RESUMEN

This report presents challenging psychopharmacotherapy management of a psychotic disorder in a patient with a delicate pharmacogenetic profile and drug-drug interactions. A 31-year old woman diagnosed with schizophrenia in 2017 was referred by her psychiatrist to a clinical pharmacologist for interpretation of a pharmacogenetic test and advice regarding optimal psychopharmacotherapy. In spite of adherence to aripiprazole, olanzapine, risperidone, and levomepromazine, and rational anxiolytic therapy, she still experienced anxiety, anhedonia, loss of appetite, sleeping problems, and auditory hallucinations with commands to harm herself. Due to a lack of alternative therapeutic steps, low aripiprazole serum concentrations, and a lack of explanation for pharmacotherapy unresponsiveness, pharmacogenetic testing was performed. The patient was defined as CYP2D6 *1/*1, CYP1A2 *1F/*1F, CYP3A4 *1/*1B, CYP3A5 *1/*3, and having increased activity of the enzymes UGT1A4 and UGT2B7, intermediate activity of ABCB1 transporter, and low activity of COMT. Carbamazepine was discontinued, aripiprazole was increased to a maximum of 30 mg/day orally with long-acting injection (400 mg monthly), and olanzapine was increased to a daily dose of 35 mg orally. These changes led to an optimal therapeutic drug concentration and improved clinical status. At the last follow-up, the patient was without severe auditory hallucinations, became more engaged in daily life, had more interaction with others, had found a job, and even had started an emotional relationship. In psychiatry, pharmacogenetic testing is an important tool for guiding pharmacological therapy, particularly in patients with an unsatisfactory clinical response and a lack of alternative therapeutic steps for pharmacotherapy unresponsiveness.

Asunto(s)

Antipsicóticos , Interacciones Farmacológicas , Humanos , Adulto , Femenino , Antipsicóticos/administración & dosificación , Antipsicóticos/uso terapéutico , Trastornos Psicóticos/tratamiento farmacológico , Trastornos Psicóticos/genética , Aripiprazol/administración & dosificación , Aripiprazol/uso terapéutico , Esquizofrenia/tratamiento farmacológico , Esquizofrenia/genética , Citocromo P-450 CYP1A2/genética , Pruebas de Farmacogenómica , Farmacogenética , Citocromo P-450 CYP3A/genética , Citocromo P-450 CYP2D6/genética

RESUMEN

Aripiprazole once-monthly (AOM) exhibits an important interindividual pharmacokinetic variability with significant implications for its clinical use. CYP2D6 and CYP3A4 highly contributes to this variability, as they metabolize aripiprazole (ARI) into its active metabolite, dehydroaripiprazole (DHA) and the latter into inactive metabolites. This study aims to evaluate the effect of CYP2D6 and CYP3A4 polymorphisms in combination and the presence of concomitant inducers and inhibitors of this cytochromes on ARI and DHA plasma concentrations in a real clinical setting. An observational study of a cohort of 74 Caucasian patients under AOM treatment was conducted. Regarding CYP2D6, higher concentrations were found for active moiety (ARI plus DHA) (AM) (67 %), ARI (67 %) and ARI/DHA ratio (77 %) for poor metabolizers (PMs) compared to normal metabolizers (NMs). No differences were found for DHA. PMs for both CYP2D6 and CYP3A4 showed a 58 % higher AM and 66 % higher plasma concentration for ARI compared with PMs for CYP2D6 and NMs for CYP3A4. In addition, PMs for both CYP2D6 and CYP3A4 have 45 % higher DHA concentrations than NMs for both cytochromes and 41 % more DHA than PMs for CYP2D6 and NMs for CYP3A4, suggesting a significant role of CYP3A4 in the elimination of DHA. Evaluating the effect of CYPD26 and CYP3A4 metabolizing state in combination on plasma concentrations of ARI, DHA and parent-to-metabolite ratio, considering concomitant treatments with inducers and inhibitor, could optimize therapy for patients under AOM treatment.

Asunto(s)

Antipsicóticos , Aripiprazol , Citocromo P-450 CYP2D6 , Citocromo P-450 CYP3A , Humanos , Citocromo P-450 CYP2D6/genética , Citocromo P-450 CYP2D6/metabolismo , Aripiprazol/farmacocinética , Citocromo P-450 CYP3A/genética , Citocromo P-450 CYP3A/metabolismo , Masculino , Femenino , Adulto , Antipsicóticos/farmacocinética , Antipsicóticos/sangre , Antipsicóticos/uso terapéutico , Persona de Mediana Edad , Polimorfismo Genético/genética , Quinolonas/farmacocinética , Quinolonas/sangre , Adulto Joven , Piperazinas/farmacocinética , Piperazinas/sangre , Anciano , Preparaciones de Acción Retardada/farmacocinética

Asunto(s)

Enfermedad Hepática Inducida por Sustancias y Drogas , Citocromo P-450 CYP2D6 , Trazodona , Humanos , Enfermedad Hepática Inducida por Sustancias y Drogas/genética , Enfermedad Hepática Inducida por Sustancias y Drogas/etiología , Trazodona/efectos adversos , Citocromo P-450 CYP2D6/genética , Polimorfismo Genético , Femenino , Masculino , Antidepresivos de Segunda Generación/efectos adversos , Persona de Mediana Edad

