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Tweetable abstract Clinical phenoconversion needs to be incorporated when interpreting and applying

Pharmacogenomic (PGx) testing of cytochrome P450 (CYP) enzymes may improve the efficacy and/or safety of some medications. This is facilitated by increased availability and affordability of genotyping, the development of clinical practice PGx guidelines and regulatory support. However, the common occurrence of CYP phenoconversion, a mismatch between genotype-predicted CYP phenotype and the actual CYP phenotype, currently limits the application of PGx testing for precision dosing in psychiatry. This review proposes a stepwise approach to assist precision dosing in psychiatry via the introduction of PGx stewardship programs and innovative PGx education strategies. A future perspective on delivering precision dosing for psychiatrists is discussed that involves innovative clinical decision support systems powered by model-informed precision dosing.

Background: Germline sequencing of individual genomes can detect alleles responsible for adverse drug reactions (ADRs) in relation to chemotherapy, targeted agents, antiemetics or pain treatment. Materials & methods: To evaluate the interest of such pharmacogenetic information, the authors retrospectively analyzed genes known to have an impact on cancer therapy in a cohort of 445 solid cancers patients. Results: Six patients treated with 5-fluorouracil carrying one DPYD variant classified as 1A showed decreased drug mean clearance (p = 0.01). Regarding CYP2D6, all patients (n = 5) with predicted CYP2D6 poor or ultra-rapid metabolizer status experienced adverse drug reactions related to opioid therapy. Conclusion: Genomic germline sequencing performed for theragnostic issues in patients with a solid tumor, can provide relevant information about common pharmacogenetic alleles.

The discovery of haplotypes with unknown or uncertain function in the CYP2D6 pharmacogene is outpacing the capabilities of traditional in vitro and in vivo approaches to characterize their function. This challenge will undoubtedly grow as pharmacogenomic research becomes more inclusive of globally diverse populations. As accurate phenotypic assignment is paramount to the utility of pharmacogenomics, high-throughput technologies are needed for this complex pharmacogene. We describe the evolving landscape of innovative approaches to assign function to CYP2D6 haplotypes and possibilities for adopting these technologies into cohesive processes. Promising approaches include ADME-optimized prediction frameworks, machine learning algorithms, deep mutational scanning and phenoconversion predictions. Implementing these approaches will lead to improved personalization of treatment for patients.

Genetic variation in the gene encoding CYP2D6 is used to guide drug prescribing in clinical practice. However, genetic variants in CYP2D6 show substrate-specific effects that are currently not accounted for. With a systematic literature, we retrieved 22 original studies describing in vitro experiments focusing on CYP2D6 alleles ( CYP2D6*1, *2, *10 and *17) and substrates. Allele activity (clearance of the allele of interest divided by the clearance of the wildtype) was extracted. The results support the hypothesis of the existence of substrate specificity of the CYP2D6*17-allele (higher debrisoquine clearance), a subtle effect of the CYP2D6*10-allele (lower dextromethorphan clearance) but no substrate-specific effect of the CYP2D6*2-allele. Although our results support substrate specificity, for most substrates data are too sparse and require further studies.

Oxycodone is a semisynthetic μ- and κ-opioid receptor with agonist with a broad scope of use including postoperative analgesia as well as control of neuropathic and cancer pain. Advantages over other opioids include prolonged duration of action, greater potency than morphine and lack of histamine release or ceiling effect. Individual responses to oxycodone can vary due to genetic differences. This review article aims to summarize the oxycodone literature and provide context on its pharmacogenomics and pharmacokinetics. The evidence for clinical effect of genetic polymorphisms on oxycodone is conflicting. There is stronger evidence linking polymorphic genetic enzymes CYP2D6 and CYP3A with therapeutic outcomes. Further, research is needed to discern all of oxycodone’s metabolites and their contribution to the overall analgesic effect.

