CYP2D6 Polymorphisms Research Articles

CYP2C9, CYP2C19, CYP2D6 and CYP3A5 polymorphisms in South-East and East Asian populations: A systematic review.

Genetic polymorphism is one of the most important factors responsible for interindividual and interethnic variability in drug response. Studies in major populations, ie, Caucasians, Asians, and Africans, have provided evidence of differences in the genotype frequencies of major drug-metabolizing enzyme cytochrome P450 (CYP). This study aimed to review systematically, all relevant articles related to the genetic polymorphisms in CYP2C9, CYP2C19, CYP2D6 and CYP3A5 in South-East and East Asian (SEEA) populations. Articles that report genetic polymorphisms, genotype frequencies and allele frequencies in CYP2C9, CYP2C19, CYP2D6 and CYP3A5 were retrieved from the PubMed database. A total of 86 studies that fulfilled the eligibility criteria representing different ethnic populations of SEEA, ie, Burmese, Chinese, Japanese, Karen ethnic minority, Korean, Malaysian, Philippino, Singaporean, Taiwanese, Thai, Indonesian, and Vietnamese, were included in the analysis. In general, the genotype frequencies across SEEA populations are comparable. The CYP2C9*1/*1 (69.3%-99.1%), *1/*3 (2.3%-20.1%) and *3/*3 (0%-2.2%) genotypes are reported in most SEEA populations. Six major CYP2C19 genotypes, ie, *1/*1 (6.25%-88.07%), *1/*2 (21.5%-86.46%), *1/*3 (0.8%-15.8%), *2/*2 (3.4%-14.5%), *2/*3 (0%-7.3%) and *3/*3 (0%-10.2%), are reported in most SEEA populations. Major CYP2D6 genotypes include *10/*10 (0%-69.6%), *1/*1 (0%-61.21%) and *1/*10 (0%-62.0%). Major CYP3A5 genotypes are *3/*3 (2.0%-71.4%), *1/*3 (16.0%-57.1%) and *1/*1 (0%-82.0%). Genotyping of abnormal genotypes of CYP2C9 (*1/*3), CYP2C19 (*1/*2, *1/*3), CYP3A5 (*1/*3) and CYP2D6 (*5/*10) associated with IM (Intermediate metabolizer) status, may be clinically beneficial in SEEA populations. Similarly, with CYP2C19 (*2/*2, *2/*3), CYP2D6 (*5/*5 ) linked to PM (Poor metabolizer), CYP2D6 (*10/*10, *1/*5 and to lesser extent *1/*4, *2/*5, *10/*41, *10/*49, *10/*14) and CYP3A5 (*1/*1) associated with EM (extensive metabolizer). Sufficient number of studies has provided comparable results in general. This review suggests that comparable genotype frequencies of CYP2C9, CYP2C19, CYP2D6 and CYP3A5 exist among the SEEA populations. It is noted that more research data are reported from East Asians compared with South-East Asians. Concerned efforts are required to establish partnerships among SEEA countries that will ensure sufficient data from South-East Asian countries which will assist in establishing the databases for SEEA populations.

Assessment of CYP2C9, CYP2C19, and CYP2D6 Polymorphisms in Allergic Patients with Chemical Sensitivity

Background: Self-reported chemical sensitivity (SCS) is characterized by adverse effects due to exposure to low levels of chemical substances. The clinical manifestations of SCS are similar to the allergy, and a high percentage of individuals with both diseases have been found. Various genes, especially genes of importance to the metabolism of xenobiotic compounds, have been associated with SCS. Objectives: The purpose of this study was to investigate whether allergic individuals with chemical sensitivity differed from allergic patients without chemical sensitivity with regard to the distribution of genotype and phenotype of CYP2C9, CYP2C19, and CYP2D6 polymorphisms. Methods: A total of 180 patients were enrolled for this study. A questionnaire was employed to collect information on individual chemical sensitivity, while the Skin prick test and the PATCH test were used to verify the presence of an allergic condition against inhalants or contact allergens, respectively. For the evaluation of the CYP2C9, CYP2C19, and CYP2D6 polymorphisms, we used a strategy based on the amplification of the entire gene coupled to direct genomic DNA sequencing analysis. Results: Overall, a total of 15 different CYP2C9, CYP2C19, and CYP2D6 haplotypes were identified in our population. If the 5 CYP2C9 and the 2 CYP2C19 identified alleles correspond to the previously described ones, 4 of the 8 CYP2D6 haplotypes, detected in the study group, present new SNPs combinations. These new suballeles were categorized as CYP2D6*2M Sa­lento Variant 1, CYP2D6*35B Salento Variant 2, CYP2D6*41 Salento Variant 3, and CYP2D6*4P Salento Variant 4 due to the presence of the key SNPs 2,850 C>T, 31G>A, 2,988 G>A, and 1,846 G>A, respectively. When the allergic individuals are divided into 2 groups according to their SCS score, we observed that the distribution of the CYP2D6 phenotypes was significantly different between the 2 groups. Conclusions: Our idea is that the application of the questionnaire that we have adopted has enabled us to diagnose a degree of chemical sensitivity, which results as comorbid of the allergic disease and in which a condition of poor or intermediate metabolizes for the detrimental CYP2D6 alleles, could represent a discriminant between the chemical sensitivity and the health state.

