CYP2D6 Phenotype Research Articles

Impact of polymorphisms in transporter and metabolizing enzyme genes on olanzapine pharmacokinetics and safety in healthy volunteers

Olanzapine is an atypical antipsychotic widely used for the treatment of schizophrenia, which often causes serious adverse drug reactions. Currently, there are no clinical guidelines implementing pharmacogenetic information on olanzapine. Moreover, the Dutch Pharmacogenomics Working Group (DPWG) states that CYP2D6 phenotype is not related to olanzapine response or side effects. Thus, the objective of this candidate-gene study was to investigate the effect of 72 polymorphisms in 21 genes on olanzapine pharmacokinetics and safety, including transporters (e.g. ABCB1, ABCC2, SLC22A1), receptors (e.g. DRD2, HTR2C), and enzymes (e.g. UGT, CYP and COMT), in a cohort of healthy volunteers. Polymorphisms in CYP2C9, SLC22A1, ABCB1, ABCC2, and APOC3 were related to olanzapine pharmacokinetic variability. The incidence of adverse reactions was related to several genes: palpitations to ABCB1 and SLC22A1, asthenia to ABCB1, somnolence to DRD2 and ABCB1, and dizziness to CYP2C9. However, further studies in patients are warranted to confirm the influence of these genetic polymorphisms on olanzapine pharmacokinetics and tolerability.

Using the drug repositioning approach to develop a novel therapy, tipepidine hibenzate sustained-release tablet (TS-141), for children and adolescents with attention-deficit/hyperactivity disorder

BackgroundAsverin® (tipepidine hibenzate) has been used as an antitussive for > 50 years in Japan. Studies revealed that tipepidine modulates monoamine levels, by inhibiting G-protein-activated inwardly rectifying potassium (GIRK) channels, expecting the potential therapeutic effects of tipepidine for attention-deficit/hyperactivity disorder (ADHD) in recent years. In this study, TS-141, a sustained-release tablet of tipepidine, was developed for the treatment of ADHD through a drug repositioning approach.MethodsThe sustained-release profile of TS-141 in healthy adults was investigated, and tipepidine exposure in the plasma after the TS-141 administration was compared to that of Asverin in the phase I study. Phase II study was conducted to examine the effects of TS-141 30 (once a day), 60 (once a day), 120 mg (60 mg twice a day), or placebo, that is within the exposure in the maximum dosage of Asverin, in children and adolescents with ADHD, and was designed as an 8-week treatment, randomized, parallel group, double-blind, placebo-controlled trial recruiting 6–17-year-old children and adolescents diagnosed with ADHD. A total of 216 patients were randomized according to the CYP2D6 phenotype. The primary end-point was ADHD Rating Scale IV-J changes. Furthermore, effects of CYP2D6 phenotype on the efficacy in the subgroup analysis were investigated.ResultsTS-141 had the sustained-release profile, and the CYP2D6 phenotype had effects on the plasma exposure of tipepidine. ADHD RS-IV-J scores in all TS-141 dosages decreased from their baseline scores; however, no significant difference was observed in ADHD RS-IV-J score changes between the placebo and TS-141-administered groups. In patients with intermediate metabolizer CYP2D6, ADHD RS-IV-J score changes in the 120 mg group tended to be larger than that in the placebo group.ConclusionsADHD RS-IV-J changes on TS-141 may depend on the interaction between the TS-141 dose and CYP2D6 phenotype, suggesting that further clinical trials should be conducted with careful consideration of polymorphism. Drug repositioning approach of TS-141 was attempted at the same dose as that of antitussive; however, dose setting according to the indication was necessary.Trial registrationPhase I study: JapicCTI-205235 (Registered 25 March 2020), Phase II study: JapicCTI-163244 (Registered 9 May 2016), https://www.clinicaltrials.jp/cti-user/trial/Show.jsp