RESUMEN

Tramdol is one of most popular opioids used for postoperative analgesia worldwide. Among Arabic countries, there are reports that its dosage is not appropriate due to cultural background. To provide theoretical background of the proper usage of tramadol, this study analyzed the association between several genetic polymorphisms (CYP2D6/OPRM1) and the effect of tramadol. A total of 39 patients who took tramadol for postoperative analgesia were recruited, samples were obtained, and their DNA was extracted for polymerase chain reaction products analysis followed by allelic variations of CYP2D6 and OPRM A118G determination. Numerical pain scales were measured before and 1 h after taking tramadol. The effect of tramadol was defined by the difference between these scales. We concluded that CYP2D6 and OPRM1 A118G single nucleotide polymorphisms may serve as crucial determinants in predicting tramadol efficacy and susceptibility to post-surgical pain. Further validation of personalized prescription practices based on these genetic polymorphisms could provide valuable insights for the development of clinical guidelines tailored to post-surgical tramadol use in the Arabic population.

Asunto(s)

Analgésicos Opioides , Árabes , Citocromo P-450 CYP2D6 , Dolor Postoperatorio , Receptores Opioides mu , Tramadol , Adulto , Anciano , Femenino , Humanos , Masculino , Persona de Mediana Edad , Analgésicos Opioides/uso terapéutico , Árabes/genética , Citocromo P-450 CYP2D6/genética , Dolor Postoperatorio/tratamiento farmacológico , Dolor Postoperatorio/genética , Farmacogenética/métodos , Polimorfismo de Nucleótido Simple , Receptores Opioides mu/genética , Tramadol/uso terapéutico

RESUMEN

Chronic pain is a prevalent condition with enormous economic burden. Opioids such as tramadol, codeine, and hydrocodone are commonly used to treat chronic pain; these drugs are activated to more potent opioid receptor agonists by the hepatic CYP2D6 enzyme. Results from clinical studies and mechanistic understandings suggest that CYP2D6-guided therapy will improve pain control and reduce adverse drug events. However, CYP2D6 is rarely used in clinical practice due in part to the demand for additional clinical trial evidence. Thus, we designed the ADOPT-PGx (A Depression and Opioid Pragmatic Trial in Pharmacogenetics) chronic pain study, a multicenter, pragmatic, randomized controlled clinical trial, to assess the effect of CYP2D6 testing on pain management. The study enrolled 1048 participants who are taking or being considered for treatment with CYP2D6-impacted opioids for their chronic pain. Participants were randomized to receive immediate or delayed (by 6 months) genotyping of CYP2D6 with clinical decision support (CDS). CDS encouraged the providers to follow the CYP2D6-guided trial recommendations. The primary study outcome is the 3-month absolute change in the composite pain intensity score assessed using Patient-Reported Outcomes Measurement Information System (PROMIS) measures. Follow-up will be completed in July 2024. Herein, we describe the design of this trial along with challenges encountered during enrollment.

Asunto(s)

Analgésicos Opioides , Dolor Crónico , Citocromo P-450 CYP2D6 , Adulto , Femenino , Humanos , Masculino , Persona de Mediana Edad , Analgésicos Opioides/uso terapéutico , Analgésicos Opioides/efectos adversos , Dolor Crónico/tratamiento farmacológico , Citocromo P-450 CYP2D6/genética , Citocromo P-450 CYP2D6/metabolismo , Manejo del Dolor/métodos , Dimensión del Dolor , Pruebas de Farmacogenómica , Medicina de Precisión/métodos

RESUMEN

CYP2D6 variants contain various single nucleotide polymorphisms as well as differing levels of metabolic activity. Among these, one of the less active variants CYP2D6*10 (100C > T) is the most prevalent mutation in East Asians, including Japanese. This mutation leads to an amino acid substitution from proline to serine, which reduces the stability of CYP2D6 and consequently decreases its metabolic activity. In this study, we used a genome editing technology called the Precise Integration into Target Chromosome (PITCh) system to stably express six drug-metabolizing enzymes (CYP3A4, POR, uridine diphosphate glucuronosyltransferase 1A1 (UGT1A1), CYP1A2, CYP2C19, CYP2C9, and CYP2D6*10) in HepG2 (CYP2D6*10 KI-HepG2) cells to examine the effect of CYP2D6*10 on drug metabolism prediction. The protein expression levels of CYP2D6 in CYP2D6*10 KI-HepG2 cells were reduced relative to those in the CYP3A4-POR-UGT1A1-CYP1A2-CYP2C19-CYP2C9-CYP2D6 knock-in-HepG2 (CYPs-UGT1A1 KI-HepG2) cells. Consistent with the CYP2D6 protein expression results, CYP2D6 metabolic activity in CYP2D6*10 KI-HepG2 cells was reduced relative to CYPs-UGT1A1 KI-HepG2 cells. We successfully generated CYP2D6*10 KI-HepG2 cells with highly expressed, functional CYP2D6*10, as well as CYP1A2, 2C9, 2C19 and 3A4. CYP2D6*10 KI-HepG2 cells could be an invaluable model for hepatic metabolism and hepatotoxicity studies in East Asians, including Japanese.

