Impact of amiodarone use on metoprolol concentrations, α-OH-metoprolol concentrations, metoprolol dosing and heart rate: A cross-sectional study.

Small studies suggest that amiodarone is a weak inhibitor of cytochrome P450 (CYP) 2D6. Inhibition of CYP2D6 leads to increases in concentrations of drugs metabolized by the enzyme, such as metoprolol. Considering that both metoprolol and amiodarone have ß-adrenergic blocking properties and that the modest interaction between the two drugs would result in increased metoprolol concentrations, this could lead to a higher risk of bradycardia and atrioventricular block. The primary objective of this study was to evaluate whether metoprolol plasma concentrations collected at random timepoints from patients enrolled in the Montreal Heart Institute Hospital Cohort could be useful in identifying the modest pharmacokinetic interaction between amiodarone and metoprolol. We performed an analysis of a cross-sectional study, conducted as part of the Montreal Heart Institute Hospital Cohort. All participants were self-described "White" adults with metoprolol being a part of their daily pharmacotherapy regimen. Of the 999 patients being treated with metoprolol, 36 were also taking amiodarone. Amiodarone use was associated with higher metoprolol concentrations following adjustment for different covariates (p = .0132). Consistently, the association between amiodarone use and lower heart rate was apparent and significant after adjustment for all covariates under study (p = .0001). Our results highlight that single randomly collected blood samples can be leveraged to detect modest pharmacokinetic interactions.

Implementation of CYP2D6-guided opioid therapy at Cincinnati Children's Hospital Medical Center.

PURPOSE: We describe the implementation of CYP2D6-focused pharmacogenetic testing to guide opioid prescribing in a quaternary care, nonprofit pediatric academic medical center. SUMMARY: Children are often prescribed oral opioids after surgeries, for cancer pain, and occasionally for chronic pain. In 2004, Cincinnati Children's Hospital Medical Center implemented pharmacogenetic testing for CYP2D6 metabolism phenotype to inform codeine prescribing. The test and reports were updated to align with changes over time in the testing platform, the interpretation of genotype to phenotype, the electronic health record, and Food and Drug Administration (FDA) guidance. The use of the test increased when a research project required testing and decreased as prescribing of oxycodone increased due to FDA warnings about codeine. Education about the opioid-focused pharmacogenetic test was provided to prescribers (eg, the pain and sickle cell teams) as well as patients and families. Education and electronic health record capability increased provider compliance with genotype-guided postsurgical prescribing of oxycodone, although there was a perceived lack of utility for oxycodone prescribing. CONCLUSION: The implementation of pharmacogenetic testing to inform opioid prescribing for children has evolved with accumulating evidence and guidelines, requiring changes in reporting of results and recommendations.

Variability Between Clinical Pharmacogenetics Implementation Consortium (CPIC®) Guidelines and a Commercial Pharmacogenetics Laboratory in Genotype to Phenotype Interpretations For Patients Utilizing Psychotropics.

Clinical practice environments without in-house pharmacogenetic testing often rely on commercial laboratories, especially in the setting of pharmacogenetic testing intended to guide psychotropic use. There are occasionally differences in phenotype assignment and medication recommendations between commercial laboratories and the Clinical Pharmacogenetics Implementation Consortium (CPIC). This may be problematic as many institutions that implement pharmacogenetics consider CPIC to be an important source of guidelines for recommended prescribing actions based on genetics, as well as a tool towards standardizing pharmacogenetics implementation. Here, we completed a retrospective chart review of our academic health system's (Michigan Medicine) electronic health record with the goal of comparing phenotypic assignment of CYP2D6 and CYP2C19 genotypes between the commercial pharmacogenetic lab used most at our institution, and CPIC. Ultimately, we identified 205 patients with available pharmacogenetic results from this lab. The prevalence of conflicting phenotype assignment was 28.8% for CYP2D6 and 32.2% for CYP2C19 genotypes when comparing the commercial lab to CPIC guidelines. In several cases, the phenotypic assignment differences for antidepressants led to significant differences in medication recommendations when comparing the commercial lab report and CPIC guidelines. These results may also have implications for medications outside of psychiatry with recommendations for dose adjustments based on CYP2D6 or CYP2C19 metabolizing phenotype.

A single low dose of primaquine is safe and sufficient to reduce transmission of Plasmodium falciparum gametocytes regardless of cytochrome P450 2D6 enzyme activity in Bagamoyo district, Tanzania.