BackgroundWith up to 70% of adverse drug reactions (ADRs) having high genetic associations, the clinical utility of pharmacogenomics (PGx) has been gaining traction. Nala PGx Core™ is a multi-gene qPCR-based panel that comprises 18 variants and 2 CYP2D6 Copy Number markers across 4 pharmacogenes – CYP2C9, CYP2C19, CYP2D6 and SLCO1B1.ObjectivesIn this study, we validated the performance of Nala PGx Core™ against benchmark methods, on the Singaporean and Indonesian populations. Additionally, we examined the allele and diplotype frequencies across 5 major ethnic groups present in these populations namely, Indonesians, Chinese, Malays, Indians and Caucasians.MethodsHuman gDNA samples, extracted from the buccal swabs of 246 participants, were tested on Nala PGx Core™ and two chosen benchmarks, Agena VeriDose® Core and CYP2D6 Copy Number Variation (CNV) Panel, and TaqMan® DME Genotyping Assays. Performance was evaluated based on assay robustness, precision and accuracy at the genotype- and diplotype-level.ResultsNala PGx Core™ demonstrated high genotype- and diplotype-level call rates of >97% and >95% respectively in CYP2D6, and 100% for CYP2C9, CYP2C19 and SLCO1B1. A precision rate of 100% was observed on both intra- and inter-precision studies. Variant-level concordance to the benchmark methods was ≥96.9% across all assays, which consequently resulted in a diplotype-level concordance of ≥94.7% across CYP2C9, CYP2C19 and CYP2D6. Overall, the allele frequencies of CYP2D6*10 and CYP2D6*36 were higher in our cohort as compared to previous records. Notably, CYP2D6 copy number variation (CNV) analysis demonstrated a CYP2D6 *10/*36 frequency of 26.5% amongst the Indonesian cohort.ConclusionNala PGx Core™ produced robust and accurate genotyping when compared to other established benchmarks. Furthermore, the panel successfully characterized alleles of clinical relevance in the Singaporean and Indonesian populations such as CYP2D6*10 and CYP2D6*36, suggesting its potential for adoption in clinical workflows regionally.

Aim: We evaluated the application and clinical impact of multi-gene pharmacogenetic testing in oncology palliative medicine. Patients & methods: In a single-arm pilot trial, cancer patients with uncontrolled pain were assessed in a palliative medicine clinic at baseline and received pharmacogenetic testing. Results were used as applicable up to the final visit (day 30). Pain scores, opioid prescribing, and use of pharmacogenetic test results were collected. Results: In 75 patients, the median baseline pain score was 7/10. Of 54 evaluable at the final visit, 28 required opioid modifications and 19 had actionable genotypes, mostly CYP2D6. Pain improvement (≥2-point reduction) was higher than historical data (56 vs 30%; p

Antidepressant response could be from 42 to 50% genetically determined. Venlafaxine (VEN) was the sixth most-prescribed antidepressant in the USA in 2017. Therefore, we reviewed studies which focused on the pharmacogenetics of VEN and found that there is a lack of guidelines for pharmacogenetic testing for VEN. Within investigated genetic polymorphisms, few of them can be indicated as potential predictors of VEN efficacy and tolerance. However, additional pharmacogenetic studies of VEN should be performed to reproduce already obtained results or explain contradictory ones. The individualization of pharmacotherapy is a key issue in providing patients with the highest possible quality of treatment, therefore pharmacogenetic studies should be one of the components of therapy optimization.

Pharmacogenetic analysis to explain or predict the response of a specific patient to drug therapy is increasingly used in clinical practice. This holds especially true for CYP genotyping in psychiatry. We present a patient with genetic polymorphisms in more than one CYP450 enzyme, resulting in reduced effectiveness of CYP enzymes, explaining the high drug serum trough levels of antipsychotics and antidepressants and difficulty in optimizing therapy and dosing. Mrs X was found to be a CYP1A2, CYP2D6, CYP3A4 intermediate and in addition a CYP2C19 poor metabolizer. For Mrs X, pharmacogenetic analysis has contributed to reconsider choice and use of medication. Prior knowledge of the genetic polymorphisms in this patient might have avoided treatment delay and discomfort.