Asunto(s)

Citocromo P-450 CYP2D6 , Hepatocitos , Humanos , Citocromo P-450 CYP2D6/genética , Citocromo P-450 CYP2D6/metabolismo , Células Hep G2 , Hepatocitos/metabolismo , Edición Génica/métodos , Glucuronosiltransferasa/genética , Glucuronosiltransferasa/metabolismo , Polimorfismo de Nucleótido Simple , Modelos Biológicos

RESUMEN

Pharmacogenomics (PGx) investigates the influence of genetics on drug responses, enabling tailored treatments for personalized healthcare. This study assessed the accuracy of genotyping six genes using whole genome sequencing with four different computational tools and various sequencing depths. The effects of using different reference genomes (GRCh38 and GRCh37) and sequence aligners (BWA-MEM and Bowtie2) were also explored. The results showed generally minor variations in tool performance across most genes; however, more notable discrepancies were observed in the analysis of the complex CYP2D6 gene. Cyrius, a CYP2D6-specific tool, demonstrated the most robust performance, achieving the highest concordance rates for CYP2D6 in all instances, comparable to the consensus approach in most cases. There were rather small differences between the samples with 20× coverage depth and those with higher depth, but the decreased performance was more evident at lower depths, particularly at 5×. Additionally, variations in CYP2D6 results were observed when samples were aligned to different reference genomes using the same method, or to the same genome using different aligners, which led to reporting incorrect rare star alleles in several cases. These findings inform the selection of optimal PGx tools and methodologies as well as suggest that employing a consensus approach with two or more tools might be preferable for certain genes and tool combinations, especially at lower sequencing depths, to ensure accurate results. Additionally, we show how the upstream alignment can affect the performance of tools, an important factor to take into account.

Asunto(s)

Benchmarking , Citocromo P-450 CYP2D6 , Farmacogenética , Humanos , Citocromo P-450 CYP2D6/genética , Farmacogenética/normas , Farmacogenética/métodos , Citocromo P-450 CYP2C19/genética , Secuenciación Completa del Genoma/normas , Secuenciación Completa del Genoma/métodos , Técnicas de Genotipaje/métodos , Genotipo , Citocromo P-450 CYP2C9/genética , Citocromo P-450 CYP2A6/genética , Pruebas de Farmacogenómica/normas , Pruebas de Farmacogenómica/métodos , Secuenciación de Nucleótidos de Alto Rendimiento/normas , Vitamina K Epóxido Reductasas

RESUMEN

Cytochrome P450 2D6 (CYP2D6) plays a crucial role in metabolizing approximately 20% of medications prescribed clinically. This enzyme is encoded by the CYP2D6 gene, known for its extensive polymorphism with over 170 catalogued haplotypes or star alleles, which can have a profound impact on drug efficacy and safety. Despite its importance, a gap exists in the global genomic databases, which are predominantly representative of European ancestries, thereby limiting comprehensive knowledge of CYP2D6 variation in ethnically diverse populations. In an effort to bridge this knowledge gap, we focused on elucidating the CYP2D6 variation landscape within a multi-ethnic Asian cohort, encompassing individuals of Chinese, Malay, and Indian descent. Our study comprised data analysis of 1850 whole genomes from the SG10K_Health dataset using an in-house consensus algorithm, which integrates the capabilities of Cyrius, Aldy, and StellarPGx. This analysis unveiled distinct population-specific star-allele distribution trends, highlighting the unique genetic makeup of the Singaporean population. Significantly, 46% of our cohort harbored actionable CYP2D6 variants-those with direct implications for drug dosing and treatment strategies. Furthermore, we identified 14 potential novel CYP2D6 star-alleles, of which 7 were observed in multiple individuals, suggesting their broader relevance. Overall, our study contributes novel data on CYP2D6 genetic variations specific to the Southeast Asian context. The findings are instrumental for the advancement of pharmacogenomics and personalized medicine, not only in Southeast Asia but also in other regions with comparable genetic diversity.

Asunto(s)

Alelos , Pueblo Asiatico , Citocromo P-450 CYP2D6 , Citocromo P-450 CYP2D6/genética , Citocromo P-450 CYP2D6/metabolismo , Humanos , Pueblo Asiatico/genética , Etnicidad/genética , Singapur , Variación Genética , Frecuencia de los Genes , Polimorfismo de Nucleótido Simple , Haplotipos

RESUMEN

Cytochrome P450 2D6 (CYP2D6) is one of the most important enzymes involved in drug metabolism. Genetic polymorphism can influence drug metabolism by CYP2D6 such that a therapy is seriously affected by under- or overdosing of drugs. However, a general explanation at the atomistic level for poor activity is missing so far. Here we show for the 20 most common single nucleotide polymorphisms (SNPs) of CYP2D6 that poor metabolism is driven by four mechanisms. We found in extensive all-atom molecular dynamics simulations that the rigidity of the I-helix (central helix), distance between central phenylalanines (stabilizing bound substrate), availability of basic residues on the surface of CYP2D6 (binding of cytochrome P450 reductase), and position of arginine 132 (electron transfer to heme) are essential for an extensive function of the enzyme. These results were applied to SNPs with unknown effects, and potential SNPs that may lead to poor drug metabolism were identified. The revealed molecular mechanisms might be important for other drug-metabolizing cytochrome P450 enzymes.

