A precision medication study of atomoxetine in children with attention deficit hyperactivity disorder: CYP2D6 genetic testing and therapeutic drug monitoring / 中国当代儿科杂志

Atomoxetine is the first non-stimulant drug for the treatment of children and adults with attention deficit hyperactivity disorder (ADHD), and its safety and efficacy show significant differences in the pediatric population. This article reviews the genetic factors influencing the pharmacokinetic differences of atomoxetine from the aspect of the gene polymorphisms of the major metabolizing enzyme CYP2D6 of atomoxetine, and then from the perspective of therapeutic drug monitoring, this article summarizes the reference ranges of the effective concentration of atomoxetine in children with ADHD proposed by several studies. In general, there is an association between the peak plasma concentration of atomoxetine and clinical efficacy, but with a lack of data from the Chinese pediatric population. Therefore, it is necessary to establish related clinical indicators for atomoxetine exposure, define the therapeutic exposure range of children with ADHD in China, and combine CYP2D6 genotyping to provide support for the precision medication of atomoxetine.

Association of CYP2D6 (G1934A) gene and hematological disturbances in chronic pesticide exposures

Cytochrome P450 family genes (CYPs) have common polymorphisms, which are evaluated for pesticide-inducedoxidative stress susceptibility. Variant alleles in CYP enzymes may uncover susceptibility biomarkers of environmentaltoxicity. This study aims to investigate the relationship between CYP2D6 (G1934A) gene polymorphisms and chronicpesticide exposures, and to evaluate the association between CYP2D6 (G1934A) gene polymorphism on biochemicaland hematological parameters. A cross-sectional study was carried out at a health promoting hospital, Suphan Buri,Thailand. Rice farmers and a control group (n = 50 for each) were recruited and their personal data were collected. Theirblood samples were obtained by venepuncture and drawn into plain and Ethylenediaminetetraacetic acid (EDTA) tubes.Serum cholinesterase (SChE), liver function test, kidney function test, and complete blood count were assessed usingautomatic analyzers; and CYP2D6 (G1934A) genotyping was carried out by polymerase chain reaction-restrictionfragment length polymorphism (PCR-RFLP). SChE in rice farmers was significantly lower (p = 0.033), which maybe related to the use of chlorpyrifos. The genotypes were significantly different between rice farmers and the controlgroup (p = 0.0001), and the GA variant in rice farmers was more frequent. The CYP2D6 (G1934A) (rs 3892097))gene and SChE level were negatively correlated (r = −0.258, p = 0.009). However, other biochemical parameters werenot different. Blood indices, including mean corpuscular hemoglobin (MCH), mean corpuscular volume (MCV), andmean corpuscular hemoglobin concentration (MCHC), values of rice farmers were significantly lower than the controlgroup; and MCH, MCV, and MCHC values of the GA variant were also significantly lower than the wild type. The GAgenotype was associated with hematological toxicity of organophosphate metabolite in chronic exposures.

Prevalência de coprescrição clinicamente significativa de psicofármacos inibidores da enzima CYP2D6 em usuários de um centro de atenção psicossocial / The prevalence of co-prescription of clinically relevant CYP enzyme inhibitor psychotropic drugs in psychosocial care center users

Objetivo: mensurar a prevalência da coprescrição de psicofármacos inibidores clinicamente significativos da enzima CYP2D6. Métodos: estudo transversal realizado com usuários do Centro de Atenção Psicossocial de um município da Amazônia Legal. Os dados foram coletados de prontuário (medicamentos e diagnóstico clínico) e questionário semiestruturado (sociodemográficos). As informações referentes às medicações (substrato/inibidor da CYP2D6) foram consultadas no Micromedex®, Drug Interaction Checker, Food and Drug Administration e The Pharmacogene Variation Consortium. Os dados foram interpretados utilizando estatística descritiva percentual simples, considerando a média e o desvio-padrão. Para a confecção do banco de dados, utilizou-se o Office Excel®2010. Estudo aprovado pelo Comitê de Ética em Pesquisa sob o Parecer nº 289.937. Resultados: participaram deste estudo 43 pessoas com média de idade de 40,98 (±11,04) anos, sendo 55,81% do sexo masculino, 81,39% solteiros, 88,37% não brancos (pretos/pardos), 58,14% estudaram até o ensino médio e 62,79% tiveram diagnóstico F20 (esquizofrenia e subdivisões). Entre a população estudada, 100% (43/43) faziam uso diário de haloperidol, e 95,34% (41/43) encontravam-se em uso rotineiro de mais de uma droga metabolizada pela enzima CYP2D6. Verificou-se que 93% (40/43) dos participantes continham coprescrição de substratos e inibidores da enzima CYP2D6, sendo a maior prevalência de prescrições envolvendo ácido valproico, clorpromazina, levomepromazina, prometazina e risperidona. Conclusão: o estudo pôde mensurar alta prevalência de coprescrição de psicofármacos inibidores clinicamente significativos da enzima CYP2D6.

