal of the reporting quality of the included studies.ResultsMost of the included studies showed that SNPs or genotypes of CYP that modify its metabolising activity have no effect on the occurrence, frequency or severity of vasomotor symptoms, including hot flashes. One study showed no correlation of these genetic variations in CYP with musculoskeletal symptoms, and no data were available on the association between such genetic variations and vaginal symptoms.ConclusionsOverall, genetic variations in CYP have no effect on the experience of hot flashes among breast cancer patients. We recommend exploration of the link between the active metabolites of chemotherapeutic drugs and the molecules shown to affect the occurrence or severity of hot flashes, and the establishment of the relationship between such genetic variations and patients’ experience of musculoskeletal and vaginal symptoms. Subgroup analyses based on patients’ duration of adjuvant endocrine therapies in such studies are recommended.

The role of sex, age and genetic polymorphisms of CYP enzymes on the pharmacokinetics of anticholinergic drugs.

There is evidence that use of drugs with anticholinergic properties increases the risk of cognitive impairment, and increased exposure to these drugs potentiates this risk. Anticholinergic drugs are commonly used even with associated risk of adverse events. Aging, sex, and genetic polymorphisms of cytochrome P450 (CYP) enzymes are associated with alterations in pharmacokinetic processes, which increase drug exposure and may further increase the risk of adverse drug events. Due to the increasing burden of cognitive impairment in our aging population and the future of personalized medicine, the objective of this review was to provide a critical clinical perspective on age, sex, and CYP genetic polymorphisms and their role in the metabolism and exposure to anticholinergic drugs. Age‐related changes that may increase anticholinergic drug exposure include pseudocapillarization of liver sinusoidal endothelial cells, an approximate 3.5% decline in CYP content for each decade of life, and a reduction in kidney function. Sex‐related differences that may be influenced by anticholinergic drug exposure include women having delayed gastric and colonic emptying, higher gastric pH, reduced catechol‐O‐methyl transferase activity, reduced glucuronidation, and reduced renal clearance and men having larger stomachs which may affect medication absorption. The overlay of poor metabolism phenotypes for CYP2D6 and CYP2C19 may further modify anticholinergic drug exposure in a significant proportion of the population. These factors help explain findings of clinical trials that show older adults and specifically older women achieve higher plasma concentrations of anticholinergic drugs and that poor metabolizers of CYP2D6 experience increased drug exposure. Despite this knowledge neither age, sex nor CYP phenotype are routinely considered when making decisions about the use or dosing of anticholinergic medications. Future study of anticholinergic medication needs to account for age, sex and CYP polymorphisms so that we may better approach personalized medicine for optimal outcomes and avoidance of medication‐related cognitive impairment.

CYP2D6 Reduced Function Variants and Genotype/Phenotype Translations of CYP2D6 Intermediate Metabolizers: Implications for Personalized Drug Dosing in Psychiatry.

Genetic differences in cytochrome P450 (CYP)-mediated metabolism have been known for several decades. The clinically most important polymorphic CYP enzyme is CYP2D6, which plays a key role in the metabolism of many antidepressants and antipsychotics, along with a range of non-psychiatric medications. Dose individualization based on CYP2D6 genotype to improve the effect and safety of drug treatment has been an ambition for a long time. Clinical use of CYP2D6 genotyping is steadily increasing; however, for pre-emptive genotyping to be successful in predicting individual dose requirements, high precision of genotype-to-phenotype translations are required. Recently, guidelines for assigning CYP2D6 enzyme activity scores of CYP2D6 variant alleles, and subsequent diplotype-to-phenotype translations, were published by the Clinical Pharmacogenetics Implementation Consortium (CPIC) and the Dutch Pharmacogenetics Working Group. Consensus on assigning activity scores of CYP2D6 variant alleles and translating diplotype scores into CYP2D6 poor, intermediate, normal, or ultrarapid metabolizer groups were obtained by consulting 37 international experts. While assigning enzyme activities of non-functional (score 0) and fully functional (score 1) alleles are straightforward, reduced function variant alleles are more complex. In this article, we present data showing that the assigned activity scores of reduced function variant alleles in current guidelines are not of sufficient precision; especially not for CYP2D6*41, where the guideline activity score is 0.5 compared to 0.05–0.15 in pharmacogenetic studies. Due to these discrepancies, CYP2D6 genotypes with similar guidelinediplotype scores exhibit substantial differences in CYP2D6 metabolizer phenotypes. Thus, it is important that the guidelines are updated to be valid in predicting individual dose requirements of psychiatric drugs and others metabolized by CYP2D6.