BACKGROUND: Primaquine is a pro-drug and its active metabolite is potent against mature Plasmodium falciparum gametocytes. Primaquine is metabolized by a highly polymorphic cytochrome P450 2D6 (CYP2D6) enzyme. Mutations in the gene encoding this enzyme may lead to impaired primaquine activity. This study assessed if 0.25 mg/kg single-dose primaquine is safe and sufficient to reduce transmission of gametocytes in individuals with no, reduced, or increased CYP2D6 enzyme activity. METHODS: Between June 2019 and January 2020 children aged 1-10 years, attending at Yombo dispensary, Bagamoyo district, with confirmed microcopy-determined uncomplicated P. falciparum malaria were enrolled in the study. The enrolled patients were treated with a standard artemether-lumefantrine regimen plus 0.25 mg/kg single-dose primaquine and followed up for 28 days for clinical and laboratory assessment. Primaquine was administered with the first dose of artemether-lumefantrine. Safety assessment involved direct questioning and recording of the nature and incidence of clinical signs and symptoms, and measurement of haemoglobin (Hb) concentration. Blood samples collected from 100 patients were used for assessment of post-treatment infectiousness on day 7 using mosquito membrane feeding assays. Molecular methods were used to determine CYP2D6 and glucose-6-phosphate dehydrogenase (G6PD) status. The primary outcome was the safety of 0.25 mg/kg single-dose primaquine based on CYP2D6 status. RESULTS: In total, 157 children [median age 6.4 (Interquartile range 4.0-8.2) years] were recruited, of whom 21.0% (33/157) and 12.7% (20/157) had reduced CYP2D6 and deficient G6PD activity, respectively. Day 3 mean absolute Hb concentration reduction was 1.50 g/dL [95% confidence interval (CI) 1.10-1.90] and 1.51 g/dL (95% CI 1.31-1.71) in reduced and normal CYP2D6 patients, respectively (t = 0.012, p = 0.990). The day 3 mean absolute Hb concentration reduction in G6PD deficient, G6PD normal and heterozygous female was 1.82 g/dL (95% CI 1.32-2.32), 1.48 g/dL (95% CI 1.30-1.67) and 1.47 g/dL (95% CI 0.76-2.18), respectively (F = 0.838, p = 0.435). Sixteen percent (16/98) of the patients each infected at least one mosquito on day 7, and of these, 10.0% (2/20) and 17.9% (14/78) had reduced and normal CYP2D6 enzyme activity, respectively (x2 = 0.736, p = 0.513). CONCLUSION: Single-dose 0.25 mg/kg primaquine was safe and sufficient for reducing transmission of P. falciparum gametocytes regardless of CYP2D6 or G6PD status. Trial registration Study registration number: NCT03352843.

The effect of smoking on the plasma concentration of tricyclic antidepressants: a systematic review.

Smoking is highly prevalent in the psychiatric population, and hospital admittance usually results in partial or complete smoking cessation. Tobacco use is known to affect the metabolism of certain psychoactive drugs, but whether smoking influences the plasma concentration of tricyclic antidepressants (TCAs) remains unclear. This article investigates the possible effect of smoking on the plasma concentration of TCAs. A systematic review of the literature available on PubMed and EMBASE as of October 2020 was carried out using PRISMA guidelines. Studies reporting plasma concentrations of any TCA in both a smoking and a non-smoking group were included and compared. Ten eligible studies were identified and included. In the eight studies investigating the effect of smoking on amitriptyline and/or nortriptyline, five studies found no significant effect. Two studies investigating the effect of smoking on imipramine found a significant effect, and one study investigating the effect of smoking on doxepin found no significant effect. The majority of studies included in this review were influenced by small study populations and other methodical issues. The effect of smoking on the plasma concentration of TCAs is still not entirely clear. There is a possibility that smoking affects the distribution of TCA metabolites, but this is probably not of clinical importance.

[Therapeutic drug monitoring of antidepressants: Why venlafaxine is the most monitored drug? A review of literature]. / Suivi thérapeutique pharmacologique des antidépresseurs : pourquoi la venlafaxine est le médicament le plus surveillé ? Une revue de la littérature.