Introduction: Clinically significant adverse drug reactions are seldomly frequent, but their incidence rises when there is co-prescription, especially psychoactive drugs metabolized by the enzyme CYP2D6. Objective: To measure the prevalence of co-prescription of clinically significant CYP2D6 enzyme inhibitors. Methods: Cross-sectional study conducted with users of the Center for Psychosocial Attention in a city of Legal Amazon. Sociodemographic, health and drug profile data were collected from patients' records. Possible enzymatic inductions or inhibitions were researched in Micromedex®, Drug Interaction Checker, Food and Drug Administration e The Pharmacogene Variation Consortium. The data were interpreted using simple percentage descriptive statistics, considering the mean and standard deviation. To make the database, Office Excel®2010 was used. The research has the approval of the Research Ethics Committee under opinion no. 289,937. Results: Forty-three people with a mean age of 40.98 (±11.04) years participated in this study, 24 (55.81%) men, 81,39% single, 88,37% non-white, 58,14% have high school and 62,79% were diagnosed with schizophrenia. Among the studied population, 100% (43/43) used haloperidol daily and 95.34% (41/43) used more than one drug inhibitor or metabolized by the CYP2D6 enzyme. It was found that 93% of the participants contained co-prescription of CYP2D6 substrates and inhibitors, with the highest prevalence of prescriptions involving valproic acid, chlorpromazine, levomepromazine, promethazine and risperidone. Conclusion: The study was able to measure the high prevalence of co-prescription of clinically significant CYP2D6 inhibitor drugs in the studied population.

Influence of CYP2D6 gene polymorphism on the effect of tropisetron in preventing chemotherapy induced nausea and vomiting / 中国临床药理学与治疗学

Tumors pose a great threat to human health. As a systemic treatment, chemotherapy has held an unshakable position in tumor treatment. Chemotherapy induced nausea and vomiting (CINV) is a common adverse reaction during chemotherapy, which seriously affects patients' mood, quality of life and tumor control. The prevention and treatment of CINV is very important for cancer patients. As a more commonly used 5-HT3 receptor antagonist, tropisetron has a good clinical effect in the prevention and treatment of CINV. However, there are still some patients who do not have a good effect after using tropisetron. More and more studies indicated that these individual differences might be closely related to genetic polymorphisms. In order to provide ideas for clinical individualized medication under the guidance of gene polymorphisms, this article reviewed the influence of CYP2D6 gene polymorphisms on the effect of tropisetron in preventing CINV.

Polimorfismo do gene CYP2D6 1846 G/A em associação com o Acidente Vascular Encefálico/Aneurisma em uma população do Distrito Federal (Brasil) / CYP2D6 1846 G/A gene polymorphism in association with Hemorrhagic Stroke/Aneurysm in patients from the Federal District (Brazil)

Objetivo: Investigar uma possível associação do gene CYP2D6 1846 G/A em pacientes que possuem AVEH/Aneurisma, residentes no Distrito Federal (Brasil) além de cruzar as informações obtidas com as manifestações clinicas e o prognóstico. Método: Tratou-se de um estudo caso-controle de base populacional, envolvendo 81 casos com AVEH e/ou Aneurisma. Para a genotipagem dessas amostras utilizou-se a técnica laboratorial PCR-RFLP e adotou-se o nível de significância de 5%. Resultados: Ao associar as frequências genotípicas e alélicas em relação ao AVEH/Aneurisma, percebeu-se que não houve diferença estatística. Em relação à média de glicemia, participantes com genótipo GG, apresentavam índices elevados desse marcador no grupo caso quando comparado ao grupo controle. Conclusão: A presença do polimorfismo CYP2D6 1846 G/A deve ser amplamente estudada em pesquisas futuras, pois é necessário esclarecer se tais polimorfismos representam associações ao AVEH/Aneurisma.