CYP2D6 Polymorphism in Patients of General Practice in Austria

CYP2D6 Polymorphism in Patients of General Practice in Austria

Effect of genetic polymorphisms on Alzheimer's disease treatment outcomes: an update.

Genetic variations in individuals may cause differences in the response to cholinesterase inhibitor drugs used in the treatment of Alzheimer’s disease (AD). Through this review, we aimed to understand the potential relationship between genetic polymorphisms and treatment response in AD. We conducted a systematic review of the studies published from 2006 to 2018 that assessed the relationship between genetic polymorphisms and the pharmacotherapeutic outcomes of patients with AD. Via several possible mechanisms, genetic polymorphisms of many genes, including ABCA1, ApoE3, CYP2D6, CHAT, CHRNA7, and ESR1, appear to have strong correlations with the treatment response of patients with AD. Indeed, these genetic polymorphisms, either in the form of single nucleotide polymorphisms or direct changes to one or more amino acids, have been shown to cause differences in the therapeutic response. In summary, our findings indicate that genetic polymorphisms should be considered in the management of AD to achieve both effective and efficient treatment outcomes in terms of cost and prognosis.

Abstract P4-03-08: Analyzing the clinical actionability of germline CYP2D6 polymorphism in Chinese breast cancer population

Abstract Background:Tamoxifen is effective for endocrine-responsive breast cancer as adjuvant therapy. CYP2D6 enzyme metabolizes tamoxifen to clinically active metabolites, while CYP2D6 polymorphisms may adversely affect tamoxifen efficacy by some retrospective clinical evidence. This study was carried out to estimate genotype frequencies of common variants of CYP2D6 in Chinese population. The relationship between prescription of selective estrogen receptor modulators (SERMs) and CYP2D6 polymorphism was also analyzed. Methods: This was a retrospective research of early-stage patients who underwent surgical treatment at Fudan University Shanghai Cancer Center with ER+ and/or PR+ breast cancer. Genomic DNA was extracted from peripheral blood, which was used for genotyping CYP2D6*10 (C100T) single-nucleotide polymorphisms by polymerase chain reaction-based methods. Results: A total of 312 patients with primary breast cancer were identified. More than 90.0% patients were in premenopausal status. The allele frequence of CYP2D6*10 in the Chinese population was 54.3%. The genotype frequencies of CYP2D6*10 were 20.5%, 50.3%, 29.2%, for wild-type, heterozygous and homozygous type respectively. We also found this SNP had no significant correlation with clinical characteristics. 145 patients were continuing endocrine treatment in first 5 years. 34.5% patients received CYP2D6 polymorphism test before the prescription of SERMs. The results significantly effected the choice of SERMs. Only 6.2% homozygous type patients took tamoxifen, 45.5% heterozygous patients chose tamoxifen, while 75.0% for wild type. 65.5% patients received CYP2D6 polymorphism test during the treatment of tamoxifen. 63.9% homozygous type patients switched to Toremifene, while 18.9% heterozygous patients changed the endocrine treatment. Conclusions: The results showed that the frequence of CYP2D6*10 allele was high and nearly 30% Chinese breast cancer population were intermediate metabolizer for tamoxifen. The cyp2d6 polymorphism would influence prescription of SERM in premenopausal breast cancer patients. Patients with homozygous types should take other endocrine treatment instead of tamoxifen, which need more evidence of prospective clinical trials. Citation Format: Huang L, Cao A. Analyzing the clinical actionability of germline CYP2D6 polymorphism in Chinese breast cancer population [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P4-03-08.