Asunto(s)

Citocromo P-450 CYP2D6 , Simulación de Dinámica Molecular , Polimorfismo de Nucleótido Simple , Citocromo P-450 CYP2D6/metabolismo , Citocromo P-450 CYP2D6/genética , Citocromo P-450 CYP2D6/química , Humanos , Conformación Proteica

RESUMEN

BACKGROUND: Given the great interest in identifying reliable predictors of the response to antidepressant drugs, the present study investigated whether polygenic scores (PGS) for Major Depressive Disorder (MDD) and antidepressant treatment response (ADR) were related to the complex trait of antidepressant response in the Early Medication Change (EMC) cohort. METHODS: In this secondary analysis of the EMC trial (N = 889), 481 MDD patients were included and compared to controls from a population-based cohort. Patients were treated over eight weeks within a pre-defined treatment-algorithm. We investigated patients' genetic variation associated with MDD and ADR, using PGS and examined the association of PGS with treatment outcomes (early improvement, response, remission). Additionally, the influence of two cytochrome P450 drug-metabolizing enzymes (CYP2C19, CYP2D6) was determined. RESULTS: PGS for MDD was significantly associated with disorder status (NkR2 = 2.48 %, p < 1*10-12), with higher genetic burden in EMC patients compared to controls. The PGS for ADR did not explain remission status. The PGS for MDD and ADR were also not associated with treatment outcomes. In addition, there were no effects of common CYP450 gene variants on ADR. LIMITATIONS: The study was limited by variability in the outcome parameters due to differences in treatment and insufficient sample size in the used ADR genome-wide association study (GWAS). CONCLUSIONS: The present study confirms a polygenic contribution to MDD burden in the EMC patients. Larger GWAS with homogeneity in antidepressant treatments are needed to explore the genetic variation associated with ADR and realize the potential of PGS to contribute to specific response subtypes.

Asunto(s)

Antidepresivos , Trastorno Depresivo Mayor , Herencia Multifactorial , Humanos , Trastorno Depresivo Mayor/tratamiento farmacológico , Trastorno Depresivo Mayor/genética , Antidepresivos/uso terapéutico , Masculino , Femenino , Adulto , Persona de Mediana Edad , Resultado del Tratamiento , Citocromo P-450 CYP2D6/genética , Citocromo P-450 CYP2C19/genética , Estudios de Cohortes , Variación Genética

RESUMEN

Cytochrome P450 (CYP) 2Ds are drug metabolizing enzymes found in brain and liver which metabolize numerous centrally acting drugs. Inhibition and induction of CYP2D-mediated metabolism in rodent brain alters brain drug and metabolite concentrations and resulting drug response. In female rats, brain CYP2D metabolism varies across the estrous cycle and with exogenous estrogen, changing brain drug concentrations and response. In this study harmine-induced hypothermia was lower in humanized CYP2D6 transgenic female mice during estrus compared to diestrus. Pretreatment into the cerebral ventricles with propranolol, a selective irreversible inhibitor of human CYP2D6 in brain, increased hypothermia in estrus but not in diestrus. In vivo enzyme activity was higher in brains of transgenic mice in estrus compared to diestrus and was lower after pretreatment with inhibitor in estrus, but not in diestrus. Hepatic activity and plasma harmine concentrations were unaffected by either estrous phase or inhibition of brain CYP2D6. In wild-type female mice, harmine-induced hypothermia was unaffected by either estrous phase or inhibitor pretreatment. Male mice were used as positive controls, where pretreatment with inhibitor increased harmine-induced hypothermia in transgenic but not wild-type, mice. This study provides evidence for female hormone cycle-based regulation of drug metabolism by human CYP2D6 in brain and resulting drug response. This suggests that brain CYP2D6 metabolism may vary, for example, during the menstrual cycle, pregnancy, or menopause, or while taking oral contraceptives or hormone therapy. This variation could contribute to individual differences in response to centrally acting CYP2D6-substrate drugs by altering local brain drug and/or metabolite concentrations.

Asunto(s)

Encéfalo , Citocromo P-450 CYP2D6 , Ciclo Estral , Ratones Transgénicos , Animales , Femenino , Citocromo P-450 CYP2D6/metabolismo , Citocromo P-450 CYP2D6/genética , Humanos , Encéfalo/metabolismo , Encéfalo/efectos de los fármacos , Ratones , Ciclo Estral/efectos de los fármacos , Harmina/farmacología , Propranolol/farmacología , Masculino , Hígado/metabolismo , Hígado/efectos de los fármacos , Inhibidores del Citocromo P-450 CYP2D6/farmacología , Hipotermia/inducido químicamente , Hipotermia/metabolismo