Aim: To comprehensively interrogate CYP2D6 by integrating genotyping, copy number analysis and novel strategies to identify CYP2D6*36 and characterize CYP2D6 duplications. Methods: Genotyping of 16 CYP2D6 alleles, multiplex ligation-dependent probe amplification (MLPA) and CYP2D6*36 and duplication allele-specific genotyping were performed on 427 African–American, Asian, Caucasian, Hispanic, and Ashkenazi Jewish individuals. Results: A novel PCR strategy determined that almost half of all CYP2D6*10 (100C>T) alleles are actually *36 (isolated or in tandem with *10) and all identified duplication alleles were characterized. Integrated results from all testing platforms enabled the refinement of genotype frequencies across all studied populations. Conclusion: The polymorphic CYP2D6 gene requires comprehensive interrogation to characterize allelic variation across ethnicities, which was enabled in this study by integrating multiplexed genotyping, MLPA copy number analysis, novel PCR strategies and duplication allele-specific genotyping.

Tweetable abstract High-quality studies examining the influence of CYP2D6 on the exposure and tolerability of antipsychotics in youth are needed to mitigate the limitations of prior studies.

AIM: Several CYP2D6 Luminex xTAG genotype calls were identified as inconsistent or suspicious among Thai subjects and further characterized to identify the root causes. MATERIAL & METHODS: Forty-eight subjects were followed-up with long-range-PCR, quantitative copy number assays and/or Sanger sequencing. RESULTS: Most of the Luminex-duplication calls were either negative or had hybrid structures involving CYP2D6*36 in various configurations. Ten samples were inaccurately called as CYP2D6*2, *29 or *35 alleles. Sequencing revealed three novel haplotypes, CYP2D6*142, *143 and *144 of which two are nonfunctional. CONCLUSION: The Luminex platform produced a relatively high number of false genotype calls for Thai subjects. Our findings underscore the need for the systematic characterization of the CYP2D6 locus in diverse populations and rigorous platform validation.

BACKGROUND: Tardive dyskinesia (TD) is an iatrogenic involuntary movement disorder occurring after extended antipsychotic use with unclear pathogenesis. CYP2D6 is a liver enzyme involved in antipsychotic metabolism and a well-studied gene candidate for TD. MATERIALS & METHODS: We tested predicted CYP2D6 metabolizer phenotype with TD occurrence and severity in our two samples of European chronic schizophrenia patients (total n = 198, of which 82 had TD). RESULTS: TD occurrence were associated with extreme metabolizer phenotype, controlling for age and sex (p = 0.012). In other words, individuals with either increased and no CYP2D6 activity were at higher risk of having TD. CONCLUSION: Unlike most previous findings, TD occurrence may be associated with both extremes of CYP2D6 metabolic activity rather than solely for poor metabolizers.

Aim: To evaluate plasma endoxifen levels and metabolic phenotype-associated factors in Mexican Mestizo patients under tamoxifen treatment. Patients & methods: A total of 138 breast cancer patients under tamoxifen treatment were cross-sectionally evaluated and side effects (SE) were recorded. CYP2D6 genetic phenotypes (GP) and metabolic phenotypes (MP) were assessed (metabolic poor [mPM], intermediate [mIM], normal [mNM], and ultrarapid [mUM] metabolizer). Associations were tested in uni-multivariate models for endoxifen >5.9 ng/ml and for mNM + mUM MP. Results: The main SE was hot flashes (62%). Distribution of the CYP2D6 MP was 4.3% mPM; 14.5% mIM; 75.4% mNM; and 5.8% mUM. Endoxifen >5.9 ng/ml was partially associated with SE (p = 0.06); the mNM + mUM MP was associated with treatment time (p = 0.03). Conclusion: The endoxifen-associated factors in Mexican Mestizo patients remain inconclusive, although treatment time was associated with MP.

This study included 24 healthy volunteers who received a single 37.5 mg oral dose of tramadol. We analyzed 18 polymorphisms within CYP2D6, CYP2B6, CYP3A, COMT, ABCB1, SLC22A1 and OPRM1 genes by quantitative PCR, to study whether these polymorphisms affect its pharmacokinetics, pharmacodynamics and safety. CYP2D6 intermediate metabolizers (n = 6) showed higher tramadol plasma concentrations and lower clearance compared with normal and ultrarapid metabolizers. CYP2B6 G516T T/T (n = 2) genotype was also associated to higher tramadol plasma levels. No other polymorphism affected tramadol pharmacokinetics. Three volunteers experienced a prolonged QTc not associated with the genetic variants studied or altered phamacokinetic parameters. The correlation of CYP2B6 genotype with higher tramadol concentrations is remarkable since its influence on its elimination is also relevant and has been less studied to date. However, given our small sample size, it is important to interpret our results with caution.