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

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

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

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

Temporal patterns of tramadol in hair after a single dose

This controlled study aimed to measure concentrations of tramadol (TRA) and its two main metabolites, N-desmethyltramadol (NDMT) and O-desmethyltramadol (ODMT), in hair following a single dose ingestion and to investigate the distribution patterns in hair by segmental analysis of hair samples taken at several sampling time points after ingestion. An oral dose (50 or 100mg) of TRA was administered to 17 healthy volunteers. Hair samples were collected prior to drug administration and 14, 30, 60 and 120 days after ingestion. Each sample was segmented in 5mm segments and washed. The analytes were extracted from pulverized hair by incubation in extraction media for 18h at 37°C. A validated UHPLC–MS/MS method was used to quantify the analytes at a LLOQ of 0.001ng/mg. Hair segments corresponding to the time of ingestion were positive for TRA and the metabolites of each sampling time point, although neighboring segments also showed positive results. The highest concentrations for both dosage groups were observed in the proximal segment of hair collected 14 days after ingestion for all subjects: 0.061–0.95ng TRA/mg, 0.012–0.86ng NDMT/mg and 0.009–0.17ng ODMT/mg (n=16). Generally, the TRA concentration was higher than the metabolites concentrations but depended on the CYP2D6 phenotype. The metabolite to TRA ratios were stable within a subject over the sampling time points, however it varied greatly between subjects. No significant differences in hair concentrations were found between the two dosage groups at each sampling time. Several confounding factors were identified such as hair pigmentation and internal sweat. We showed that analysis of 5mm segments improved the determination of the exposure time after a single ingestion of TRA. In addition, in the later sampling time points the analytes were spread more between segments and the total drug amount of each later sampling time point declined up to a 100% (median: 75%) due to wash out. The presented results are important additions to the sparse literature reporting single dose of psychoactive drugs in hair.

Relationships between CYP1A2, CYP2C9, CYP2C19, CYP2D6 and CYP3A4 metabolic phenotypes and genotypes in a Nicaraguan Mestizo population.

Interethnic variability in the drug-metabolizing capacity of CYP450 enzymes may lead to discrepancies in the relationship between genotypes and phenotypes worldwide. The present study was aimed to analyze for the first time whether there is a relationship between clinically relevant CYP450 genetic polymorphisms and their drug oxidation capacity (metabolic phenotype) in a population of healthy Nicaraguan volunteers. Two hundred and twelve participants were genotyped for CYP1A2, CYP2C9, CYP2C19, CYP2D6, and CYP3A4, and their actual metabolic phenotype (evaluated by the Metabolic Ratio, MR) was analyzed by using the CEIBA cocktail approach. The results showed the wide interindividual variability in all the studied enzymes and a significant difference (p < 0.004) in the activity of CYP1A2 between male and female subjects. The number of CYP2C19 (p < 0.0001) and CYP2D6 (p < 0.0001) active alleles were shown inversely correlated with their corresponding MR, although there were marked genotype-phenotype discrepancies. There was an actual enzyme capacity overlapping (MR) between genotypically Poor (gPMs) and Extensive Metabolizers (gEMs) of 3.14% subjects for CYP2D6 and 0.94% for CYP2C9. Similarly, there was an overlapping for metabolic phenotypes of 11.48% of genotypically ultrarapid metabolizers (gUMs) for CYP2C19 and 2.09% for CYP2D6 and gEMs. Therefore, the current approach for metabolic phenotype prediction based just on genotype does not predict properly for all individuals within this Nicaraguan Mestizo population, thus representing a potential barrier for the clinical implementation of personalized medicine in this region. However, it is necessary to improve the prediction of phenotype from genotype in order to improve the pharmacogenetic implementation in populations with specific ethnic backgrounds.

CYP2D6 Phenotype Influences Aripiprazole Tolerability in Pediatric Patients with Mood Disorders.

