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1.
Artigo em Inglês | MEDLINE | ID: mdl-39237024

RESUMO

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.


Assuntos
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 , Feminino , Adulto , Antipsicóticos/farmacocinética , Antipsicóticos/sangue , Antipsicóticos/uso terapêutico , Pessoa de Meia-Idade , Polimorfismo Genético/genética , Quinolonas/farmacocinética , Quinolonas/sangue , Adulto Jovem , Piperazinas/farmacocinética , Piperazinas/sangue , Idoso , Preparações de Ação Retardada/farmacocinética
2.
Asian Pac J Cancer Prev ; 25(9): 3059-3065, 2024 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-39342583

RESUMO

BACKGROUND: Cytochrome P450 (CYP) is a family phase I metabolizing enzymes important in xenobiotics metabolism. Genetic polymorphisms of CYPs have been comprehensively studied for their association with a range of diseases including cancer risk. In this study we assessed single nucleotide polymorphism (SNP) CYP2D6 and CYP2E1 genes and their role in gastrointestinal (GI) cancer susceptibility in the rural population of Maharashtra. METHODS: Genotyping of CYP2D6*4, CYP2E1*5B, CYP2E1*6, CYP2E1*7B genes among 200 GI cancer cases and equal number of controls was studied by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method. The Odds ratio (OR) with 95% confidence interval and p-value were evaluated to get the level of association of polymorphisms with risk of GI cancer, where p ≤0.005 was considered as statistically significant. RESULTS: After the analysis of CYP2D6 and CYP2E1 gene polymorphisms, we noticed that CYP2D6*4 (rs3892097) with heterozygous genotype (G/C) showed negative association with GI cancer risk (OR=0.43, 95% CI: 0.25-0.74; p=0.002) and CYP2E1*6 (rs6413432) variant genotype showed positive association (OR=2.85, 95% CI: 1.40-5.81; p=0.003) showed positive association with GI cancer risk in studied population. CONCLUSION: The findings obtained from this study concluded that the polymorphic CYP2D6 was negatively associated; however CYP2E1*6 polymorphism was significantly associated with GI cancer risk in studied population.


Assuntos
Citocromo P-450 CYP2D6 , Citocromo P-450 CYP2E1 , Neoplasias Gastrointestinais , Predisposição Genética para Doença , Genótipo , Polimorfismo de Nucleotídeo Único , População Rural , Humanos , Neoplasias Gastrointestinais/genética , Neoplasias Gastrointestinais/epidemiologia , Estudos de Casos e Controles , Citocromo P-450 CYP2E1/genética , Masculino , Feminino , Citocromo P-450 CYP2D6/genética , Pessoa de Meia-Idade , Fatores de Risco , Índia/epidemiologia , Seguimentos , Prognóstico , Adulto , Polimorfismo de Fragmento de Restrição , Biomarcadores Tumorais/genética , Idoso , Hospitais
3.
J Psychopharmacol ; 38(9): 771-783, 2024 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-39262167

RESUMO

BACKGROUND: The enzyme expression (i.e. phenotype) of the Cytochrome P450 2D6 (CYP2D6) gene is highly relevant to the metabolism of psychotropic medications, and therefore to precision medicine (i.e. personalised prescribing). AIMS: This review aims to assess the improvement in CYP2D6 phenotyping sensitivity (IPS) and accuracy (IPA) offered by long-read sequencing (LRS), a new genetic testing technology. METHODS: Human DNA samples that underwent LRS genotyping of CYP2D6 in published, peer-reviewed clinical research were eligible for inclusion. A systematic literature search was conducted until 30 September 2023. CYP2D6 genotypes were translated into phenotypes using the international consensus method. IPS was the percentage of non-normal LRS CYP2D6 phenotypes undetectable with FDA-approved testing (AmpliChip). IPA was the percentage of LRS CYP2D6 phenotypes mischaracterised by non-LRS genetic tests (for samples with LRS and non-LRS data). RESULTS: Six studies and 1411 samples were included. In a meta-analysis of four studies, IPS was 10% overall (95% CI = (2, 18); n = 1385), 20% amongst Oceanians (95% CI = (17, 23); n = 582) and 2% amongst Europeans (95% CI = (1, 4); n = 803). IPA was 4% in a large European cohort (95% CI = (2, 7); n = 567). When LRS was used selectively (e.g. for novel or complex CYP2D6 genotypes), very high figures were observed for IPS (e.g. 88%; 95% CI = (72, 100); n = 17; country = Japan) and IPA (e.g. 76%; 95% CI = (55, 98); n = 17; country = Japan). CONCLUSIONS: LRS improves CYP2D6 phenotyping compared to established genetic tests, particularly amongst Oceanian and Japanese individuals, and those with novel or complex genotypes. LRS may therefore assist in optimising personalised prescribing of psychotropic medications. Further research is needed to determine associated clinical benefits, such as increased medication safety and efficacy.