Aim: This study aimed to assess the impact of CYP2D6 and CYP2C19 variation on venlafaxine (VEN) at steady state in patients from Trinidad and Tobago of Indian and African descent with major depressive disorder. Patients & methods: Patients were phenotyped with dextromethorphan, genotyped for CYP2D6 and CYP2C19, and metabolic ratios for VEN obtained at 2-week intervals. Results: Of 61 patients, 55 were genotyped and phenotyped and 47 completed 8 weeks of VEN treatment. The majority of patients had metabolic ratios for VEN that were consistent with those for dextromethorphan and genotype-predicted phenotype using activity scores. One subject presented with a novel no-function allele, CYP2D6*99. No correlations were observed with CYP2C19 genotype. Conclusion: CYP2D6 genotype analysis provides valuable information to individualize drug therapy with VEN.

Aim: The present review was aimed at analyzing the pharmacogenetic scientific activity in Central America and the Caribbean. Materials & methods: A literature search for pharmacogenetic studies in each country of the region was conducted on three databases using a list of the most relevant pharmacogenetic biomarkers including ‘phenotyping probe drugs’ for major drug metabolizing enzymes. The review included 132 papers involving 47 biomarkers and 35,079 subjects (11,129 healthy volunteers and 23,950 patients). Results: The country with the most intensive pharmacogenetic research was Costa Rica. The most studied medical therapeutic area was oncology, and the most investigated biomarkers were CYP2D6 and HLA-A/B. Conclusion: Research activity on pharmacogenetics in Central American and the Caribbean populations is limited or absent. Therefore, strategies to promote effective collaborations, and foster interregional initiatives and research efforts among countries from the region could help for the rational clinical implementation of pharmacogenetics and personalized medicine.

CYP2D6 is a high polymorphic enzyme from P450, responsible for metabolizing almost 25% of drugs. The distribution of different mutations among CYP2D6 alleles has been associated with poor, intermediate, extensive and ultra-metabolizers. Aim: To evaluate how missenses mutations in CYP2D6*7 and CYP2D6*14A poor metabolizer alleles affect CYP2D6 stability and function. Materials & methods: CYPalleles database was used to collect polymorphisms data present in 105 alleles. We selected only poor metabolizers alleles that presented exclusively missenses mutations. They were analyzed through seven algorithms to predict the impact on CYP2D6 structure and function. Results: H324P, the unique mutation in CYP2D6*7, has high impact in enzyme function due to its occurrence between two alpha-helixes involved in active site dynamics. G169R, a mutation that occurs only in CYP2D6*14A, leads to the gain of solvent accessibility and severe protein destabilization. Conclusion: Our in silico analysis showed that missenses mutations in CYP2D6*7 and CYP2D6*14A cause CYP2D6 dysfunction.

Aim: We investigated the interaction of CYP2C19 and CYP2D6 genotype on clinical outcome in tamoxifen-treated breast cancer patients. Materials & methods: A cohort of 306 patients on tamoxifen treatment for a minimum of 1 year were employed to analyze the effect of genotype-predicted phenotype on relapse-free survival. Results & conclusion: We show that the group with worst outcome and highest risk of relapse is that of 2C19↑–2D6↓ (hazard ratio: 2.94), when adjusting for age, Nottingham prognostic index and adjuvant chemotherapy. Furthermore, the effect of 2C19↑–2D6↓genotype-predicted phenotype is greatly enhanced in premenopausal patients (hazard ratio: 21.08). We hypothesize that poor bioactivation of tamoxifen in patients with low CYP2D6 activity and high CYP2C19 metabolism represents a tamoxifen-treated patient group that has the worst clinical outcome.