Objective: To determine the effect of CYP2D6 metabolizer status on aripiprazole tolerability in pediatric patients with mood disorders. Methods: We retrospectively reviewed electronic medical record data for 277 patients ≤18 years of age (at the time of CYP2D6 testing) with a mood disorder, receiving oral aripiprazole, and CYP2D6 genotyped as part of routine care. The maximum aripiprazole dose and concomitant medications were extracted from the medical record. The reason for aripiprazole discontinuation was determined to be from side effects (e.g., weight gain, akathisia, GI upset), nonresponse, or other reasons (e.g., financial). Associations with CYP2D6 were analyzed using multivariate linear regression models and chi-square tests. Results: Of the 277 patients (mean age: 14.3 ± 2.4), 57% were normal metabolizers (NMs), 37% were intermediate metabolizers (IMs), 5% were poor metabolizers (PMs), and 1.4% were ultrarapid metabolizers (UMs). A total of 72.2% of the cohort were concomitantly taking a CYP2D6 inhibitor, resulting in phenoconversion. Accounting for phenoconversion resulted in 27% phenoconverted NMs (pNMs), 24% phenoconverted IMs (pIMs), 48% phenoconverted PMs (pPMs), and <1% phenoconverted ultrarapid metabolizers. CYP2D6 pPMs discontinued treatment due to side effects more often than any other CYP2D6 group (67% for pPM, 51% pIM, 57% pNM, chi-square p = 0.024). Body mass index percentile change was associated with the CYP2D6 phenotype (p = 0.038), the time on aripiprazole (p = 0.001), and the number of concomitant CYP2D6 substrates (p = 0.044) in multivariable models. Conclusions: Phenoconverted CYP2D6 metabolizer status is associated with aripiprazole discontinuation. In addition, dose adjustments based on CYP2D6 metabolizer status and concomitant medications could improve aripiprazole treatment outcomes.

Determination of novel CYP2D6 haplotype using the targeted sequencing followed by the long-read sequencing and the functional characterization in the Japanese population.

Next-generation sequencing (NGS) has identified variations in cytochrome P450 (CYP) 2D6 associated with drug responses. However, determination of novel haplotypes is difficult because of the short reads generated by NGS. We aimed to identify novel CYP2D6 variants in the Japanese population and predict the CYP2D6 phenotype based on in vitro metabolic studies. Using a targeted NGS panel (PKSeq), 990 Japanese genomes were sequenced, and then novel CYP2D6 haplotypes were determined. Km, Vmax, and intrinsic clearance (Vmax/Km) of N-desmethyl-tamoxifen 4-hydroxylation were calculated by in vitro metabolic studies using cDNA-expressed CYP2D6 proteins. After determination of the CYP2D6 diplotypes, phenotypes of the individuals were predicted based on the in vitro metabolic activities. Targeted NGS identified 14 CYP2D6 variants not registered in the Pharmacogene Variation Consortium (PharmVar) database. Ten novel haplotypes were registered as CYP2D6*128 to *137 alleles in the PharmVar database. Based on the Vmax/Km value of each allele, *128, *129, *130, *131, *132, and *133 were predicted to be nonfunctional alleles. According to the results of the present study, six normal metabolizers (NM) and one intermediate (IM) metabolizers were designated as IM and poor metabolizers (PM), respectively. Our findings provide important insights into novel haplotypes and haplotypes of CYP2D6 and the effects on in vitro metabolic activities.

Quantification of In Vivo Metabolic Activity of CYP2D6 Genotypes and Alleles Through Population Pharmacokinetic Analysis of Vortioxetine.

Assignment of CYP2D6 phenotype from genotype data can be challenging and despite efforts to standardize translation, there is currently no universally accepted method. To facilitate standardization, there remains a need to precisely quantify the in vivo function of different CYP2D6 genotypes. Vortioxetine is metabolized to its major metabolite, Lu AA34443, primarily via CYP2D6. The aim of this study was to quantify the in vivo CYP2D6 activity of different CYP2D6 alleles and genotypes through population pharmacokinetic (PopPK) modeling of vortioxetine and Lu AA34443. Plasma concentration data of vortioxetine and Lu AA34443 from 1,140 subjects originating from 29 clinical pharmacology studies were pooled for the analysis. A joint PopPK model described the pharmacokinetics of vortioxetine and Lu AA34443 simultaneously and provided estimates of the CYP2D6‐mediated metabolism for each subject. Subjects normally classified as CYP2D6 intermediate metabolizers (IMs) showed different levels of CYP2D6 activity with carriers of one fully functional allele and one null function allele having 77% higher CYP2D6 activity compared with carriers of two decreased function alleles (P < 0.0001). The decreased function alleles were associated with different levels of reduction of CYP2D6 activity. Fixing the activity of fully functional alleles to 1.0, the relative activities of CYP2D6*9, CYP2D6*10, CYP2D6*17, and CYP2D6*41 were 0.22, 0.37, 0.17, and 0.21, respectively. The activity of CYP2D6*10 was shown to be significantly greater than that of CYP2D6*17 (P = 0.01) and CYP2D6*41 (P = 0.02). These results warrant further discussion of current CYP2D6 genotype‐phenotype classification systems particularly regarding decreased function alleles and the IM phenotype.