Venlafaxine is the third most frequently prescribed antidepressant in France the last decade, with about 400,000 daily doses. Therapeutic drug monitoring (TDM) of this medication, by measuring the active moiety venlafaxine (V) and O-desmethylvenlafaxine (ODV), is recommended (level of recommendation 2). However, this antidepressant seems to be the one for which clinicians most often use TDM, much more frequently than escitalopram, which is more prescribed and for which TDM is also recommended. The main goal of this review is to provide an update on the TDM of venlafaxine: its therapeutic interval, its level of recommendation and the origin of its "success". From the literature does not enable to define a therapeutic interval for the active moiety V+ODV, that is to say a steady-state trough concentration allowing a clinical response without toxicity. Nevertheless, a target concentration from 100 to 400µg/L is certainly relevant for the majority of patients without any pharmacodynamic resistance ; though a greater concentration could result in an earlier response or could be required for a clinical response in a minority of patients. A patient with no clinical response despite a concentration greater than 1000µg/L should be proposed another antidepressant. Measurement of the ODV/V ratio is also a useful tool, values below 0.3 usually reflecting a slow metabolizer phenotype for cytochrome P-450 2D6, which is more at risk of adverse effects. Research for this phenotype probably explains many prescriptions for TDM.

The effects of cytochrome P450 2D6 inhibitors on a high-dose tramadol taper for medically supervised opioid withdrawal: a retrospective chart review.

Background: Tramadol is used off-label for medically supervised opioid withdrawal. Tramadol is metabolized by CYP2D6 to an active metabolite with significantly more pharmacologic activity compared to the parent compound.Objectives: The objective of this study is to evaluate the effects of CYP2D6 inhibitors on patient response to a tramadol taper for medically supervised opioid withdrawal.Methods: A retrospective chart review of patients who received a tramadol taper for medically supervised opioid withdrawal was conducted comparing patients who received concomitant moderate-to-strong CYP2D6 inhibitors to patients without concomitant therapy. The primary outcome was the change in Clinical Institute Narcotic Assessment (CINA) scores from baseline to discharge. Secondary outcomes included area under the curve of CINA scores over time, additional CINA outcomes, length of stay, and readmissions.Results: Of 100 charts reviewed, 30 patients received a concomitant moderate-to-strong CYP2D6 inhibitor. There were no statistically significant differences between the baseline demographics of the two groups. Change from baseline CINA to discharge did not differ significantly between the Non-2D6 group and the 2D6 group (-4.0 ± 3.83 and -4.5 ± 4.48 respectively; p = 0.606). The average CINA score for nausea and vomiting was significantly higher in the Non-2D6 group compared to the 2D6 group (0.34 ± 0.35 and 0.18 ± 0.33 respectively; p = 0.019). Otherwise there were no significant differences found in any secondary outcomes.Conclusions: Based on these results, moderate-to-strong CYP2D6 inhibitors do not appear to have a significant impact on the withdrawal course for patients treated with a high-dose tramadol taper.

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.

Consequences of CYP2D6 Copy-Number Variation for Pharmacogenomics in Psychiatry.

Pharmacogenomics represents a potentially powerful enhancement to the current standard of care for psychiatric patients. However, a variety of biological and technical challenges must be addressed in order to provide adequate clinical decision support for personalized prescribing and dosing based on genomic data. This is particularly true in the case of CYP2D6, a key drug-metabolizing gene, which not only harbors multiple genetic variants known to affect enzyme function but also shows a broad range of copy-number and hybrid alleles in various patient populations. Here, we describe several challenges in the accurate measurement and interpretation of data from the CYP2D6 locus including the clinical consequences of increased copy number. We discuss best practices for overcoming these challenges and then explore various current and future applications of pharmacogenomic analysis of CYP2D6 in psychiatry.

A Single Site Population Study to Investigate CYP2D6 Phenotype of Patients with Persistent Non-Malignant Pain.