The highly polymorphic CYP2D6 gene locus leads to a wide range of enzyme activity. Since there are limited data for Thai, the major aim was to investigate CYP2D6 genetic variation in a large Thai population (n = 920). CYP2D6 genotyping was performed using four different platforms. Genotype call rates of the Luminex xTAG® and AmpliChip CYP450 test were 96.5% and 87.4%, respectively. Based on Luminex xTAG® data, the most common alleles and genotypes were *1 0 (49.6%), *1 (24.6%), *2 (10.8%), *5 (6.7%), *41 (6.5%) and *1/*10 (23.9%), *10/*10 (21.5%), *2/*10 (9.4%), *5/*10 (6.9%), *10/*41 (5.7%), respectively. Challenges and limitations of the platforms evaluated are discussed. These data add to our knowledge regarding interethnic variability in CYP2D6 activity and contribute to improving drug therapy in the Thai.

Aim: The role of sex on the association of plasma prolactin levels with risperidone (R) and 9-hydroxyrisperidone (9-OHR) concentrations is investigated. Methods: Plasma R and prolactin concentrations, CYP2D6 and exon 21 and 26 ABCB1 gene variants were studied in 110 patients. Results: In females, a 1 ng/ml increase in R levels was associated with a significant 1.02% increase in prolactin levels. In males, a 1 ng/ml increase in 9-OHR levels was associated with a significant 1.18% increase in prolactin levels. ABCB1 haplotype 12 had significant but opposite effects in males and females. In the combined sample, 9-OHR, but not R levels had significant effects on prolactin levels. Conclusion: Genes had sex-specific effects on risperidone-associated prolactin elevations.

Aim: To assess impact and value of using clinical decision support (CDS) to drive providers toward online pharmacogenomics education. Materials & methods: CDS was used to target prescribers of codeine/tramadol, send an educational email, display alert/inbox and provide links to an online resource. Providers were surveyed to assess impact. Results: Of the methods used to target providers, educational email was more effective (7.2%). Survey response rate was 29.2% (n = 528/1817). Of respondents, 57.4% reported opening the email and 27.1% accessed the online resource. Of those accessing the resource, 89% found it useful and learned something new about pharmacogenomics. Conclusion: The impact of using CDS to target pharmacogenomics education was limited. However, providers accessing the online resource found it useful and educational.

Aim: To analyze the distribution of CYP2D6 variants in two ethnically-related Mexican Native and Mestizo populations cohabitating the same econiche and their relationships with a distant Mestizo community. Materials & methods: 314 volunteers were genotyped for CYP2D6 gene variants (*2, *3, *4, *6, *10, *13, *17, *35 and *41) using predesigned TaqMan probes. CYP2D6*5 and CYP2D6 wtxN were assessed by XL-PCR. Results: CYP2D6*1, *2, *4 and *10 variants represented above 80.9% of total alleles. Chiapanecan communities showed low allele diversity compared with the northeastern population. Principal component analyses demonstrated clustering of both Mestizo populations. Variants associated to ultrarapid and poor metabolism were rare in Natives. Conclusion: Sharing of CYP2D6 alleles in both Chiapanecan populations suggests an ongoing gene-flow. Original submitted 8 December 2014; Revision submitted 13 February 2015

Tamoxifen has been used not only for the treatment or prevention of recurrence in patients with estrogen receptor positive breast cancers but also for recurrent breast cancer. Because CYP2D6 is known to be an important enzyme responsible for the generation of the potent tamoxifen metabolite, ‘endoxifen’, lots of studies reported that genetic variation which reduced its enzyme activity were associated with poor clinical outcome of breast cancer patients treated with tamoxifen. However, there are some discrepant reports questioning the association between CYP2D6 genotype and clinical outcome after tamoxifen therapy. Dose-adjustment study of tamoxifen based on CYP2D6 genotypes provides the evidence that dose adjustment is useful for the patients carrying reduced or null allele of CYP2D6 to maintain the effective endoxifen level. This review describes critical issues in pharmacogenomic studies as well as summarizes the results of the association of CYP2D6 genotype with tamoxifen efficacy.

Currently, most guidelines on drug–drug interaction (DDI) neither consider the potential effect of genetic polymorphism in the strength of the interaction nor do they account for the complex interaction caused by the combination of DDI and drug–gene interaction (DGI) where there are multiple biotransformation pathways, which is referred to as drug–drug–gene interaction (DDGI). In this systematic review, we report the impact of pharmacogenetics on DDI and DDGI in which three major drug-metabolizing enzymes – CYP2C9, CYP2C19 and CYP2D6 – are central. We observed that several DDI and DDGI are highly gene-dependent, leading to a different magnitude of interaction. Precision drug therapy should take pharmacogenetics into account when drug interactions in clinical practice are expected.