Obesity Alters Endoxifen Plasma Levels in Young Breast Cancer Patients: A Pharmacometric Simulation Approach.

Endoxifen is one of the most important metabolites of the prodrug tamoxifen. High interindividual variability in endoxifen steady-state concentrations (CSS,min ENDX ) is observed under tamoxifen standard dosing and patients with breast cancer who do not reach endoxifen concentrations above a proposed therapeutic threshold of 5.97ng/mL may be at a 26% higher recurrence risk compared with patients with endoxifen concentrations exceeding this value. In this investigation, 10 clinical tamoxifen studies were pooled (1,388 patients) to investigate influential factors on CSS,min ENDX using nonlinear mixed-effects modeling. Age and body weight were found to significantly impact CSS,min ENDX in addition to CYP2D6 phenotype. Compared with postmenopausal patients, premenopausal patients had a 30% higher risk for subtarget CSS,min ENDX at tamoxifen 20mg per day. In treatment simulations for distinct patient subpopulations, young overweight patients had a 3.1-13.8-fold higher risk for subtarget CSS,min ENDX compared with elderly low-weight patients. Considering ever-rising obesity rates and the clinical importance of tamoxifen for premenopausal patients, this subpopulation may benefit most from individualized tamoxifen dosing.

Design and Early Implementation Successes and Challenges of a Pharmacogenetics Consult Clinic.

Pharmacogenetic testing (PGT) is increasingly being used as a tool to guide clinical decisions. This article describes the development of an outpatient, pharmacist-led, pharmacogenetics consult clinic within internal medicine, its workflow, and early results, along with successes and challenges. A pharmacogenetics-trained pharmacist encouraged primary care physicians (PCPs) to refer patients who were experiencing side effects/ineffectiveness from certain antidepressants, opioids, and/or proton pump inhibitors. In clinic, the pharmacist confirmed the need for and ordered CYP2C19 and/or CYP2D6 testing, provided evidence-based pharmacogenetic recommendations to PCPs, and educated PCPs and patients on the results. Operational and clinical metrics were analyzed. In two years, 91 referred patients were seen in clinic (mean age 57, 67% women, 91% European-American). Of patients who received PGT, 77% had at least one CYP2C19 and/or CYP2D6 phenotype that would make conventional prescribing unfavorable. Recommendations suggested that physicians change a medication/dose for 59% of patients; excluding two patients lost to follow-up, 87% of recommendations were accepted. Challenges included PGT reimbursement and referral maintenance. High frequency of actionable results suggests physician education on who to refer was successful and illustrates the potential to reduce trial-and-error prescribing. High recommendation acceptance rate demonstrates the pharmacist’s effectiveness in providing genotype-guided recommendations, emphasizing a successful pharmacist–physician collaboration.

ABCB1, ABCG2 and CYP2D6 polymorphism effects on disposition and response to long-acting risperidone