Background and Objectives: Codeine requires biotransformation by the CYP2D6 enzyme, encoded by the polymorphic CYP2D6 gene, to morphine for therapeutic efficacy. CYP2D6 phenotypes of poor, intermediate, and ultra-rapid metabolisers are at risk of codeine non-response and adverse drug reactions due to altered CYP2D6 function. The aim of this study was to determine whether genotype, inferred phenotype, and urinary and oral fluid codeine O-demethylation metabolites could predict codeine non-response following a short course of codeine. Materials and Methods: There were 131 Caucasians with persistent pain enrolled. Baseline assessments were recorded, prohibited medications ceased, and DNA sampling completed before commencing codeine 30 mg QDS for 5 days. Day 4 urine samples were collected 1-2 h post morning dose for codeine O-demethylation metabolites analysis. Final pain assessments were conducted on day 5. Results: None of the poor, intermediate, ultra-rapid metabolisers and only 24.5% of normal metabolisers responded to codeine. A simple scoring system to predict analgesic response from day 4 urinary metabolites was devised with overall prediction success of 79% (sensitivity 0.8, specificity 0.78) for morphine and 79% (sensitivity 0.76, specificity 0.83) for morphine:creatinine ratio. Conclusions: In conclusion, this study provides tentative evidence that day 4 urinary codeine O-demethylation metabolites could predict non-response following a short course of codeine and could be utilised in the clinical assessment of codeine response at the point of care to improve analgesic efficacy and safety in codeine therapy. We offer a scoring system to predict codeine response from urinary morphine and urinary morphine:creatinine ratio collected on the morning of day 4 of codeine 30 mg QDS, but this requires validation before it could be considered for use to assess codeine response in clinical practice.

The Use of Codeine and Tramadol in the Pediatric Population-What is the Verdict Now?

Codeine and tramadol are opioid analgesics approved for the management of pain in the United States. Both agents are metabolized in the liver to active compounds via the cytochrome P450 2D6 enzyme. Case reports of pediatric patients with overactive CYP2D6 enzymes have been reported. These ultra-rapid metabolizers experience an increase in the production of active metabolites of codeine and tramadol, which can lead to oversedation, respiratory depression, and death. In 2017, the U.S. Food and Drug Administration updated their warnings regarding codeine and tramadol use in the pediatric population, making their use contraindicated in patients under the age of 12 years.

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.

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

Pharmacokinetics of risperidone in different application forms - Comparing long-acting injectable and oral formulations.

We aimed to explore the differences in the pharmacokinetics of risperidone between oral and long-acting injectable (LAI) formulations using a large database of therapeutic drug monitoring (TDM). Plasma concentrations of risperidone (RIS), its active metabolite (9-OH-RIS) and the active moiety (AM) (RIS+9-OH-RIS), their concentration-to-dose (C/D) ratios and ratio of RIS/9-OH-RIS (an index of CYP2D6 metabolic activity) were used to compare patients receiving risperidone orally (n = 851) and those treated with LAI RIS (n = 63). Patients taking CYP inducers or inhibitors or with liver/renal impairment were eliminated. Our study demonstrated that patients on LAI RIS, despite slightly higher RIS doses in the oral group, showed no significant differences in total AM or 9-OH-RIS. Conversely, RIS concentration, RIS C/D ratio and total C/D ratio were slightly higher in the LAI RIS group, reaching significance due to the large sample size. More importantly, the median ratio of RIS/9-OH-RIS was 0.52 in LAI RIS vs. 0.25 in the oral group, providing a significant difference (p < 0.001). After controlling for confounding factors, we replicated the RIS/9-OH-RIS ratio increases in patients with LAI RIS, probably reflecting a decrease in first-pass metabolism. More studies are required to establish the clinical use of TDM for patients on LAI RIS.

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.

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.

Elección del mejor antidepresivo en pacientes con cáncer de mama en tratamiento con tamoxifeno: revisión de la evidencia básica y clínica / Antidepressants agents in breast cancer patients using tamoxifen: review of basic and clinical evidence

Tamoxifen (Tmf), is a standard of care for women with estrogen receptor positive (ER+) breast cancer. Endoxifen is a Tmf metabolite generated by cytochrome P450 2D6 (CYP2D6). Antidepressive agents (AD) are often prescribed to women with breast cancer not only for depression, but also for anxiety and hot flashes. Some AD are substrates or inhibitors of the Tmf metabolic pathway. Therefore there may be interactions when Tmf and AD are prescribed simultaneously. Oncologic protection afforded by Tmf may become less effective or null when AD are indicated, especially in poor metabolizing patients. We performed an update of the literature about the criteria for choosing AD in women receiving Tmf. Tricyclic AD, paroxetine and fluoxetine should be avoided in patients receiving Tmf, because they are strong inhibitors of CYP2D6. Bupropion, duloxetine and sertraline are only moderate inhibitors of the cytochrome and are not contraindicated. Citalopram, desvenlafaxine, escitalopram, milnacipran and venlafaxine are recommended, because they do not influence the metabolism and clinical efficacy of Tmf and have fewer drug interactions. However, other additional pharmacological and clinical issues should be considered when choosing an antidepressant in women with breast cancer.