Pharmacogenomic\u2013pharmacokinetic study of selective estrogen-receptor modulators with intra-patient dose escalation in breast cancer

BackgroundAn association between CYP2D6 polymorphisms and tamoxifen (TAM) efficacy has not been confirmed, partly due to unreliable prediction of active metabolite exposure solely by CYP2D6 activity. The efficacy of TAM dose escalation appears limited in poor TAM metabolizers. Since the chlorine atom on the side chain of toremifene (TOR) prevents 4-hydroxylation by CYP2D6, its contribution to active conversion of TOR is minor. We examined the role of TOR and its dose escalation among poor TAM metabolizers.MethodsThe pharmacokinetics (PK) and pharmacogenomics (PGx) of TAM and TOR were studied. Correlation between PK and CYP2D6 inhibitor use, smoking status, and PGx were examined by regression analysis. For patients showing low endoxifen levels, an intra-patient dose escalation of TOR was conducted, and TOR was increased from 40 to 120 mg for ≥ 24 weeks with PK sampling. Total activity was calculated as the sum of the concentration of each active metabolite adjusted by their respective in vitro activities.ResultsFifty and 11 of the 273 participating patients had endoxifen levels < 15 and < 7.5 ng/mL, respectively. The CYP2D6 genotype was the major determinant for TAM activity (p < 0.01). Smoking status (p = 0.07) and the CYP2C19 phenotype (p = 0.07), but not the CYP2D6 genotype (p = 0.61), showed marginally significant effects on TOR activity. TOR activity increased significantly with dose escalation, even among poor TAM metabolizers, and was maintained for ≥ 24 weeks.ConclusionTOR might be a valid alternative to TAM in patients predicted to be poor TAM metabolizers.

An economic model of the cost-utility of pre-emptive genetic testing to support pharmacotherapy in patients with major depression in primary care.

The pharmacokinetics of many antidepressants (tricyclic antidepressants (TCA) or selective serotonin re-uptake inhibitors (SSRI)) are influenced by the highly polymorphic CYP2D6 enzyme. Therefore, pharmacogenetics could play an important role in the treatment of depressive patients. The potential cost-utility of screening patients is however still unknown. Therefore, a Markov model was developed to compare the strategy of screening for CYP2D6 and subsequently adjust antidepressant treatment according to a patient's metabolizer profile of poor, extensive, or ultra metabolizer, with the strategy of no screening ('one size fits all' principle). Each week a patient had a probability of side effects, which was followed by dosage titration or treatment switching. After 6 weeks treatment effect was evaluated followed by treatment adjustments if necessary, with a total time horizon of the model of 12 weeks. The analysis was performed from a societal perspective. The strategy of screening compared with no screening resulted in incremental costs of €91 (95 percentiles: €39; €152) more expensive but also more effect with 0.001 quality adjusted life years (QALYs) (95 percentiles: 0.001; 0.002) gain. The incremental cost-effectiveness ratio (ICER) was therefore €77,406 per QALY gained, but varied between €22,500 and €377,500 depending on the price of screening and productivity losses. According to our model, we cannot unequivocally conclude that screening for CYP2D6 in primary care patients using antidepressants is be cost-effective, as the results are surrounded by large uncertainty. Therefore, information from ongoing studies should be used to reduce these uncertainties.

Analysis of Lithuanian CYP2D6 polymorphism and its relevance to psychiatric care of the local population

Background: CYP450 system gene CYP2D6 polymorphisms have been associated with an altered response to psychotropic drugs. While there exists interindividual and interethnic differences of clinical significance, there is no data concerning the Lithuanian population.Aims: To determine the distribution of CYP2D6 alleles and predicted phenotype in the Lithuanian population, compare it to other Europeans and find the differences between patients with affective disorders and the healthy population.Methods: Our study sample consisted of 179 subjects that included 104 healthy volunteers and 75 patients with clinical diagnosis of affective disorders according to ICD-10AM classification, treated in hospital settings. DNA samples were taken from the blood and alleles of the CYP2D6 gene were determined for each participant. Frequencies were compared to other Europeans.Results: The frequency of the most common alleles *1 and *2 was 45.0% and 28.8% accordingly. Dysfunctional *5 (1 vs. 30, p < .002) allele was less frequent in Lithuania inhabitants than previously established in other Europeans. There were no polymorphisms of the CYP2D6 gene that could be associated with changes in drug metabolism in the patients. The functional CYP2D6 *2 allele was more prevalent in the control group, while the non functional CYP2D6 *4 allele was more prevalent in the patient group (p < .05 for both cases).Conclusion: The genetic makeup of Lithuanians was generally comparable to other Europeans, but fewer Lithuanians had non-functional *5 allele. More patients had non-functional alleles. Study findings contradict previous results from other countries, where CYP2D6 gene polymorphism was associated with treatment outcomes.