Objective: To investigate a possible association of the CYP2D6 1846 G/A gene in HS/aneurysm patients residing in the Federal District (Brazil), as well as to crosscheck the information obtained with clinical manifestations and prognosis. Method: The investigation was a population-based case-control study involving 81 cases with HS/aneurysm. The samples genotyping employed the PCR-RFLP technique with a significance level of 5%. Results: The attempt to associate genotypic and allelic frequencies to the HVA/Aneurysm resulted in no statistical difference. Nevertheless, in patients with the GG genotype and hypertension, the risk for HS increased 44 times. Participants with GG genotype also had statistically higher glycemia mean levels in the case group. Conclusion: The presence of the CYP2D6 1846 G/A polymorphism should be extensively, as it is necessary to clarify whether such polymorphisms represent associations with HS and Intracerebral Aneurysm.

Correlation between CYP2D6 polymorphism and risperidone metabolism in schizophrenic patients / 中华检验医学杂志

Objective To investigate the effect of CYP2D6 gene polymorphism on risperidone (RISP) metabolism in schizophrenic patients. Methods CYP2D6 allele polymorphisms including*10,*4,*41 and *2 was detected by real-time fluorescent PCR in 120 schizophrenic patients who have taken risperidone continually. Alleles without SNP mutations were classified as wild-type (WT). At the same time, serum risperidone and 9-hydroxyrisperidone concentration of all patients were detected by mass spectrometric analysis. Some samples were selected for DNA sequencing of CYP2D6*10, which is the most common CYP2D6 allele in Oriental population. The 120 patients were divided into three groups according to their allele variants. Group 1 was defined as carriers of two functional alleles, group 2 was defined as carriers of one defective allele, group 3 was defined as carriers of two defective alleles. Genotype distributions, alleles frequencies, RISP, 9-oh-RISP, RISP+9-OH-RISP, 9-oh-RISP/RISP among three groups were calculated.Results Group 1 amount to 23 cases including 13 cases of WT/WT, 7 cases of*2/*2, 3 cases of WT/*2. Group 2 amount to 51 cases, including 38 cases of WT/*10, 8 cases of *2/*10, 1 case of *2/*41, 4 cases of WT/*41. Group 3 amount to 46 cases, including 44 cases of *10/*10, 2 cases of *10/*41. The*4 allele was not detected. The allele frequency of WT, *2, *10 and *41 was 29.6％, 10.8％, 56.7％ and 2.9％, respectively. The 9-hydroxyrisperidone/risperidone-ratio of three groups were 15.24±5.77, 11.06±4.56 and 2.39 ± 1.06, respectively. There was a significant difference in 9-hydroxyrisperidone/risperidone-ratio between Group 3 and the first two groups (P<0.001). Conclusions The frequency of *10 allele was the highest among the subjects. The frequency of WT and*2 allele was over 95％in the population. Individuals carrying one defective allele of CYP2D6 will decrease the rate of risperidone metabolism slightly, while individuals carrying two defective alleles of CYP2D6 may decrease the rate of risperidone metabolism significantly.

Effects of CYP2D610 on plasma trough concentration of metoprolol in patients with coronary artery disease / 南方医科大学学报

OBJECTIVE@#To study the effect of CYP2D610 (c.100 C>T) on plasma trough concentrations of metoprolol and its metabolite α-hydroxy metoprolol, blood pressure and heart rate in patients with coronary artery disease.@*METHODS@#The patients with coronary artery disease taking metoprolol tablets (=128) and those taking metoprolol sustained-release tablets (=126) were genotyped for CYP2D610 using Taqman real-time quantitative PCR. The trough concentrations of metoprolol and α-hydroxy metoprolol were determined with UPLC-MS/MS, and the dose-normalized concentrations (C/D) were compared among the patients with different CYP2D610 genotypes in both groups. Resting blood pressure and heart rate were recorded in all the patients when the concentration of metoprolol reached the steady state and were compared among the patients with different genotypes.@*RESULTS@#In patients taking metoprolol sustained-release tablets, the plasma trough concentration of α-hydroxy metoprolol was significantly associated with the systolic blood pressure (=0.0204). The CYP2D610 poor metabolizers showed a significant association with the C/D of metoprolol and α-hydroxy metoprolol ( < 0.01) in patients receiving metoprolol in both formulations, and in both groups, the C/D of metoprolol was significantly higher in the patients with a TT genotype than in those with a CC or CT genotype ( < 0.01); compared with those with the CT genotype, the patients with the TT genotype had a significantly lower C/D of α-hydroxy metoprolol ( < 0.01). In patients taking metoprolol sustained-release tablets, those with the CT (=0.0281) and TT (=0.0196) genotypes had lower diastolic blood pressure than patients with the CC genotypes, but the systolic blood pressure or heart rate did not differ significantly among them.@*CONCLUSIONS@#CYP2D610T allele mutation can reduce the metabolism of metoprolol, increase the C/D of metoprolol and decrease the C/D of α-metoprolol and diastolic blood pressure in patients with coronary artery disease, but CYP2D610 variation does not significantly affect systolic blood pressure or heart rate in the patients when the concentration of metoprolol reaches a steady state.