Aim: The antidepressant venlafaxine (VEN) is metabolized by CYP2D6 and CYP2C19. The aim of this study was to assess the relevance of generalizing to daily practice the genotyping of CYP2D6 and CYP2C19 to predict VEN efficacy in depressed patients treated in psychiatric settings. Patients & Methods: This study was nested in a naturalistic cohort, with 206 patients requiring a new antidepressant treatment and genotyped for CYP2D6 *3, *4, *5 del, *6, *2xN, *10, *41 and CYP2C19 *2, *3, *4, *5, *17 alleles. Results: CYP2D6 and CYP2C19 phenotypes were associated neither with the Hamilton depression rating scale score improvement, nor with response and remission. Conclusion: Routine CYP2D6 and CYP2C19 genotyping cannot be recommended to predict VEN efficacy in depressed patients treated in psychiatry settings.

Pharmacogenetics within psychiatry has the potential to aid in the dose and selection of medications. A substantial number of psychiatric medications are metabolized through either of the highly polymorphic drug-metabolizing enzymes CYP2D6 and CYP2C19. Of these, clomipramine is subject to metabolism by both CYP2C19 and CYP2D6, leaving individuals with deficiencies of these drug-metabolizing enzymes at risk of higher concentrations of the parent molecule. Herein, we present the case of a 29-year-old male with diagnoses of depression and obsessive compulsive disorder who had trialed and failed a dozen psychiatric medications, many of which are subject to metabolism by CYP2D6 and/or CYP2C19, and had most recently been taking clomipramine for approximately 2.5 years. Pharmacogenetic testing revealed this patient to be an intermediate metabolizer for both CYP2C19 (*1/*2) and CYP2D6 (*4/*41), which resulted in considerably elevated serum trough concentrations of clomipramine and its active metabolite desmethylclomipramine. This case provides a retrospective view of how the knowledge of an individual’s pharmacogenetic test results can aid in their clinical care.

Aim: Therapy with low-dose amitriptyline is commonly used to treat painful diabetic peripheral neuropathy. There is a knowledge gap, however, regarding the role of variable CYP2D6-mediated drug metabolism and side effects (SEs). We aimed to generate pilot data to demonstrate that SEs are more frequent in patients with variant CYP2D6 alleles. Method: To that end, 31 randomly recruited participants were treated with low-dose amitriptyline for painful diabetic peripheral neuropathy and their CYP2D6 gene sequenced. Results: Patients with predicted normal or ultra-rapid metabolizer phenotypes presented with less SEs compared with individuals with decreased CYP2D6 activity. Conclusion: Hence, CYP2D6 genotype contributes to treatment outcome and may be useful for guiding drug therapy. Future investigations in a larger patient population are planned to support these preliminary findings.

CYP2D6*84 was first described in a Black South African subject, however, its function remains unknown. Astrolabe, a probabilistic scoring tool developed in our laboratory to call genotypes from whole genome sequence, identified CYP2D6*84 in a trio. The father presented with intermediate metabolism when challenged with the CYP2D6 probe drug dextromethorphan (DM/dextrorphan [DX] = 0.0839). Since his second allele, CYP2D6*12, is nonfunctional, the observed activity is derived by CYP2D6*84. This finding suggests that the allele's hallmark P267H causes decreased activity toward DM and that this allele should receive a value of 0.5 for Activity Score calculations. The mother's DM/DX of 0.0543 was consistent with the decreased activity classification of CYP2D6*29. The child, a critically ill neonate, was not phenotyped, but predicted to be a normal metabolizer.