Influence of CYP3A Activity on the Efficacy and Safety of Fluvoxamine in Patients Depressive Disorders and Comorbid Alcohol Use Disorder

Background: Alcohol dependence is often combined with affective disorders, in particular, depressive disorder (DD), which worsens adversely affects the prognosis of the course of both diseases and their outcomes. For the treatment of DD, drugs from the group of selective serotonin reuptake inhibitors, whose representative is fluvoxamine, are used. Fluvoxamine therapy is often associated with a risk of development is shown to be ineffective, and a part of patients develop dose-dependent adverse drug reactions (ADR) and pharmacoresistance.Objective: To study the effects of CYPD6 isoenzyme activity on the efficacy and safety of fluvoxamine therapy in patients with depressive disorders, comorbid with alcoholism.Methods: The study was conducted on 117 Russian patients with DD, alcohol-dependent comorbid. For the purpose of correction of depressive disorders within the framework of cyclothymia, fluvoxamine (Fevarin) was administered to patients at a dosage of 50−150 mg/day. Genotyping was carried out by the method of polymerase chain reaction in Real-time mode with allele-specific hybridization. Efficacy and safety were assessed using validated psychometric scales and an assessment of the severity of ADR. To evaluate the activity of CYP2D6, the method of high performance liquid chromatography with mass spectrometry was used to measure the urinary content of the endogenous substrate of this isoenzyme and its metabolite, the ratio of 6-hydroxy-1,2,3,4-tetrahydro-beta-carboline.Results: By the 9th day of the study, the severity of depressive symptoms on the HAMD scale was statistically significantly different in patients with different genotypes: (GG) 7.0 [6.0; 8.0], (GA) 4.0 [3.0; 5.0] (p0.001); safety indicator, estimated on a UKU scale: 3.0 [2.0; 4.0], (GA) 4.0 [4.0; 4.2] (p0.001). The presence of differences persisted on the 16th day: (GG) 5.0 [3.0; 6.0], (GA) 1.5 [1.0; 3.0] (p0.001); safety indicator, estimated on a UKU scale: (GG) 9.0 [9.0; 10.0], (GA) 6.0 [6.0; 7.0] (p0.001). The calculation of the correlation coefficients between the difference in the number of scores on psychometric scales and the metabolic ratio showed a statistically significant inverse correlation of the average power degree between the efficiency index estimated by the HAMD scale (r=-0.467, p0.05). There was no connection with the difference on the UKU scale (r=0.173, p0.05).Conclusion: In a study of a group of 117 patients with DD, comorbid with alcohol dependence, the effect of CYP2D6 activity, estimated by the ratio of the endogenous substrate concentrations of pinolin and its metabolite 6-hydroxy-1,2,3,4-tetrahydro-beta-carboline, on the efficacy of fluvoxamine therapy. This effect was also shown using the results of genotyping. The results of genotyping also showed the existence of a difference in the safety index in patients with different genotypes from the polymorphic marker CYP2D6 1846GA.

Association of CYP2D6 polymorphisms and extrapyramidal symptoms in schizophrenia patients receiving risperidone: a retrospective study