Correlation between CYP2D6 gene polymorphism and tamoxifen metabolism in breast cancer patients / 实用肿瘤学杂志

Objective The objective of this study was to investigate the relationship between CYP2D6 gene polymorphisms and the concentrations of tamoxifen metabolites in breast cancer patients. Methods Peripheral blood samples from breast cancer pa-tients were collected to detect the single nucleotide polymorphism(SNP)of s16947,rs1065852 and rs28371725 gene sites on CYP2D6 gene from January 2010 to December 2012. Genotypes of the three SNPs of CYP2D6 and the concentrations of tamoxifen metabolites were detected in breast cancer patients. Statistical analysis was performed using an independent sample Kruskal-Wallis test in a non-parametric test. Results There was a statistical difference in the concentrations of tamoxifen metabolites 4-OH-N-D-TAM and 4′OH-N -D -TAM in the blood in different CYP2D6 gene genotype carriers at rs16947 site ( P =0. 049), indicating that the rs16947 site of CYP2D6 gene affected the metabolism of tamoxifen drug in breast cancer patients. Conclusion The genotype of CYP2D6 gene at rs16947 site is related to the blood concentration of tamoxifen metabolites in breast cancer patients.

Pharmacogenetics and Depression: A Critical Perspective

Depression leads the higher personal and socio-economical burden within psychiatric disorders. Despite the fact that over 40 antidepressants (ADs) are available, suboptimal response still poses a major challenge and is thought to be partially a result of genetic variation. Pharmacogenetics studies the effects of genetic variants on treatment outcomes with the aim of providing tailored treatments, thereby maximizing efficacy and tolerability. After two decades of pharmacogenetic research, variants in genes coding for the cytochromes involved in ADs metabolism (CYP2D6 and CYP2C19) are now considered biomarkers with sufficient scientific support for clinical application, despite the lack of conclusive cost/effectiveness evidence. The effect of variants in genes modulating ADs mechanisms of action (pharmacodynamics) is still controversial, because of the much higher complexity of ADs pharmacodynamics compared to ADs metabolism. Considerable progress has been made since the era of candidate gene studies: the genomic revolution has made possible to assess genetic variance on an unprecedented scale, throughout the whole genome, and to analyze the cumulative effect of different variants. The results have revealed key information on the biological mechanisms mediating ADs effect and identified hypothetical new pharmacological targets. They also paved the way for future availability of polygenic pharmacogenetic panels to predict treatment outcome, which are expected to explain much higher variance in ADs response compared to CYP2D6 and CYP2C19 only. As the demand and availability of AD pharmacogenetic testing is projected to increase, it is important for clinicians to keep abreast of this evolving area to facilitate informed discussions with their patients.

Impacts of cytochrome P450 2D6 (CYP2D6) genetic polymorphism in tamoxifen therapy for breast cancer impactos do polimorfismo genético do citocromo P450 2D6 (CYP2D6) na terapia com tamoxifeno para câncer de mama

Abstract Tamoxifen (TMX) is the main drug used both in pre and postmenopausal women as adjuvant treatment for hormone receptor-positive breast cancer. An important barrier to the use of TMXis the development ofdrug resistance causedby molecular processes related to genetic and epigenetic mechanisms, such as the actions of cytochrome P450 2D6 (CYP2D6) polymorphisms and of its metabolites. The present study aimed to review recent findings related to the impact of CYP2D6 polymorphisms and how they can affect the results of TMX in breast cancer treatment. The keywords CYP2D6, tamoxifen, and breast cancer were searched in the PubMed, Scopus, The Cochrane Library, Scielo, and Bireme databases. Studies related to other types of neoplasms or based on other isoenzymes from cytochrome P450, but not on CYP2D6, were excluded. The impact of CYP2D6 polymorphisms in the TMX resistance mechanism remains unclear. The CYP2D6 gene seems to contribute to decreasing the efficacy of TMX, while the main mechanism responsible for therapy failure, morbidity, and mortality is the progression of the disease.