Genetic Polymorphism of CYP2D6 and Clomiphene Concentrations in Infertile Patients with Ovulatory Dysfunction Treated with Clomiphene Citrate.

CYP2D6 is primarily responsible for the metabolism of clomiphene citrate (CC). The purpose of the present study was to investigate the relationship between CYP2D6 genotypes, concentrations of CC and its major metabolites and drug response in infertility patients. We studied 42 patients with ovulatory dysfunction treated with only CC. Patients received a dose of 100 mg/day CC on days 3-7 of the menstrual cycle. CYP2D6 genotyping and measurement of CC and the major metabolite concentrations were performed. Patients were categorized into CC responders or non-responders according to one cycle response for the ovulation. Thirty-two patients were CC responders and 10 patients were non-responders with 1 cycle treatment. The CC concentrations were highly variable within the same group, but non-responders revealed significantly lower (E)-clomiphene concentration and a trend of decreased concentrations of active metabolites compared to the responders. Nine patients with intermediate metabolizer phenotype were all responders. We confirmed that the CC and the metabolite concentrations were different according to the ovulation status. However, our results do not provide evidence for the contribution of CYP2D6 polymorphism to either drug response or CC concentrations.

Genetic Polymorphism of CYP2D6 and Clomiphene Concentrations in Infertile Patients with Ovulatory Dysfunction Treated with Clomiphene Citrate

CYP2D6 is primarily responsible for the metabolism of clomiphene citrate (CC). The purpose of the present study was to investigate the relationship between CYP2D6 genotypes, concentrations of CC and its major metabolites and drug response in infertility patients. We studied 42 patients with ovulatory dysfunction treated with only CC. Patients received a dose of 100 mg/day CC on days 3-7 of the menstrual cycle. CYP2D6 genotyping and measurement of CC and the major metabolite concentrations were performed. Patients were categorized into CC responders or non-responders according to one cycle response for the ovulation. Thirty-two patients were CC responders and 10 patients were non-responders with 1 cycle treatment. The CC concentrations were highly variable within the same group, but non-responders revealed significantly lower (E)-clomiphene concentration and a trend of decreased concentrations of active metabolites compared to the responders. Nine patients with intermediate metabolizer phenotype were all responders. We confirmed that the CC and the metabolite concentrations were different according to the ovulation status. However, our results do not provide evidence for the contribution of CYP2D6 polymorphism to either drug response or CC concentrations.

Relationship between CYP2D6*10 gene polymorphism and metoprolol therapeutic effect for hypertension / 心血管康复医学杂志

Objective: To study the relationship between CYP2D6*10 gene polymorphism and metoprolol therapeutic effect for hypertension. Methods: A total of 60 patients with essential hypertension (EH) received metoprolol 47.5mg/d for 3d. After 3d the plasma metoprolol concentration after oral 2h was measured. Polymorphism of CYP2D6*10 gene was detected by PCR-RFLP. According to results of gene detection, the patients were divided into CC genotype group (wild type homozygote, fast metabolism type, n=14), CT genotype group (heterozygous mutation, intermediate metabolism type, n=25) and TT genotype group (homozygous mutation, slow metabolism, n=19). Metoprolol dosage was adjusted according to CYP2D6*10 genotype. After one week, plasma concentration of metoprolol after oral 2h was measured again, and mean heart rate and blood pressure were measured before and after gene-directed therapy. Results: Before gene-directed therapy, compared with CC and CT group there was significant increase in plasma concentration of metoprolol [(26.57±19.40) ng/ml vs. (23.88±12.86) ng/ml vs. (64.74±32.94) ng/ml, P0.05 all; Compared with before gene-directed therapy, there was significant increase in plasma concentration of metoprolol, and significant decrease in mSBP, mDBP and mHR in CC group (P0.05). Conclusion: CYP2D6*10 gene polymorphism affects metoprolol metabolism and its therapeutic effect on hypertension, gene-directed therapy can significantly improve drug therapeutic effect and reach ideal therapeutic goal in short time.