BackgroundRisperidone is mainly metabolized by cytochrome P450 (CYP) 2D6 in the liver. The gene encoding CYP2D6 is highly polymorphic. The average steady-state plasma concentration of risperidone active moiety is higher in the CYP2D6 intermediate metabolizers (IMs) compared with that in the extensive metabolizers (EMs). An association between drug-induced extrapyramidal symptoms scale (DIEPSS) score and CYP2D6 polymorphisms has not been reported to date. This study investigates the association of CYP2D6 polymorphisms with the severity of extrapyramidal symptoms in schizophrenia patients receiving risperidone therapy.MethodsSchizophrenia patients undergoing risperidone treatment were recruited for the study in the Kobe University Hospital. We evaluated extrapyramidal symptoms of schizophrenia using the DIEPSS. CYP2D6*10 and CYP2D6*14 were analyzed using TaqMan® assays, and CYP2D6*5 was analyzed using the long-PCR method. Patients with CYP2D6*1/*5, *1/*14, *5/*10, *10/*10, and *10/*14 were classified as IMs, and patients with CYP2D6*1/*1 and *1/*10 were classified as EMs. Patients with CYP2D6*5/*5, *5/*14, and *14/*14 were classified as poor metabolizers (PMs).ResultsA total of 22 patients were included in the study. No patients were classified as PMs. The dose of risperidone (mg/day) was not significantly different between EMs (n = 15) and IMs (n = 7) (median with the interquartile range: 4.0 (2.0–6.0) vs. 4.0 (2.0–7.0) mg, p = 0.31). The age and disease duration of schizophrenia were not significantly different between the EMs and IMs. The DIEPSS score in the IMs was significantly higher than that in the EMs (median with the interquartile range: 5.0 (3.5–6.5) vs. 0.0 (0.0–3.0), p < 0.001). The multiple regression analysis showed that CYP2D6 IMs is a significant risk factor for the DIEPSS (p < 0.05).ConclusionSpecial attentions should be paid to the onset of extrapyramidal symptoms in schizophrenia patients identified as CYP2D6 IM undergoing risperidone therapy.

Genetic Polymorphisms and In Silico Mutagenesis Analyses of CYP2C9, CYP2D6, and CYPOR Genes in the Pakistani Population.

Diverse distributions of pharmacogenetically relevant variants of highly polymorphic CYP2C9, CYP2D6 and CYPOR genes are responsible for some varied drug responses observed across human populations. There is limited data available regarding the pharmacogenetic polymorphisms and frequency distributions of major allele variants in the Pakistani population. The present in silico mutagenesis study conducted on genotype pharmacogenetic variants and comparative analysis with a global population aims to extend the currently limited pharmacogenetic available evidence for the indigenous Pakistani population. Extracted genomic DNA from 244 healthy individuals’ venous blood samples were amplified for distinct variant loci in the CYP2C9, CYP2D6 and CYPOR genes. Two-way sequencing results were compared with standard PubMed data and sequence variant loci confirmed by Chromas. This study revealed significant variations in CYP2C9 (rs1799853, rs1057910 and rs72558189), CYP2D6 (rs16947 and rs1135840), and CYPOR (rs1057868, rs781919285 and rs562750402) variants in intraethnic and interethnic frequency distributions. In silico mutagenesis and three-dimensional protein structural alignment analysis approaches clearly exposed the possible varied impact of rare CYPOR (rs781919285 and rs562750402) single nucleotide polymorphisms (SNPs) and confirmed that the influences of CYP2C9 and CYP2D6 variants are consistent with what was found in earlier studies. This investigation highlighted the need to study pharmacogenetic relevance loci and documentation since evidence could be utilized to elucidate genetic backgrounds of drug metabolism, and provide a basis for future pharmacogenomic studies and adequate dose adjustments in Pakistani and global populations.

How to Treat Hypertension in Venlafaxine-Medicated Patients-Pharmacokinetic Considerations in Prescribing Amlodipine and Ramipril.

Amlodipine (AMLO) and ramipril (RAMI) belong to the most prescribed drugs in patients with hypertension, a condition also encountered in depression. Venlafaxine may worsen hypertension because of noradrenergic properties. Although of special clinical relevance, data on pharmacokinetic interactions between AMLO, RAMI, and venlafaxine (VEN) are lacking. Two TDM databases consisting of plasma concentrations of VEN and its active metabolite O-desmethylvenlafaxine (ODVEN) were analyzed. We considered a group of patients comedicated with AMLO, VAMLO (n = 22); a group comedicated with RAMI, VRAMI (n = 20); and a 4:1 control group age matched to the VAMLO group receiving VEN without confounding medications, V0 (n = 88). Plasma concentrations of VEN, ODVEN, and active moiety, AM (VEN + ODVEN); metabolic ratio (ODVEN/VEN); and dose-adjusted plasma concentrations (C/D) were compared using nonparametric tests. Groups did not differ in daily VEN dose, age, or sex. The metabolic ratio (ODVEN/VEN) was lower in the AMLO group (P = 0.029), whereas the RAMI group showed lower values for ODVEN (P = 0.029). All other parameters showed no significant differences. Significantly lower values for the metabolic ratio in the AMLO group are unlikely to be explained by cytochrome P450 (CYP) 3A4 and weak CYP2D6 inhibition by AMLO. Other factors such as differences in CYP2D6 polymorphisms and metabolizer status may better explain the findings. Ramipril showed modest effects with changes in ODVEN concentrations that did not remain significant after dose-adjusted comparisons.