The relevance of the multidrug resistance (ABCB1) and breast cancer resistance (ABCG2) protein transporter polymorphisms for treatment with long-acting intramuscular (LAI) risperidone is largely unknown. We explored the relationship between these polymorphisms and cytochrome P450 (CYP) 2D6 genotype-predicted phenotype in their effects on drug disposition and clinical outcomes in adults with schizophrenia. In a 24-week observational study, patients initiated on LAI-risperidone (n=101) were genotyped [enzymes (CYP2D6 dupl,*3,*4,*5,*6,*41; CYP3A4*22, CYP3A5*3), transporters (ABCG2 421C>A; ABCB1 1236C>T, 2677G>T/A, 3435C>T)] and evaluated for steady-state (weeks 6–8) serum levels of dose-corrected risperidone, 9-OH-risperidone, risperidone+9-OH-risperidone (active moiety), and for response to treatment (PANSS, reduction vs. baseline ≥30% at week 12 and ≥45% at week 24). CYP2D6 normal/ultrarapid metabolizers (NM/UM) (vs. other) had lower risperidone (29%) and active moiety levels (24%) (9-OH-risperidone not affected). The effect on the three analytes was mild (0 to 23% reduction) in ABCG2 wild-type homozygotes and pronounced (44–55% reduction) in ABCG2 variant allele carriers. ABCG2 variant had no effect on disposition in CYP2D6 “other” phenotypes, while the effect was pronounced in CYP2D6 NM/UM subjects (31–37% reduction). ABCB1 polymorphisms had no effect on exposure to risperidone. CYP2D6 NM/UM phenotype tended to lower odds of PANSS response, ABCG2 variant was associated with 4-fold higher odds and ABCB1 (1236C>T, 2677G>T/A, 3435C>T) overall mainly wild-type genotype was associated with around 4--fold lower odds of response. In patients treated with LAI-risperidone, CYP2D6 phenotype effect on systemic exposure is conditional on the ABCG2 421C>A polymorphism. ABCG2 and ABCB1 polymorphisms affect clinical response independently of systemic risperidone disposition.

Treatment of Iraqi People with Hyperkinetic Movement Disorders by Tetrabenazine in Relation to Genetic Polymorphism of CYP450 2D6

Genetic polymorphism is defined as the inheritance of a trait controlled by a single genetic locus with two alleles in which the least common allele has a frequency of about 1% or greater. The Cytochrome P450 (CYP2D6) enzyme metabolizes about 25% of clinically used drugs from many different drug classes including antidepressants, antipsychotics, antihypertensives, and analgesics. The CYP2D6 is a highly polymorphic gene locus with more than 75 allelic variants, thus subjects can be classified into poor metabolizers (PM), ), intermediate metabolizers (IMs), extensive metabolizers (EM), or ultra-rapid metabolizers (UM) of a given CYP2D6 substrate. By using pharmacogenomics, the pharmacotherapy can be optimized, thereby increasing the treatments overall efficacy and decreasing the incidence of adverse events. The present study is aimed to predicted phenotypes of CYP2D6 as : poor metabolizers, intermediate metabolizers, extensive metabolizers, and ultra rapid metabolizers for tetrabenazine in patients with hyperkinetic movement disorders compared to healthy subjects in Iraq . The study was carried on 75 subjects participated (30 male, 45 female) ; fifty of them were with hyperkinetic movement disorders( 25 dystonia , 25 chorea ) the reminder 25 were healthy . Genotyping of CYP2D6 gene was performed by polymerase chain reaction (PCR) conventional (allele specific method). Plasma concentration of Tetraberazine was measured by High-performance liquid chromatography (HPLC) . Data were collected through direct interview with the subjects besides the assessment of genetic polymorphism of CYP 450 2D6 enzyme for Iraqi people. The results of this study show there were a significant CYP 450 2D6 enzyme polymorphism. the number (percentage) of subjects with CYP 450 2D6 gene polymorphisms was 17 (22.66%) of the total study population. The number (percentage) of subjects with CYP 450 2D6*2 was 58 (76.32%), whereas, subjects with CYP450 2D6 *10 was 17 (22.66%).However , no subjects were observed with CYP 450 2D6 *4 polymorphisms in this study. The tetrabenazine concentration with mean ± SD was 3.08± 0.231 and 2.506±0.235 ng/ml for chorea and dystonia patients respectively , while alpha and beta dihydrotetrabenazine range was 37.72± (2.18 ng/ml _38.13± 2.00 ng/ml ) and (21.376±0.583ng/ml_ 18.252±0.874ng/ml ) respectively .