RESUMEN

PURPOSE: The CYP2D6 gene exhibits significant polymorphism, contributing to variability in responses to drugs metabolized by CYP2D6. While CYP2D6*2 and CYP2D6*35 are presently designated as alleles encoding normal metabolism, this classification is based on moderate level evidence. Additionally, the role of the formerly called "enhancer" single nucleotide polymorphism (SNP) rs5758550 is unclear. In this study, the impacts of CYP2D6*2, CYP2D6*35 and rs5758550 on CYP2D6 activity were investigated using risperidone clearance as CYP2D6 activity marker. METHODS: A joint parent-metabolite population pharmacokinetic model was used to describe 1,565 serum concentration measurements of risperidone and 9-hydroxyrisperidone in 512 subjects. Risperidone population clearance was modeled as the sum of a CYP2D6-independent clearance term and the partial clearances contributed from each individually expressed CYP2D6 allele or haplotype. In addition to the well-characterized CYP2D6 alleles (*3-*6, *9, *10 and *41), *2, *35 and two haplotypes assigned as CYP2D6*2-rs5758550G and CYP2D6*2-rs5758550A were evaluated. RESULTS: Each evaluated CYP2D6 allele was associated with significantly lower risperidone clearance than the reference normal function allele CYP2D6*1 (p < 0.001). Further, rs5758550 differentiated the effect of CYP2D6*2 (p = 0.005). The haplotype-specific clearances for CYP2D6*2-rs5758550A, CYP2D6*2-rs5758550G and CYP2D6*35 were estimated to 30%, 66% and 57%, respectively, relative to the clearance for CYP2D6*1. Notably, rs5758550 is in high linkage disequilibrium (R2 > 0.85) with at least 24 other SNPs and cannot be assigned as a functional SNP. CONCLUSION: CYP2D6*2 and CYP2D6*35 encode reduced risperidone clearance, and the extent of reduction for CYP2D6*2 is differentiated by rs5758550. Genotyping of these haplotypes might improve the precision of genotype-guided prediction of CYP2D6-mediated clearance.

Asunto(s)

Antipsicóticos , Citocromo P-450 CYP2D6 , Haplotipos , Palmitato de Paliperidona , Polimorfismo de Nucleótido Simple , Risperidona , Risperidona/farmacocinética , Risperidona/sangre , Humanos , Citocromo P-450 CYP2D6/genética , Citocromo P-450 CYP2D6/metabolismo , Masculino , Femenino , Adulto , Antipsicóticos/farmacocinética , Antipsicóticos/sangre , Palmitato de Paliperidona/farmacocinética , Palmitato de Paliperidona/sangre , Persona de Mediana Edad , Tasa de Depuración Metabólica , Alelos , Adulto Joven , Genotipo , Modelos Biológicos

RESUMEN

Cytochrome P450 enzymes including CYP2C19 and CYP2D6 are important for antidepressant metabolism and polymorphisms of these genes have been determined to predict metabolite levels. Nonetheless, more evidence is needed to understand the impact of genetic variations on antidepressant response. In this study, individual clinical and genetic data from 13 studies of European and East Asian ancestry populations were collected. The antidepressant response was clinically assessed as remission and percentage improvement. Imputed genotype was used to translate genetic polymorphisms to metabolic phenotypes (poor, intermediate, normal, and rapid+ultrarapid) of CYP2C19 and CYP2D6. CYP2D6 structural variants cannot be imputed from genotype data, limiting the determination of metabolic phenotypes, and precluding testing for association with response. The association of CYP2C19 metabolic phenotypes with treatment response was examined using normal metabolizers as the reference. Among 5843 depression patients, a higher remission rate was found in CYP2C19 poor metabolizers compared to normal metabolizers at nominal significance but did not survive after multiple testing correction (OR = 1.46, 95% CI [1.03, 2.06], p = 0.033, heterogeneity I2 = 0%, subgroup difference p = 0.72). No metabolic phenotype was associated with percentage improvement from baseline. After stratifying by antidepressants primarily metabolized by CYP2C19, no association was found between metabolic phenotypes and antidepressant response. Metabolic phenotypes showed differences in frequency, but not effect, between European- and East Asian-ancestry studies. In conclusion, metabolic phenotypes imputed from genetic variants using genotype were not associated with antidepressant response. CYP2C19 poor metabolizers could potentially contribute to antidepressant efficacy with more evidence needed. Sequencing and targeted pharmacogenetic testing, alongside information on side effects, antidepressant dosage, depression measures, and diverse ancestry studies, would more fully capture the influence of metabolic phenotypes.

Asunto(s)

Antidepresivos , Citocromo P-450 CYP2C19 , Citocromo P-450 CYP2D6 , Femenino , Humanos , Masculino , Antidepresivos/uso terapéutico , Pueblo Asiatico/genética , Citocromo P-450 CYP2C19/genética , Citocromo P-450 CYP2D6/genética , Citocromo P-450 CYP2D6/metabolismo , Trastorno Depresivo Mayor/tratamiento farmacológico , Trastorno Depresivo Mayor/genética , Trastorno Depresivo Mayor/metabolismo , Genotipo , Fenotipo , Resultado del Tratamiento , Población Blanca/genética