Resumo Otamoxifeno é a principal drogaque pode ser utilizada comotratamentohormonal adjuvante empacientesportadoras de câncer demamareceptor hormonal positivotanto na pré- quanto na pós-menopausa.Umadasmaiores barreirasemseu uso é o desenvolvimento de resistência medicamentosa causada por meio de processos moleculares relacionados a mecanismos genéticos e epigenéticos, como a ação dos polimorfismos do gene citocromo P450 2D6 (CYP2D6) e seus metabólitos.Opresente estudo busca revisar as descobertas recentes acerca dos impactos dos polimorfismos do gene CYP2D6 e de como eles podem afetar os resultados do tamoxifeno na terapêutica do câncer de mama. As palavras-chave CYP2D6, tamoxifeno e câncer de mama foram buscadas nas bases de dados Pubmed, Scopus, The Cochrane Library, Scielo e Bireme. Estudos relacionados com outros tipos de câncer ou relacionados a outras isoenzimas do citocromo P450 que não o CYP2D6 foram excluídos. O impacto do polimorfismo do CYP2D6 nos mecanismos de resistência ao tamoxifeno permanecem controversos. O gene CYP2D6 parece reduzir a eficácia do TMX; entretanto, os principais fatores associados a falha terapêutica são morbimortalidade e a progressão da doença

Pharmacogenetic testing in oncology: a Brazilian perspective

Pharmacogenetics, a major component of individualized or precision medicine, relies on human genetic diversity. The remarkable developments in sequencing technologies have revealed that the number of genetic variants modulating drug action is much higher than previously thought and that a true personalized prediction of drug response requires attention to rare mutations (minor allele frequency, MAF<1%) in addition to polymorphisms (MAF>1%) in pharmacogenes. This has major implications for the conceptual development and clinical implementation of pharmacogenetics. Drugs used in cancer treatment have been major targets of pharmacogenetics studies, encompassing both germline polymorphisms and somatic variants in the tumor genome. The present overview, however, has a narrower scope and is focused on germline cancer pharmacogenetics, more specifically, on drug/gene pairs for which pharmacogenetics-informed prescription guidelines have been published by the Clinical Pharmacogenetics Implementation Consortium and/or the Dutch Pharmacogenetic Working Group, namely, thiopurines/TPMT, fluoropyrimidines/UGT1A1, irinotecan/UGT1A1 and tamoxifen/CYP2D6. I begin by reviewing the general principles of pharmacogenetics-informed prescription, pharmacogenetics testing and the perceived barriers to the adoption of routine pharmacogenetics testing in clinical practice. Then, I highlight aspects of the pharmacogenetics testing of the selected drug-gene pairs and finally present pharmacogenetics data from Brazilian studies pertinent to these drug-gene pairs. I conclude with the notion that pharmacogenetics testing has the potential to greatly benefit patients by enabling precision medicine applied to drug therapy, ensuring better efficacy and reducing the risk of adverse effects.

Analysis of CYP2D6 gene polymorphism of Chinese population in Hubei / 国际检验医学杂志

Objective To preliminary study the distribution of CYP2D6 polymorphism in Hubei popula-tion ,with the intention of solid base for further applied research .Methods Venous blood was collected from 137 volunteers ,analysed CYP2D6 * 10 Gene Polymorphism by using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method .genotypes can be distinguished by agarose gel electro-phoresis and gene sequencing .Hardy-Weinberg equilibrium law could be used to detect whether the genotype distribution was balanced ,and chi-square test was used for verification ,and the results were compared with the previous literature .Results Among the 137 samples ,wild type (CC) was 35 ,the frequency was 25 .5% .Het-erozygote (CT) was 52 ,the frequency was 38 .0% .And mutant (TT) was 50 ,the frequency was 36 .5% .Also , Callele frequency was 44 .5% while the Tallele was 55 .5% .There was no statistical difference compared with previous studies (P＞0 .05) .Conclusion Since there is a high mutation frequency of CYP2D6*10 in Hubei population ,it is very necessary to carry out genotyping to guide clinical medication correctly .