Genetics and genomics in postoperative pain and analgesia.

The review describes recent advances in genetics and genomics of postoperative pain, the association between genetic variants and the efficacy of analgesics, and the role of pharmacogenomics in the selection of appropriate analgesic treatments for postoperative pain. Recent genetic studies have reported associations of genetic variants in catechol-O-methyltransferase (COMT), brain-derived neurotrophic factor (BDNF), voltage-gated channel alpha subunit 11 (SCN11A) and μ-opioid receptor (OPRM1) genes with postoperative pain. The recent pharmacogenetics studies revealed an association of the organic cation transporter 1 (OCT1) and ATP-binding cassette C3 (ABCC3) polymorphisms with morphine-related adverse effects, an effect of polymorphisms in cytochrome P450 gene CYP2D6 on the analgesic efficacy of tramadol and no effect of CYP2C8 and CYP2C9 variants on efficacy of piroxicam. Genetic variants associate with inter-individual variability in drug responses and they can affect pain sensitivity and intensity of postoperative pain. Despite the recent progress in genetics and genomics of postoperative pain, it is still not possible to precisely predict the patients who are genetically predisposed to have severe postoperative pain or who develop chronic postoperative pain.

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

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

Characterization CYP1A2, CYP2C9, CYP2C19 and CYP2D6 Polymorphisms Using HRMA in Psychiatry Patients with Schizophrenia and Bipolar Disease for Personalized Medicine.

The interindividual genetic variations in drug metabolizing enzymes effects the impact and toxicity in plenty of drugs. CYP1A2, CYP2C9, CYP2C19 and CYP2D6 gene polymorphisms were characterized using high resolution melting analysis (HRMA) in follow-up patients in psychiatry clinic as a preliminary preparation for personalized medicine. Genotyping of CYP1A2*1F, CYP2C9 *2, *3, CYP2C19 *2, *3 and *17 and CYP2D6 *3, *4 was conducted in 101 patients using HRMA. Genotype and allele frequencies of the CYP variants were found to be in equilibrium with the Hardy-Weinberg equation. The frequency of the CYP1A2*1F allele in schizophrenia and bipolar disease was 0.694 and 0.255, respectively. The CYP2C9 allele frequencies were 0.087 (CYP2C9*2), and 0.549 (CYP2C9*3) for bipolar; 0.278 (CYP2C9*2) and 0.648 (CYP2C9*3) in schizophrenias. The CYP2C19*2 and *17 allele frequencies was 0.111 and 0.185 in schizophrenia and variant *2 was 0.117 and variant *17 was 0.255 in bipolar group. The frequency of the CYP2D6*3 allele was 0.027 in schizophrenias. The frequencies for the CYP2D6*4 variant were 0.092 and 0.096 in schizophrenia and bipolar groups, respectively. The knowledge in pharmacogenomic and also the developments in molecular genetics are growing rapidly. In future, this can be expected to provide new methodologies in the prediction of the activity in drug metabolizing enzymes. The HRMA is a rapid and useful technique to identify the genotypes for drug dosage adjustment before therapy in psychiatry patients.

A Prospective Study to Evaluate the Effect of CYP2D6 Polymorphism on Plasma level of Risperidone and its Metabolite in North Indian Patients with Schizophrenia.

Background:Risperidone is one of commonly utilized antipsychotic in clinical practice. Various metabolizing enzymes effect the plasma levels of risperidone and its active metabolite and thus its clinical efficacy. So, we attempted to evaluate the relationship between CYP2D6*10 (rs1065852) and CYP2D6*4 (rs3892097) gene polymorphism and the plasma concentration of risperidone and its metabolite in patients with schizophrenia.Methodology:It was a 12-week prospective study carried out in patients diagnosed with schizophrenia. The dose of risperidone was increased weekly by 1 mg and rating of psychopathology was done using Positive and Negative Syndrome Scale (PANSS). Quantification of plasma level of risperidone and 9-hydroxyrisperidone was carried out at week 6 and 12 of treatment. The *4 and *10 alleles of CYP2D6 were genotyped and their effect on metabolism of risperidone was assessed.Results:The number of CYP2D6*4 alleles affected the plasma levels of risperidone, 9-hydroxyrisperidone at 6 weeks of treatment but not at 12 weeks. On the other hand, the number of mutated alleles for CYP2D6*10 influenced the dose corrected plasma concentration of risperidone and active moiety at 12 weeks of treatment. The ratio of plasma concentration of risperidone and 9-hydroxyrisperidone was more than one in all study participants, thus, suggesting that they were poor metabolizers of risperidone.Conclusion:The polymorphism of CYP2D6*10 affects the steady state plasma concentration of risperidone in Indian patients with schizophrenia.