RESUMEN

BACKGROUND: Several opioids have pharmacogenetic and drug-drug interactions which may compromise their analgesic effectiveness, but are not routinely implemented into supportive pain management. We hypothesized that CYP2D6 phenotypes and concomitant use of CYP2D6 substrates or inhibitors would correlate with opioid analgesic outcomes. MATERIALS AND METHODS: An observational cross-sectional study was conducted with 263 adult chronic non cancer pain (CNCP) patients from a real-world pain unit under long-term CYP2D6-related opioid treatment (tramadol, hydromorphone, tapentadol or oxycodone). Metabolizer phenotype (ultrarapid [UM], normal [NM], intermediate [IM] or poor [PM]) was determined by the CYP2D6 genotype. The socio-demographic (sex, age, employment status), clinical (pain intensity and relief, neuropathic component, quality of life, disability, anxiety and depression), pharmacological (opioid doses and concomitant pharmacotherapy) and safety (adverse events) variables were recorded. RESULTS: The whole population (66 % female, 65 (14) years old, 70 % retired and 63 % attended for low back pain) were classified as PM (5 %), IM (32 %), NM (56 %) and UM (6 %). Multiple linear and logistic regressions showed higher pain intensity and neuropathic component at younger ages when using any CYP2D6 substrate (p = 0.022) or inhibitor (p = 0.030) drug, respectively, with poorer pain relief when CYP2D6 inhibitors (p=0.030) were present. CONCLUSION: The concomitant use of CYP2D6 substrates or inhibitors during opioid therapy for CNCP may result in lack of analgesic effectiveness. This aspect could be relevant for pharmacological decision making during CNCP management.

Asunto(s)

Analgésicos Opioides , Inhibidores del Citocromo P-450 CYP2D6 , Citocromo P-450 CYP2D6 , Interacciones Farmacológicas , Manejo del Dolor , Humanos , Masculino , Femenino , Citocromo P-450 CYP2D6/metabolismo , Citocromo P-450 CYP2D6/genética , Analgésicos Opioides/efectos adversos , Analgésicos Opioides/uso terapéutico , Estudios Transversales , Inhibidores del Citocromo P-450 CYP2D6/farmacología , Inhibidores del Citocromo P-450 CYP2D6/efectos adversos , Persona de Mediana Edad , Anciano , Manejo del Dolor/métodos , Dolor Crónico/tratamiento farmacológico , Resultado del Tratamiento , Adulto , Dimensión del Dolor

RESUMEN

The cytochrome P450 (CYP) family of enzymes plays a central role in the metabolism of many drugs. CYP genes are highly polymorphic, which is known to affect protein levels, but for some low frequent CYP genotypes the correlation between genotype and CYP protein expression is less established. In this study, we determined the CYP2C9, CYP2C19, CYP2D6, and CYP3A5 genotypes of 250 Danish individuals included in a postmortem study. For 116 of the individuals, the hepatic CYP protein levels were investigated by a proteomics approach. Overall, we found the postmortem genetic and proteomic data to be in agreement with those of other studies performed on fresh hepatic tissue, showing the usability of postmortem hepatic tissue for this type of investigation. For less investigated genotypes, we could corroborate previously found results: 1) statistically significantly lower levels of hepatic CYP2C9 protein in individuals carrying the CYP2C9*3 variant compared with individuals with two wild type (wt) alleles; 2) comparable levels of CYP2C19 in CYP2C19*2/*17 and CYP2C19*1/*2 individuals; 3) reduced CYP2D6 protein levels in heterozygous individuals with the CYP2D6*3, CYP2D6*4, and CYP2D6*5 gene deletion variants; and 4) significantly lower levels of CYP3A5 protein in CYP3A5*3 homozygous individuals compared with individuals who were heterozygous for the CYP3A5*3 allele or homozygous individuals for the wt alleles. In conclusion, the use of postmortem tissue significantly increases the access to human specimens for research purposes, and postmortem proteomics can be used to investigate the link between CYP genotypes and hepatic protein expression. SIGNIFICANCE STATEMENT: In tissue samples from a large postmortem cohort (n = 250) we determined the CYP2C9, CYP2C19, CYP2D6, and CYP3A5 genotypes. Hepatic CYP protein levels were investigated in 116 individuals using a proteomics approach. For common genotypes, we found results similar to previous knowledge, pointing toward the usability of postmortem tissue. For the less investigated genotypes, we were able to corroborate genotype/protein expression correlations. It is a novel approach to use a large postmortem cohort to investigate genetic/protein expression correlations.

Asunto(s)

Citocromo P-450 CYP2C19 , Citocromo P-450 CYP2C9 , Citocromo P-450 CYP2D6 , Citocromo P-450 CYP3A , Genotipo , Hígado , Humanos , Dinamarca , Hígado/metabolismo , Citocromo P-450 CYP2D6/genética , Citocromo P-450 CYP2D6/metabolismo , Citocromo P-450 CYP2C19/genética , Citocromo P-450 CYP2C19/metabolismo , Citocromo P-450 CYP3A/genética , Citocromo P-450 CYP3A/metabolismo , Femenino , Masculino , Citocromo P-450 CYP2C9/genética , Citocromo P-450 CYP2C9/metabolismo , Persona de Mediana Edad , Proteómica/métodos , Autopsia , Anciano , Adulto

RESUMEN

This study aims to investigate the potential role of CYP2D6*10 (c.100 C>T) gene polymorphism in renal function injury among hypertensive patients without elevated cystatin C. A cohort of hypertensive patients without elevated cystatin C was enrolled between 2021 and 2024 in the Fourth Affiliated Hospital of Soochow University, and their peripheral venous blood was used for total RNA extraction and CYP2D6*10 genotype analysis. Based on kidney injury status, patients were categorized into two groups, hypertensive patients with kidney injury (n = 94) and those without (n = 893). General characteristics such as age, gender and hyperlipemia were compared between the two groups. Multiple genotype models were investigated between the two groups, including allele models, dominant models, recessive models, co-dominant models, and super-dominant models. The results revealed that in the co-dominant gene model (CC vs. CT vs. TT), the risk of hypertension combined with renal injury was lower with the CT genotype compared to the CC genotype (Odds Ratio (OR) = 0.55, 95% Confidence Interval (CI) = 0.32-0.93, p = 0.02). In the overdominance model (CC + TT vs. CT), the risk of hypertension and renal injury in CC and CT genotypes was 0.42 times lower than that in the CT genotype (OR = 0.42, 95% CI = 0.27-0.64, p < 0.001). This study proposes CYP2D610 gene polymorphism as a potential predictor of renal function injury in hypertensive patients with normal cystatin C levels.