Effects of Coix-seed Reactive Derivatives (CRD) on Cytochrome P450 Isoforms CYP3A4, CYP2D6, CYP2C9 In Vitro / 日本補完代替医療学会誌

CRD, a Coix-seed Reactive Derivatives, has a novel mechanism in the treatment of various diseases. In the present study, a fluorometric-based high throughput method using cytochrome P450 (CYP)screening kit was adopted to evaluate in vitro inhibition potential of CRD (CRD 1 and CRD 2) on CYP isoenzymes by calculating remaining enzyme activities and inhibitory potential (IC50 values) using the determined values of fluorescence intensity. IC50　of CRD 1 and CRD 2 were as follows: CYP3A4; >500 µg/ml, 490 µg/ml, CYP2D6; >500 µg/ml，>500 µg/ml，CYP2C9; >500 µg/ml，339 µg/ml, respectively. The result showed that CRD exhibited little activity in the inhibition of CYP3A4, CYP2D6 and CYP2C9.

Influence of CYP2D6 Polymorphism on the Pharmacokinetic/Pharmacodynamic Characteristics of Carvedilol in Healthy Korean Volunteers

BACKGROUND: Carvedilol is commonly used to treat hypertension as a β- and α1-adrenoreceptor blocker, but it is metabolized by CYP2D6, and CYP2D6*10 allele is dominant in Asian population. The objective of this study was to assess the influence of CYP2D6 polymorphisms on the pharmacokinetic (PK) and pharmacodynamic (PD) characteristics of carvedilol in healthy Korean volunteers. METHODS: A PK/PD study for a single and multiple dosing of carvedilol were conducted. All volunteers in 3 genotypic groups received single oral dose of carvedilol 12.5 mg for 3 days, then 25 mg QD for 5 days, and 12.5 mg QD for another 3 days. PK parameters for carvedilol and its three metabolites were determined using non-compartmental analysis. For PD properties, blood pressure, heart rate, and the chronotropic dose 25 (CD25) value were obtained. RESULTS: The IM_2 group with two *10 alleles (intermediate metabolizers) exhibited lower clearance of carvedilol as well as higher area under the curve (AUC) for O-desmethyl carvedilol. The ratio of CD25 to baseline at multiple dosing was significantly higher in the combined IM group (IM_1 and IM_2) than in the EM group, however, the ratio of CD25 after single and multiple dosing and the other PD markers were not significantly different between the 3 genotypic groups compared with the baseline. CONCLUSION: These findings showed that CYP2D6 genotype influenced the PK characteristics of carvedilol and no differences in PD response were observed in Korean healthy volunteers. Registered at the ClinicalTrials.gov, NCT02286934.

Variation of CYP2D6 genotype between Caucasian and Asian population and inconsistency of serum endox-ifen concentration and phenotype of CYP2D6 in Chinese breast cancer patients / 实用医学杂志

Objective To conduct a prospective phase Ⅱ clinical study to explore the distribution of CYP2D6 gene polymorphism in Chinese population and its relationship with the metabolism of tamoxifen in early-stage hormonal receptor-positive breast cancer. Methods CYP2D6 genotype was tested by Sanger sequencing using the ABI 3500 Genetic Analyzer. Plasma concentrations of tamoxifen and endoxifen were measured using the HPLC-MS/MS(API 2000)assay. We downloaded the data of CYP2D6 allele from the CPIP database. Results In Chi-nese patients,the most common alleles were CYP2D6*1,*2,and *10;the predominant diplotypes were *1/*10 (38.3%)and*10/*10(18.8%). The distribution of metabolic phenotype,plasma concentration of endoxifen,and endoxifen:tamoxifen plasma concentration ratio were inconsistent between the normal metabolic phenotype(EM) and the intermediate phenotype(IM)under different CYP2D6 activity prediction criteria.The differences in the ratios and endoxifen plasma concentrations were statistically significant between the three groups by cluster analysis. Conclusions The CYP2D6 genotype distribution in Chinese population is different from that in the Western popu-lation. There is considerable variation of serum endoxifen concentration in Chinese breast cancer patients possess-ing the phenotype previously known as the intermediate active metabolizers of CYP2D6. Therefore,in the current era of precision medicine,the standard CYP2D6 genotype-phenotype classification system cannot properly stratify the Chinese population with different levels of endoxifen plasma concentration.