Abstract 1808: The anti-estrogen endoxifen altered bone morphology and reduced muscle function in mice

Abstract Endoxifen, the predominant CYP2D6 metabolite of the selective estrogen receptor modulator (SERM) tamoxifen, is currently being developed as a novel anti-estrogen therapy for the treatment of estrogen receptor (ER)+ breast cancer. Genetic polymorphism of CYP2D6 is a predictor of response to tamoxifen in patients, implicating endoxifen as one of the most active and relevant tamoxifen metabolites. Breast cancer patients treated with adjuvant endocrine therapies including aromatase inhibitors (AIs) and SERMs often report unmanageable musculoskeletal toxicities that can result in treatment discontinuation. While ER binding affinity and anti-tumor effects have been established in preclinical models, the effects of endoxifen on the musculoskeletal system are not fully known. Twenty-week female C57BL/6 mice underwent sham surgery or ovariectomy (OVX) and were treated daily with vehicle, the AI letrozole, or the SERM endoxifen. Body composition was assessed prospectively by DXA. Bone indices and marrow adipose tissue volume were measured by μCT and muscle contractility of the extensor digitorum longus (EDL) was measured ex vivo. After eight weeks, trabecular bone volume fraction (BV/TV) decreased by 50% in OVX-vehicle and OVX-letrozole mice, whereas BV/TV increased threefold in endoxifen mice relative to sham-vehicle. Despite the presence of significantly more trabecular bone following endoxifen treatment, cortical bone analyses revealed impaired periosteal and endosteal expansion of bone, resulting in reduced polar moment of inertia, which is a measure of resistance to fracture. Uterine weight increased significantly in endoxifen-treated mice relative to all OVX groups, similar to what is observed with tamoxifen treatment. Peripheral body fat, bone marrow adipose tissue, and circulating leptin were reduced by endoxifen, suggesting that the drug may elicit positive systemic metabolic effects. At the termination of the study, muscle-specific force was reduced in OVX-endoxifen mice relative to sham-vehicle, OVX-vehicle, and OVX-AI mice, despite no change in muscle mass. While endoxifen shows promise as a potent anti-estrogen therapy for the treatment of ER+ breast cancer, it may be important to monitor patients for endometrial proliferation, morphological changes in bone that increase fracture risk, and for musculoskeletal side effects that could reduce drug compliance. Citation Format: Laura Wright, Khalid Mohammad, Theresa Guise. The anti-estrogen endoxifen altered bone morphology and reduced muscle function in mice [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 1808.

Effects of CYP2D6 and CYP3A5 genetic polymorphisms on steady-state pharmacokinetics and hemodynamic effects of tamsulosin in humans.

Tamsulosin is one of the most potent drugs currently available to treat benign prostatic hyperplasia. Cytochrome P450 (CYP) 2D6 and CYP3A are the two major enzymes responsible for tamsulosin metabolism. The purpose of this study was to evaluate the effects of CYP2D6 and CYP3A5 genetic polymorphisms on the pharmacokinetics and hemodynamic effects of tamsulosin in humans. Twenty-nine male subjects were enrolled and their CYP2D6 (*2,*4,*5,*10,*14,*21,*41, and *xN) and CYP3A5 (*5) genotypes were screened. Tamsulosin was administered daily for 6days to assess its steady-state pharmacokinetics and hemodynamic effects according to CYP2D6 and CYP3A5 genotypes. CYP2D6 group 3 (with genotype *10/*10 or *5/*10) exhibited higher plasma levels than CYP2D6 group 1 (with genotype *1/*1,*1/*2,*1/*2xN, or *2/*10xN) or CYP2D6 group 2 (with genotype *1/*10,*1/*41, or *2/*5) (trough concentrations for groups 1, 2, and 3: 1.3, 1.8, and 3.8ng/mL, respectively [P < 0.001]; peak concentrations for groups 1, 2, 3: 8.3, 10.0, and 13.8ng/mL, respectively [P < 0.005]). Similarly, CYP2D6 genotypes influenced the hemodynamic effects of tamsulosin based on systolic and diastolic blood pressures. However, the CYP3A5*3 polymorphism did not affect tamsulosin plasma levels and its hemodynamic effects. The CYP2D6 but not the CYP3A5 genetic polymorphisms affected the pharmacokinetics and the hemodynamic effects of tamsulosin.