Five genetic polymorphisms of cytochrome P450 enzymes in the Czech non-Roma and Czech Roma population samples.

Objectives Cytochromes P450 play a role in human drugs metabolic pathways and their genes are among the most variable in humans. The aim of this study was to analyze genotype frequencies of five common polymorphisms of cytochromes P450 in Roma/Gypsy and Czech (non-Roma) population samples with Czech origin. Methods Roma/Gypsy (n=302) and Czech subjects (n=298) were genotyped for CYP1A2 (rs762551), CYP2A6 (rs4105144), CYP2B6 (rs3745274) and CYP2D6 (rs3892097; rs1065852) polymorphisms using PCR-RFLP or Taqman assay. Results We found significant allelic/genotype differences between ethnics in three genes. For rs3745274 polymorphism, there was increased frequency of T allele carriers in Roma in comparison with Czech population (53.1vs. 43.7%; p=0.02). For rs4105144 (CYP2A6) there was higher frequency of T allele carriers in Roma in comparison with Czech population (68.7 vs. 49.8%; p<0.0001). For rs3892097 (CYP2D6) there was more carriers of the A allele between Roma in comparison with Czech population (39.2 vs. 38.2%; p=0.048). Genotype/allelic frequencies of CYP2D6 (rs1065852) and CYP1A2 (rs762551) variants did not significantly differ between the ethnics. Conclusions There were significant differences in allelic/genotype frequencies of some, but not all cytochromes P450 polymorphisms between the Czech Roma/Gypsies and Czech non-Roma subjects.

Five genetic polymorphisms of cytochrome P450 enzymes in the Czech non-Roma and Czech Roma population samples.

Objectives Cytochromes P450 play a role in human drugs metabolic pathways and their genes are among the most variable in humans. The aim of this study was to analyze genotype frequencies of five common polymorphisms of cytochromes P450 in Roma/Gypsy and Czech (non-Roma) population samples with Czech origin. Methods Roma/Gypsy (n=302) and Czech subjects (n=298) were genotyped for CYP1A2 (rs762551), CYP2A6 (rs4105144), CYP2B6 (rs3745274) and CYP2D6 (rs3892097; rs1065852) polymorphisms using PCR-RFLP or Taqman assay. Results We found significant allelic/genotype differences between ethnics in three genes. For rs3745274 polymorphism, there was increased frequency of T allele carriers in Roma in comparison with Czech population (53.1vs. 43.7%; p=0.02). For rs4105144 (CYP2A6) there was higher frequency of T allele carriers in Roma in comparison with Czech population (68.7 vs. 49.8%; p<0.0001). For rs3892097 (CYP2D6) there was more carriers of the A allele between Roma in comparison with Czech population (39.2 vs. 38.2%; p=0.048). Genotype/allelic frequencies of CYP2D6 (rs1065852) and CYP1A2 (rs762551) variants did not significantly differ between the ethnics. Conclusions There were significant differences in allelic/genotype frequencies of some, but not all cytochromes P450 polymorphisms between the Czech Roma/Gypsies and Czech non-Roma subjects.

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.