Research Progress in Drug Interactions of Haloperidol / 中国药师

Objective:To summarize the drug interactions of haloperidol used in combination with the other drugs to provide refer-ence for safe, reasonable and effective use of haloperidol in clinics. Methods:By retrieving Micromedex? , Pubmed, CNKI and so on, the interactions between haloperidol and the other drugs were summarized and analyzed. Results:The effect of haloperidol was on do-pamine receptors, and haloperidol was mainly metabolized by hepatic cytochrome P450 ( CYP) enzymes. When haloperidol was com-bined with the other drugs, significant interactions of pharmacokinetics and pharmacodynamics were induced by affecting CYP enzymes or dopamine receptor. Conclusion:In clinical practice, the other drugs combined with haloperidol should be reasonable and careful to ensure safe, effective and rational drug use.

Involvement of PPARs in the regulation of brain CYP2D by growth hormone / 中国药理学与毒理学杂志

OBJECTIVE CYP2D is one of the most abundant subfamily of CYPs in the brain, especially in the cerebellum. Brain CYP2D is responsible for the metabolism of endogenous neurotransmitters such as tyramine and serotonin. Our previous studies have shown brain CYP2D can be regulated by exogenous and endogenous substances with tissue- specificity. The purpose of this study is to examine the effects of cerebral CYP2D on the mice behavior and the regulatory mechanism of brain CYP2D by growth hormone. METHODS Mice received the stereotaxic injection with CYP2D inhibitor quinine in deep cerebellar nuclei of cerebellum. The animals were tested with rotarod apparatus, balance beam, water maze, elevated plus maze and open field. The changes in CYP2D22, PPARαand PPARγ in brain regions and liver were assayed in male growth hormone receptor knockout mice, SH-SY5Y cells and HepG2 cells. RESULTS The inhibition of cerebellum CYP2D significantly affected the spatial learning and exploring ability of mice. Compared with WT mice, CYP2D expression was lower in brain regions from GHR(-/- ) male mice; however, hepatic CYP2D level was similar. Pulsatile GH decreased PPARα mRNA level, and increased mRNA levels of CYP2D6 and PPARα in SH- SY5Y cells. In HepG2 cells, pulsatile GH resulted in decreases in PPARα and PPARγ mRNA levels, but not CYP2D6. PPARα inhibitor induced CYP2D6 mRNA and protein by 1.32-fold and 1.43-fold in SH-SY5Y cells. PPARγ inhibitor decreased CYP2D6 mRNA and protein by 74.76% and 40.93%. PPARα agonist decreased the level of CYP2D22 mRNA in liver and cerebellum, while PPARγ agonist rosiglitazone resulted in diametrically increases. The luciferase assay showed that PPARγ actived the CYP2D6 gene promoter while PPARα inhibited its function. Pulsatile GH declined the binding of PPARα with CYP2D6 promoter by 40%, promoted the binding of PPARγ with CYP2D6 promoter by approximate 60%. The levels of brain and liver PPARα expression in male GHR(-/- ) mice is obviously higher than those in WT mice. The level of PPARγ in male GHR(-/- ) mice was decreased in the frontal cortex and hippocampus, while remained stable in the cerebellum and striatum; meanwhile, PPARγ was increased in the liver. CONCLUSION Brain CYP2D may be involved in learning and memory functions of central system. Masculine GH secretion altered the PPARs expression and the binding of PPARs to CYP2D promoter, leading to the elevated brain CYP2D in a tissue- specific manner. Growth hormone may specifically alter the metabolic and synthetic of important endogenous substances in the central nervous system (such as serotonin) through the specific regulation of brain CYP2D expression.

Associations of polymorphisms of cytochrome P450 enzymes (CYP2D6 and CYP2C9) with early-onset severe pre-eclampsia and labetalol therapy / 中华围产医学杂志