Asunto(s)

Biomarcadores , Cistatina C , Citocromo P-450 CYP2D6 , Predisposición Genética a la Enfermedad , Hipertensión , Adulto , Anciano , Femenino , Humanos , Masculino , Persona de Mediana Edad , Biomarcadores/sangre , China/epidemiología , Cistatina C/sangre , Cistatina C/genética , Citocromo P-450 CYP2D6/genética , Frecuencia de los Genes , Estudios de Asociación Genética , Hipertensión/genética , Hipertensión/diagnóstico , Hipertensión/fisiopatología , Riñón/fisiopatología , Enfermedades Renales/genética , Enfermedades Renales/diagnóstico , Enfermedades Renales/sangre , Enfermedades Renales/enzimología , Fenotipo , Polimorfismo Genético , Polimorfismo de Nucleótido Simple , Medición de Riesgo , Factores de Riesgo

RESUMEN

Schizophrenia spectrum disorders (SSD) are a group of diseases characterized by one or more abnormal features in perception, thought processing and behavior. Patients suffering from SSD are at risk of developing life-threatening complications. Pharmacogenetic studies have shown promising results on personalized treatment of psychosis. In the current study, 103 patients diagnosed with SSD treated with risperidone as antipsychotic monotherapy were enrolled. Socio-demographics and clinical data were recorded, and laboratory tests and genotyping standard procedure for cytochrome P450 (CYP) 2D6*4 were performed. Patients were evaluated by the Positive and Negative Syndrome Scale (PANSS) on admission and at discharge. Based on the reduction in the PANSS total score, subjects were divided into non-responders, partial responders and full responders. Only 11 subjects had a full response to risperidone (10.67%), 53 subjects (51.45%) had a partial response, and 39 participants (37.86%) were non-responders. Patients at first episode psychosis showed significantly higher levels of blood glucose and prolactin levels, while chronic patients showed significantly higher LDL levels. Adverse drug reactions (ADR) such as tremor and stiffness significantly correlated with genetic phenotypes (p = 0.0145). While CYP2D6 showed no impact on treatment response, ADR were significantly more frequent among poor and intermediate metabolizers.

Asunto(s)

Antipsicóticos , Citocromo P-450 CYP2D6 , Risperidona , Esquizofrenia , Humanos , Citocromo P-450 CYP2D6/genética , Citocromo P-450 CYP2D6/metabolismo , Risperidona/efectos adversos , Risperidona/uso terapéutico , Masculino , Femenino , Esquizofrenia/tratamiento farmacológico , Adulto , Antipsicóticos/efectos adversos , Antipsicóticos/uso terapéutico , Persona de Mediana Edad , Genotipo , Adulto Joven

RESUMEN

OBJECTIVES: Primaquine is essential for the radical cure of Plasmodium vivax malaria and must be metabolized into its bioactive metabolites. Accordingly, polymorphisms in primaquine-metabolizing enzymes can impact the treatment efficacy. This pioneering study explores the influence of monoamine oxidase-A (MAO-A) on primaquine metabolism and its impact on malaria relapses. METHODS: Samples from 205 patients with P. vivax malaria were retrospectively analysed by genotyping polymorphisms in MAO-A and cytochrome P450 2D6 (CYP2D6) genes. We measured the primaquine and carboxyprimaquine blood levels in 100 subjects for whom blood samples were available on the third day of treatment. We also examined the relationship between the enzyme variants and P. vivax malaria relapses in a group of subjects with well-documented relapses. RESULTS: The median carboxyprimaquine level was significantly reduced in individuals carrying low-expression MAO-A alleles plus impaired CYP2D6. In addition, this group experienced significantly more P. vivax relapses. The low-expression MAO-A status was not associated with malaria relapses when CYP2D6 had normal activity. This suggests that the putative carboxyprimaquine contribution is irrelevant when the CYP2D6 pathway is fully active. CONCLUSIONS: We found evidence that the low-expression MAO-A variants can potentiate the negative impact of impaired CYP2D6 activity, resulting in lower levels of carboxyprimaquine metabolite and multiple relapses. The findings support the hypothesis that carboxyprimaquine may be further metabolized through CYP-mediated pathways generating bioactive metabolites that act against the parasite.