Aim: Oxycodone is partly metabolized to the active metabolite oxymorphone by hepatic CYP2D6 in the liver. Significant genetic variability in CYP2D6 activity affects oxymorphone formation. This study aimed to associate CYP2D6 genotype and oxycodone's metabolism. Methods: 30 children were administered oral oxycodone postoperatively. Plasma levels of oxycodone and oxymorphone, and CYP2D6 genotype were analyzed. CYP2D6 genotype and oxycodone metabolism phenotype were determined based on CYP2D6 total activity score (TAS) and metabolism phenotype: poor metabolizer (PM), intermediate metabolizer (IM), extensive metabolizer (EM) or ultrarapid metabolizer (UM). Results: Compared with PM/IM subjects, significantly greater oxymorphone exposure was seen in EM subjects (p = 0.02 for Cmax, p = 0.016 for AUC0–6 and p = 0.026 for AUC0–24). Similarly, higher TAS value was found to be associated with greater oxymorphone exposure. Higher conversion of oxycodone to oxymorphone was observed in EM subjects compared with PM/IM subjects (p = 0.0007 for Cmax, p = 0.001 for AUC0–6 and p = 0.004 for AUC0–24). Conclusion: CYP2D6 phenotypes explain metabolism of oxycodone in children, and oxymorphone exposure is higher in CYP2D6 EM phenotype. Further studies are needed to predict the occurrence of adverse event and tailor oxycodone dose for a specific CYP2D6 phenotype.

AIM: Genetic variants for selective serotonin reuptake inhibitor (SSRI) metabolizing enzymes have been hypothesized to be a risk factor for aggression as adverse drug effect of SSRIs. Our aim was to assess the possible involvement of these polymorphisms on aggression when using SSRIs.MATERIALS & METHODS: A retrospective noninterventional case-control study was performed on 18 cases. The genetic profile of two main genes involved in the metabolism of SSRIs was determined, and predicted phenotype frequencies were compared with Dutch controls and literature data.RESULTS: Predicted CYP2C19 and CYP2D6 phenotypes for all SSRIs analyzed together did not show a significant difference between cases and controls.CONCLUSION: We found no supporting evidence for a significant relationship between CYP2C19 and CYP2D6 polymorphisms, and aggression in patients using SSRIs.

Aim: In previous CYP2D6 genotyping studies in Mexican–Amerindians a very low frequency of poor metabolizers (PMs) has been reported. Moreover, ultrarapid metabolizers (UMs) status has only been analyzed in some groups from Northern Mexico. Materials & methods: In the present study we evaluated the hypothesis of low frequency of PMs in Mexican–Amerindians in Southern Mexican populations from Chiapas (Lacandones [ML] vs Mestizos [MM]). The frequency of UMs is also reported. CYP2D6 alleles *2, *3, *4, *5, *6, *10, *17, *35 and *41 and copy number variations were analyzed in 154 ML and 100 MM healthy volunteers. Results: The PM frequency was 0% in MLs and 1% in MMs, and for UMs was 2.6% in MLs and 3% in MMs. Conclusion: The present data support previous findings reporting a very low frequency of CYP2D6 PMs in Mexican–Amerindians. Furthermore, the predicted UM phenotype in both MMs and MLs was lower than those reported for most Mexican populations. Original submitted 16 May 2014; Revision submitted 26 September 2014

Aim: Polymorphisms in CYP2D6 impact the interindividual and interethnic variability of drug efficiency; therefore, we determined the CYP2D6 allele distribution in eight Amerindian groups from northwestern Mexico and compared them with the frequencies in Mexican Mestizos. Materials & methods: A total of 508 Amerindians were studied. Genotyping of CYP2D6*5 and multiplication alleles was performed by long-range PCR, while CYP2D6*2, *3, *4, *6, *10, *17, *29, *35, *41 and copy number were evaluated by real-time PCR. Results: The most frequent alleles were CYP2D6*2 (0.05–0.28), CYP2D6*4 (0.003–0.21) and multiplications (0.043–0.107). CYP2D6*5, *6, * 10 and *41 were not observed in the majority of Amerindians, and CYP2D6*3, *17, *35 and *29 were not detected. The poor metabolizer genotype ( *4/*5) was lower (0.2%) in Amerindians than in Mestizos (5%); conversely, the ultrarapid metabolizer genotype was higher (12.6%) in indigenous groups than in Mestizos (7%). Conclusion: Our data show a lower frequency of CYP2D6 inactive alleles and a higher frequency of duplication/multiplication of CYP2D6 active alleles in indigenous populations that in Mestizos. Original submitted 14 August 2013; Revision submitted 7 October 2013