CYP2D6 genotyping in the daily routine of a psychiatric hospital – pharmacoeconomic evaluation

Today, pharmacogenetic tests are commonly used to improve the efficacy and safety of antipsychotic (AP) treatment. However, the economic aspects of their implementation in the psychiatry clinic routine are not well studied. Aim. To evaluate the pharmacoeconomic benefits of CYP2D6 polymorphisms genotyping in psychiatric patients. Materials and methods. CYP2D6 genetic polymorphisms (*3, *4, *5, *6, *1ХN) were tested in 298 psychiatric in-patients. The mean AP daily doses and the hospital stay duration differed between poor (PM), extensive (EM) and ulta-rapid (UM) metabolizers. Based on these data, a pharmacoeconomic decision-making model was created. The model calculates direct medical costs for the patient care with and without pharmacogenetics tests. Results. Pharmacogenetics tests (CYP2D6 genotyping) performed prior to the antipsychotic therapy were shown to be a cost-effective strategy as it gives additional clinical and pharmacological information, optimize the duration of AP treatment, and results in a lower direct medical cost of in-patient care. The cost of genotyping is less than 1% of the total direct medical costs. This strategy remains cost-effective even if the genotyping costs more than 3893.8 RUB (199% of the current value) and also if the differences in the hospital stay durations between PM, EM and UM are not less than 5 days.

Associations of polymorphisms of CYP2D6 and CYP2C9 with early onset severe pre-eclampsia and response to labetalol therapy.

Early onset preeclampsia (PPE) contributes to life-threatening maternal complications and fetal demise. Pharmacogenomics is a precision medicine, and metabolizing enzymes responsive to antihypertensive remains understudied. The aim of this study was to evaluate the associations of polymorphisms of cytochrome P450, family 2, subfamily D, polypeptide 6 (CYP2D6) and cytochrome P450, family 2, subfamily C, polypeptide 9 (CYP2C9) with PPE and the relationship among CYP2D6, CYP2C9 polymorphisms and response to labetalol therapy. Totally 105 gravidas diagnosed with PPE (case) and 103 healthy gravidas (control) were recruited between August 2013 and July 2016. Labetalol was given to control blood pressures (BP) with PPE. If labetalol administration alone did not exceed the mean dose and effectively controlled the BP, it would be considered to be valid (n = 75). Genotype and allele frequencies of CYP2C9 gene (rs1057910 and rs4918758) and CYP2D6 gene (rs1065852, rs28371725, rs35742686, and rs3892097) were analyzed by TaqMan PCR. Differences in the genotype and allele frequencies were compared between case-control groups, and the responsive and nonresponsive to labetalol in PPE. Out of six variants, only CC and CT genotypes of the CYP2D6 variants (rs28371725) in PPE were significantly higher than those in the control group [18.1% (19/105) vs 14.6% (15/103); 56.2% (59/105) vs 42.7% (44/103); χ2 = 6.707]. However, there were no differences in maternal age, diastolic pressure, BMI, BW, serum triglyceride, and creatinine were observed among women with CC, CT, or TT genotype of CYP2D6 gene rs28371725 in the experimental group (all P > 0.05). Compared with the gravidas with CT or TT genotype of CYP2D6 gene rs28371725, those with CC genotype had longer gestational age [(32.5 ± 2.1) vs (29.5 ± 1.8) and (29.8 ± 2.2)weeks] and higher plasma albumin [(27.2 ± 9.3) vs (20.3 ± 10.4) and (22.5 ± 7.4)g/L], but lower systolic pressure and 24h urine protein (LSD test, all P < 0.05). The G allele frequency in CYP2D6 gene rs1065852 nonresponsive to labetalol group was higher than that in responsive labetalol group [93.3% (56/60) vs 76.0% (114/150), χ2 = 8.351, P = 0.004]. The polymorphism of CYP2D6 gene rs28371725 may be associated with PPE, and the allele of G in CYP2D6 gene rs1065852 may be associated with the efficacy of labetalol in treatment of PPE.