Objective To explore the associations of the genetic polymorphisms of cytochrome P450, family 2, subfamily D, polypeptide 6 (CYP2D6) and cytochrome P450, family 2, subfamily C, polypeptide 9 (CYP2C9) with early-onset severe pre-eclampsia and the efficacy of labetalol therapy. Methods Totally 105 gravidas diagnosed with early-onset severe pre-eclampsia (experimental group) and 103 healthy gravidas (control group) were recruited from Beijing Obstetrics and Gynecology Hospital between August 2013 and July 2016. Labetalol was given to control blood pressures in gravidas with early-onset severe pre-eclampsia. If labetalol administration alone did not exceed the mean dose (100 mg, one dose per eight hours) and effectively controlled the blood pressures, it would be considered to be valid (n=75), otherwise it would be viewed as an invalid treatment. Genotype and allele frequencies of CYP2C9 gene (rs1057910 and rs4918758) and CYP2D6 gene (rs1065852, rs28371725, rs35742686 and rs3892097) in the gravidas were analyzed by TaqMan probe polymerase chain reaction. Differences in the genotype and allele frequencies were compared between the experimental and control groups, and the valid and invalid labetalol treatment groups. Chi-square test, analysis of variance and LSD test were used as statistical methods. Results The gravidas in both experimental and control groups were AA genotype in CYP2C9 gene rs1057910, TT genotype in CYP2D6 gene rs35742686 and CC genotype in CYP2D6 gene rs3892097. Frequencies of CC and CT genotypes in CYP2D6 gene rs28371725 in the experimental group were 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], and higher C allele frequency in CYP2D6 gene rs28371725 was also observed in the experimental group [46.2% (97/210) vs 35.9% (74/206), χ2=4.529] (all P0.05). 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 24 hours urine protein (LSD test, all P<0.05). The G allele frequency in CYP2D6 gene rs1065852 in invalid labetalol treatment group was higher than that in valid labetalol treatment group [93.3% (56/60) vs 76.0% (114/150), χ2=8.351, P=0.004]. Conclusions The polymorphism of CYP2D6 gene rs28371725 may be associated with early-onset severe pre-eclampsia, and the allele of G in CYP2D6 gene rs1065852 may be associated with the efficacy of labetalol in treatment of early-onset severe pre-eclampsia.

Prediction and visualization of CYP2D6 genotype-based phenotype using clustering algorithms

This study focused on the role of cytochrome P450 2D6 (CYP2D6) genotypes to predict phenotypes in the metabolism of dextromethorphan. CYP2D6 genotypes and metabolic ratios (MRs) of dextromethorphan were determined in 201 Koreans. Unsupervised clustering algorithms, hierarchical and k-means clustering analysis, and color visualizations of CYP2D6 activity were performed on a subset of 130 subjects. A total of 23 different genotypes were identified, five of which were observed in one subject. Phenotype classifications were based on the means, medians, and standard deviations of the log MR values for each genotype. Color visualization was used to display the mean and median of each genotype as different color intensities. Cutoff values were determined using receiver operating characteristic curves from the k-means analysis, and the data were validated in the remaining subset of 71 subjects. Using the two highest silhouette values, the selected numbers of clusters were three (the best) and four. The findings from the two clustering algorithms were similar to those of other studies, classifying *5/*5 as a lowest activity group and genotypes containing duplicated alleles (i.e., CYP2D6*1/*2N) as a highest activity group. The validation of the k-means clustering results with data from the 71 subjects revealed relatively high concordance rates: 92.8% and 73.9% in three and four clusters, respectively. Additionally, color visualization allowed for rapid interpretation of results. Although the clustering approach to predict CYP2D6 phenotype from CYP2D6 genotype is not fully complete, it provides general information about the genotype to phenotype relationship, including rare genotypes with only one subject.

Hiccup Due to Aripiprazole Plus Methylphenidate Treatment in an Adolescent with Attention Deficit and Hyperactivity Disorder and Conduct Disorder: A Case Report

Our case had hiccups arising in an adolescent with the attention deficit and hyperactivity disorder (ADHD) and conduct disorder (CD) after adding aripiprazole treatment to extended-release methylphenidate. Actually, antipsychotics are also used in the treatment of hiccups, but studies suggest that they can cause hiccups as well. Within 12 hours of taking 2.5 mg aripiprazole added to extended-release methylphenidate at a dose of 54 mg/day, 16-year-old boy began having hiccups in the morning, which lasted after 3–4 hours. As a result, aripiprazole was discontinued and methylphenidate was continued alone because we could not convince the patient to use another additional drug due to this side effect. Subsequently, when his behavior got worsened day by day, his mother administered aripiprazole alone again at the dose of 2.5 mg/day at the weekend and continued treatment because hiccup did not occur again. But when it was administered with methylphenidate on Monday, hiccup started again next morning and lasted one hour at this time. In conclusion, we concluded that concurrent use of methylphenidate and aripiprazole in this adolescent led to hiccups.