Assessment of tramadol pharmacokinetics in correlation with CYP2D6 and clinical symptoms.

Objectives Due to lack of adequate data on tramadol kinetic in relevance of CYP2D6 toxicity, this study was designed to investigate the effect of CYP2D6 phenotype in tramadol poisoning. The saliva, urine and blood samples were taken at the admission time. Consequently, concentration of tramadol and its major metabolites were measured. Methods A pharmacokinetic and metabolic study was developed in cases of tramadol poisoned (n=96). Cases of tramadol poisoned evidenced seizure, hypertension, dizziness, nausea and vomiting symptoms participated. Results Female cases showed higher N-desmethyltramadol (M2) tramadol concentrations than male cases: in urine (40.12±124.53 vs. 7.3±7.13), saliva (16.91±26.03 vs. 5.89±7.02), and blood (1.11±1.56 vs. 0.3±0.38) samples. Significant correlation between blood, saliva, and urine concentrations were found (r=0.5). Based on the metabolic ratio of O-desmethyltramadol (M1) of male (0.53±0.22) and female (0.43±0.26), poisoning and severe symptoms like seizure in female occurs statistically fewer (13.04%) than in male (50.6%). Assessment of CYP2D6 phenotype showed all of the participants were extensive metabolizers (EM) and their phenotype was associated with clinical symptoms. Conclusions According to our results, M1 as a high potent metabolite has an important role in toxicity and the likelihood of poisoning in people with EM phenotype. Finally, tramadol metabolic ratio may justify the cause of various symptoms in human tramadol poisoning.

Assessment of tramadol pharmacokinetics in correlation with CYP2D6 and clinical symptoms.

Objectives Due to lack of adequate data on tramadol kinetic in relevance of CYP2D6 toxicity, this study was designed to investigate the effect of CYP2D6 phenotype in tramadol poisoning. The saliva, urine and blood samples were taken at the admission time. Consequently, concentration of tramadol and its major metabolites were measured. Methods A pharmacokinetic and metabolic study was developed in cases of tramadol poisoned (n=96). Cases of tramadol poisoned evidenced seizure, hypertension, dizziness, nausea and vomiting symptoms participated. Results Female cases showed higher N-desmethyltramadol (M2) tramadol concentrations than male cases: in urine (40.12±124.53 vs. 7.3±7.13), saliva (16.91±26.03 vs. 5.89±7.02), and blood (1.11±1.56 vs. 0.3±0.38) samples. Significant correlation between blood, saliva, and urine concentrations were found (r=0.5). Based on the metabolic ratio of O-desmethyltramadol (M1) of male (0.53±0.22) and female (0.43±0.26), poisoning and severe symptoms like seizure in female occurs statistically fewer (13.04%) than in male (50.6%). Assessment of CYP2D6 phenotype showed all of the participants were extensive metabolizers (EM) and their phenotype was associated with clinical symptoms. Conclusions According to our results, M1 as a high potent metabolite has an important role in toxicity and the likelihood of poisoning in people with EM phenotype. Finally, tramadol metabolic ratio may justify the cause of various symptoms in human tramadol poisoning.

CYP2D6 does not impact on breast cancer-free survival in Southeast Mexican patients under tamoxifen treatment.

Aim: We conducted a retrospective analysis in 71 Mexican Mestizo patients to evaluate the breast cancer-free survival (BCFS) among the inferred genetic phenotypes (GP) of CYP2D6. Patients & methods:CYP2D6 was genotyped through Taqman-probe analysis; GP were inferred according to international guidelines. The BCFS was estimated through Kaplan-Meier method and analyzed with a log-rank test; hazard ratios were calculated with 95% CI and p < 0.05. Results: The BCFS did not differ among CYP2D6 GP (p = 0.45) and recurrence risk was similar between gNM + gUM and gPM + gIM groups (hazard ratio: 1.54, 95% CI: 0.37-6.38; p = 0.55). Conclusion: The findings do not support any impact of CYP2D6 on BCFS. Evaluation of other genetic/nongenetic biomarkers is needed in Mexican Mestizo patients under tamoxifen treatment.