PO 8261 CYTOCHROME P450 (CYP2B6*6C.516G&gt;T) VARIANTS IN CONGOLESE INDIVIDUALS WITH HIV AND TB MONO AND DUAL INFECTIONS

BackgroundThe inter-individual genetic polymorphism of cytochrome P450 enzymes (CYP), involved in the metabolism of many drugs, partly modulates drug response and toxicity. Single nucleotide polymorphisms of CYP2B6 for example, G516T have been implicated in high- and sub-therapeutic plasma concentration of the current antimalarial, HIV and TB first-line drugs in various geographical regions and thus undermines effective disease management. At present, there is no data on the frequency of CYP2B6 c.516G&gt;T among the Congolese population, despite a significant number of people undergoing antimalarial, HIV and TB treatment that relies on CYP2B6-based drug clearance or activation.MethodsA total of 418 patients with HIV-1 mono-infection, HIV-1 +TB coinfection and P. falciparum infection were genotyped for CYP2B6 c.516G&gt;T polymorphism using PCR-RFLP. The frequencies of the alleles as well as the genotypes (GG, GT and TT) were determined.ResultsThe frequency of CYP2B6 c.516G&gt;T polymorphism was 69% and frequency of G and T alleles were 45% and 55%, respectively. 17.0% (49/288) of participants were GG (extensive metaboliser), 55.2% (159/288) of participants were GT (intermediate metaboliser) and 27.8% (80/288) of participants were TT (poor metabolisers).ConclusionThis study highlights CYP2B6 c.G516T polymorphism as a potential determinant of drug response and toxicity among the Congolese population, particularly those undergoing antiretroviral, malaria and tuberculosis treatment within the current first-line drug policy framework.

Polymorphisms in CYP1A2, CYP2C9 and ABCB1 affect agomelatine pharmacokinetics.

Agomelatine is an agonist of the melatoninergic receptors used for the treatment of depression. Our aim was to evaluate the effect of genetic polymorphisms in metabolising enzymes and the P-glycoprotein transporter on agomelatine pharmacokinetics and pharmacodynamics. Twenty-eight healthy volunteers receiving a single 25 mg oral dose of agomelatine, were genotyped for nine polymorphisms in cytochrome P450 enzymes ( CYP1A2, CYP2C9 and CYP2C19) and adenosine triphosphate-binding cassette subfamily B member 1 ( ABCB1), by real-time polymerase chain reaction . Agomelatine concentrations were measured by high performance liquid chromatography coupled to a tandem mass spectrometry detector. We calculated a CYP1A2 activity score that was directly correlated with agomelatine pharmacokinetics. Individuals with a decreased enzyme activity (*1C carriers) had a lower clearance and accumulated higher concentrations of agomelatine. In contrast, individuals with a high CYP1A2 inducibility (*1F or *1B carriers) showed an extensive clearance and lower agomelatine concentrations. The apparently marked differences between races were due to the different CYP1A2 genotype distribution. CYP2C9 intermediate/poor metabolisers showed a higher area under the concentration-time curve and maximum concentration. ABCB1 G2677T/A polymorphism affected the time to reach maximum concentration, as subjects carrying A/A+A/T genotypes showed higher values. No association was found for CYP2C19 phenotype. Agomelatine did not produce any change in blood pressure, heart rate or QT interval. CYP1A2 polymorphisms affect agomelatine pharmacokinetics. CYP1A2 phenotype inferred from the genotyping of CYP1A2*1C, *1F and *1B alleles might be a potential predictor of agomelatine exposure. ABCB1 G2677T/A could affect agomelatine absorption, as subjects with A/A+A/T genotypes had lower agomelatine concentration and they take more time to reach the maximum concentration.

Cytochrome P450 Structure, Function and Clinical Significance: A Review.

The cytochrome P450 (CYP) enzymes are membrane-bound hemoproteins that play a pivotal role in the detoxification of xenobiotics, cellular metabolism and homeostasis. Induction or inhibition of CYP enzymes is a major mechanism that underlies drug-drug interactions. CYP enzymes can be transcriptionally activated by various xenobiotics and endogenous substrates through receptor-dependent mechanisms. CYP enzyme inhibition is a principal mechanism for metabolism- based drug-drug interactions. Many chemotherapeutic drugs can cause drug interactions due to their ability to either inhibit or induce the CYP enzyme system. Predictions based on in silico analyses followed by validation have identified several microRNAs that regulate CYPs. Genetic polymorphisms and epigenetic changes in CYP genes may be responsible for inter-individual and interethnic variations in disease susceptibility and the therapeutic efficacy of drugs. The present review is a comprehensive compilation of cytochrome P450 structure, function, pharmacogenetics, pharmacoepigenetics and clinical significance. Knowledge about the substrates, inducers, and inhibitors of CYP isoforms, as well as the polymorphisms of CYP enzymes may be used as an aid by clinicians to determine therapeutic strategy, and treatment doses for drugs that are metabolized by CYP gene products.