Asunto(s)

Antimaláricos , Citocromo P-450 CYP2D6 , Malaria Vivax , Monoaminooxidasa , Primaquina , Adulto , Femenino , Humanos , Masculino , Persona de Mediana Edad , Antimaláricos/uso terapéutico , Citocromo P-450 CYP2D6/genética , Citocromo P-450 CYP2D6/metabolismo , Genotipo , Malaria Vivax/tratamiento farmacológico , Malaria Vivax/genética , Monoaminooxidasa/genética , Plasmodium vivax/genética , Polimorfismo Genético , Primaquina/uso terapéutico , Recurrencia , Estudios Retrospectivos

RESUMEN

Specific selective serotonin reuptake inhibitors (SSRIs) metabolism is strongly influenced by two pharmacogenes, CYP2D6 and CYP2C19. However, the effectiveness of prospectively using pharmacogenetic variants to select or dose SSRIs for depression is uncertain in routine clinical practice. The objective of this prospective, multicenter, pragmatic randomized controlled trial is to determine the effectiveness of genotype-guided selection and dosing of antidepressants on control of depression in participants who are 8 years or older with ≥3 months of depressive symptoms who require new or revised therapy. Those randomized to the intervention arm undergo pharmacogenetic testing at baseline and receive a pharmacy consult and/or automated clinical decision support intervention based on an actionable phenotype, while those randomized to the control arm have pharmacogenetic testing at the end of 6-months. In both groups, depression and drug tolerability outcomes are assessed at baseline, 1 month, 3 months (primary), and 6 months. The primary end point is defined by change in Patient-Reported Outcomes Measurement Information System (PROMIS) Depression score assessed at 3 months versus baseline. Secondary end points include change inpatient health questionnaire (PHQ-8) measure of depression severity, remission rates defined by PROMIS score < 16, medication adherence, and medication side effects. The primary analysis will compare the PROMIS score difference between trial arms among those with an actionable CYP2D6 or CYP2C19 genetic result or a CYP2D6 drug-drug interaction. The trial has completed accrual of 1461 participants, of which 562 were found to have an actionable phenotype to date, and follow-up will be complete in April of 2024.

Asunto(s)

Citocromo P-450 CYP2C19 , Citocromo P-450 CYP2D6 , Depresión , Pruebas de Farmacogenómica , Inhibidores Selectivos de la Recaptación de Serotonina , Adulto , Femenino , Humanos , Masculino , Antidepresivos/uso terapéutico , Antidepresivos/administración & dosificación , Antidepresivos/efectos adversos , Citocromo P-450 CYP2C19/genética , Citocromo P-450 CYP2D6/genética , Depresión/tratamiento farmacológico , Depresión/genética , Depresión/diagnóstico , Variantes Farmacogenómicas , Ensayos Clínicos Pragmáticos como Asunto , Estudios Prospectivos , Inhibidores Selectivos de la Recaptación de Serotonina/administración & dosificación , Inhibidores Selectivos de la Recaptación de Serotonina/uso terapéutico

RESUMEN

OBJECTIVE: The CYP2D6 enzyme is crucial for the metabolism and disposition of a variety of drugs. This study was conducted to examine the relationship between CYP2D6 gene polymorphisms and the response to angiotensin receptor blocker (ARB)-based treatment in patients of Chinese Bai ethnicity with hypertension. METHODS: Seventy-two hypertensive adults from the Chinese Bai ethnic group, exhibiting systolic blood pressure (SBP) ≥ 140 mmHg or diastolic blood pressure (DBP) ≥ 90 mmHg, were recruited. Targeted regional sequencing was utilized to genotype single nucleotide polymorphisms in the CYP2D6 gene, aiming to assess their frequency and to evaluate their influence on the therapeutic efficacy of ARB medications. RESULTS: Our research identified nine significant CYP2D6 polymorphisms associated with the efficacy of ARB treatment in the Bai hypertensive cohort. Specifically, patients possessing certain mutant genotype at rs111564371 exhibited substantially greater reductions in SBP and DBP, with P -values of 0.021 and 0.016, respectively, compared to those carrying the wild genotype. Additionally, these mutant genotype at rs111564371 and rs112568578 were linked to approximately 20% higher overall efficacy rates and a 10% increased achievement rate relative to the wild genotype. CONCLUSION: Our research with the Bai hypertensive group shows that certain CYP2D6 polymorphisms significantly influence ARB treatment outcomes. Mutations at rs111564371 led to better blood pressure control ( P -values: 0.021 for SBP, 0.016 for DBP), improving ARB efficacy by appromixately 20% and increasing treatment goal achievement by 10% over the wild-type genotype. STATEMENTS: Our investigation into CYP2D6 polymorphisms within the Bai hypertensive cohort marks a substantial advancement towards personalized healthcare, underscoring the pivotal influence of genetic constitution on the effectiveness of ARB therapy.

Asunto(s)

Citocromo P-450 CYP2D6 , Hipertensión , Polimorfismo de Nucleótido Simple , Humanos , Citocromo P-450 CYP2D6/genética , Hipertensión/tratamiento farmacológico , Hipertensión/genética , Masculino , Femenino , Persona de Mediana Edad , Anciano , Antagonistas de Receptores de Angiotensina/uso terapéutico , Presión Sanguínea/efectos de los fármacos , Presión Sanguínea/genética , Pueblo Asiatico/genética , Genotipo , Adulto , Antihipertensivos/uso terapéutico , Antihipertensivos/administración & dosificación , Antihipertensivos/farmacología , Resultado del Tratamiento