Adverse Drug Reactions in the Emergency Department: Is There a Role for Pharmacogenomic Profiles at Risk?-Results from the ADRED Study.

Individual differences in required drug dosages exist based on the pharmacogenomic (PGx) profiles. This study aimed to assess associations between PGx profiles and adverse drug reactions (ADR) that lead to admissions to the emergency department (ED). ADR cases of the prospective multi-center observational trial in EDs (ADRED study) were analyzed (n = 776) together with the relevant PGx phenotypes of the enzymes CYP2D6, CYP2C19, CYP2C9, and VKORC1. Overall, the allele frequency distribution in this cohort did not differ from the population frequencies. We compared the frequencies of phenotypes in the subgroups with the drugs suspected of certain ADR, in the remaining cases. The frequency distribution of CYP2C19 differed for the ADR bleeding cases suspected of clopidogrel (p = 0.020). In a logistic regression analysis, higher CYP2C19 activity (OR (95% CI): 4.97 (1.73−14.27)), together with age (1.05 (1.02−1.08)), showed an impact on the clopidogrel-suspecting ADRs, when adjusting for the clinical parameters. There was a trend for an association of phenprocoumon-risk profiles (low VKORC1 or CYP2C9 activity) with phenprocoumon-suspecting ADRs (p = 0.052). The PGx impact on serious ADRs might be highest in drugs that cannot be easily monitored or those that do not provoke mild ADR symptoms very quickly. Therefore, patients that require the intake of those drugs with PGx variability such as clopidogrel, might benefit from PGx testing.

Distribution and linkage disequilibrium of the enhancer SNP rs5758550 among Latin American populations: influence of continental ancestry.

A single nucleotide polymorphism (SNP), rs5758550, in a critical enhancer region downstream of the CYP2D6 promoter was proposed to modulate CYP2D6 activity, depending on its linkage disequilibrium (LD) with the common CYP2D6 SNP, rs16947. We examined the influence of individual biogeographical ancestry on the frequency distribution of rs5758550 and its LD with rs16947 in Latin American populations. We then inferred the impact of rs5758550 on the predictive accuracy of CYP2D6 metabolizer status based on CYP2D6 haplotypes. The study cohorts consisted of the Admixed American (AMR) superpopulation of the 1000 Genomes Project (n = 347) plus an admixed Brazilian (BR) cohort (N = 224). Individual proportions of Native, African and European ancestry estimated by ADMIXTURE analysis, were used to design four sub-cohorts, in which one of the three ancestral roots predominated largely (>6 fold) over the other two: AMR-NAT and AMR-EUR, comprised 80 AMR individuals each, with >70% Native or >70% European ancestry, BR-EUR and BR-AFR comprised Brazilians with >90% European (n = 80) or >70% African ancestry (n = 64), respectively. CYP2D6 haplotypes were inferred based on 10 commonly reported CYPD6 variants with or without addition of the enhancer rs5758550 SNP, pairwise LD was assessed by the R parameter, and activity scores were used to infer CYP2D6 metabolizer status. Minor allele frequency (MAF) of all CYP2D6 SNPs, except the rare (<0.02) rs5030656 and rs35742688, differed significantly across sub-cohorts, whereas no difference was observed for rs5758550. The R values for LD between rs5758550 and rs16947 ranged from 0.15 (BR-AFR) to 0.85 (AMR-NAT), with intermediate values in the predominantly European sub-cohorts (0.34-0.67). As a consequence, distribution of CYP2D6 haplotypes containing the rs16947 SNP plus rs5758550 wild-type (A) or variant (G) allele differed markedly across sub-cohorts. Comparison of the CYP2D6 activity scores assigned to the wild-type (CYP2D6*1) and the rs16947-containing haplotypes with or without inclusion of rs5758550, showed that knowledge of the rs5758550 genotype has negligible impact on predicted CYP2D6 phenotypes in AMR-EUR and AMR-NAT, but affects prediction in 10.7 and 21.6% of BR-EUR and BR-AFR individuals, respectively. Collectively, the present results reveal potential pharmacogenomic (PGx) implications of the population diversity in Latin America, affecting a major drug-metabolizing pathway. Thus, the influence of enhancer rs5758550 on assignment of CYP2D6 metabolic phenotypes varies markedly, according to the individual proportions of Native, European and African ancestry. This conclusion reinforces the notion that extrapolation of PGx data across the heterogeneous Latin American is risky, if not inappropriate.

Modelling Age-Related Changes in the Pharmacokinetics of Risperidone and 9-Hydroxyrisperidone in Different CYP2D6 Phenotypes Using a Physiologically Based Pharmacokinetic Approach

PurposeDose-optimization strategies for risperidone are gaining in importance, especially in the elderly. Based on the genetic polymorphism of cytochrome P 450 (CYP) 2D6 genetically and age-related changes cause differences in the pharmacokinetics of risperidone and 9-hydroxyrisperidone. The goal of the study was to develop physiologically based pharmacokinetic (PBPK) models for the elderly aged 65+ years. Additionally, CYP2D6 phenotyping using metabolic ratio were applied and different pharmacokinetic parameter for different age classes predicted.MethodsPlasma concentrations of risperidone and 9-hydroxyrisperidone were used to phenotype 17 geriatric inpatients treated under naturalistic conditions. For this purpose, PBPK models were developed to examine age-related changes in the pharmacokinetics between CYP2D6 extensive metabolizer, intermediate metabolizer, poor metabolizer, (PM) and ultra-rapid metabolizer.ResultsPBPK-based metabolic ratio was able to predict different CYP2D6 phenotypes during steady-state. One inpatient was identified as a potential PM, showing a metabolic ratio of 3.39. About 88.2% of all predicted plasma concentrations of the inpatients were within the 2-fold error range. Overall, age-related changes of the pharmacokinetics in the elderly were mainly observed in Cmax and AUC. Comparing a population of young adults with the oldest-old, Cmax of risperidone increased with 24–44% and for 9-hydroxyrisperidone with 35–37%.ConclusionsMetabolic ratio combined with PBPK modelling can provide a powerful tool to identify potential CYP2D6 PM during therapeutic drug monitoring. Based on genetic, anatomical and physiological changes during aging, PBPK models ultimately support decision-making regarding dose-optimization strategies to ensure the best therapy for each patient over the age of 65 years.

Use of antidepressants with pharmacogenetic prescribing guidelines in a 10-year depression cohort of adult primary care patients

To describe the usage patterns of antidepressants with published CYP2D6- and CYP2C19-based prescribing guidelines among depressed primary care patients and estimate the proportion of patients taking antidepressants not recommended for them based on their CYP2C19 and CYP2D6 genotype-predicted metabolizer status. Medication use and pharmacogenetic testing results were collected on 128 primary care patients enrolled in a 10-year depression cohort study. At each 12-month interval, we calculated the proportion of patients that: (1) reported use of one or more of the 13 antidepressant medications (i.e. amitriptyline, citalopram, escitalopram, clomipramine, desipramine, doxepin, fluvoxamine, imipramine, nortriptyline, paroxetine, sertraline, trimipramine, venlafaxine) with published CYP2D6- and CYP2C19-based prescribing guidelines, (2) were taking an antidepressant that was not recommended for them based on their CYP2C19 and CYP2D6 genotype-predicted metabolizer phenotype, and (3) switched medications from the previous 12-month interval. The annual proportion of individuals taking an antidepressant with a CYP2D6- and CYP2C19-based prescribing guidelines ranged from 45 to 84%. The proportion of participants that used an antidepressant that was not recommended for them, based on available CYP2D6 and CYP2C19 metabolizer phenotype, ranged from 18 to 29% and these individuals tended to switch medications more frequently (10%) compared to their counterparts taking medication aligned with their metabolizer phenotype (6%). One-quarter of primary care patients used an antidepressant that was not recommended for them based on CYP2D6- and CYP2C19-based prescribing guidelines and switching medications tended to be more common in this group. Studies to determine the impact of CYP2D6 and CYP2C19 genotyping on reducing gene-antidepressant mismatches are warranted.