Assuntos
Citocromo P-450 CYP2D6 , Psicotrópicos , Citocromo P-450 CYP2D6/genética , Humanos , Psicotrópicos/uso terapêutico , Fenótipo , Genótipo , Resultado do Tratamento , Medicina de Precisão/métodos , Testes Genéticos/métodos
4.
Croat Med J ; 65(4): 383-395, 2024 08 31.
Artigo em Inglês | MEDLINE | ID: mdl-39219201

RESUMO

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.


Assuntos
Antipsicóticos , Interações Medicamentosas , Humanos , Adulto , Feminino , Antipsicóticos/administração & dosagem , Antipsicóticos/uso terapêutico , Transtornos Psicóticos/tratamento farmacológico , Transtornos Psicóticos/genética , Aripiprazol/administração & dosagem , Aripiprazol/uso terapêutico , Esquizofrenia/tratamento farmacológico , Esquizofrenia/genética , Citocromo P-450 CYP1A2/genética , Testes Farmacogenômicos , Farmacogenética , Citocromo P-450 CYP3A/genética , Citocromo P-450 CYP2D6/genética
5.
Lupus ; 33(12): 1328-1335, 2024 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-39287122

RESUMO

OBJECTIVE: This study aims to explore possible susceptibility genes and clinical features for systemic lupus erythematosus (SLE) patients in a Chinese population. METHODS: Expanding on the results of a prior single-center observational study involving 60 systemic lupus erythematosus patients, a subsequent single-center prospective observational study was conducted on SLE patients undergoing treatment at Nanfang Hospital Affiliated to Southern Medical University from 2021 to 2023. The identification process for drug-related target genes entailed an extensive search across PharmGKB (https://www.pharmgkb.org/), the Clinical Pharmacogenetics Implementation Consortium (CPIC),and PubMed literature databases, to pinpoint common drugs and target single nucleotide polymorphisms(SNPs)for SLE. Blood samples were individually collected and genotyped using MassARRAY® high-throughput nucleic acid mass spectrometry. Genotype frequency differences were assessed through Chi-square tests against both the larger East Asian population as well as kidney transplant recipients. Data collection relied on electronic medical records, encompassing demographic details(age, gender),medication regimens(hormones, NSAIDs, hydroxychloroquine, DMARDs, biologic agents, stomach medications, calcitriol, etc.),laboratory indicators(RF, Anti-CCP antibody, ESR, CRP, anti-ANA antibodies, dsDNA antibodies, anti-SM antibodies, S m. RNP antibodies, A LT, ALB, CR, UA, WBC, PLT, HGB, Ca, K, Glu, CHOL, TG, LDL-C, HDL-C) and lupus activity scores(SLEDAI-2K). Possible disease susceptibility genes were categorized, and SPSS26 software facilitated statistical analyses. RESULTS: The research encompassed a total of 137 SLE patients along with 50 SNPs. After conducting statistical analyses, it emerged that there existed significant disparities in CYP2D6 gene (rs1065852) distribution when compared against allele mutation rates within both East Asian populations (p < .05) and kidney transplant patients(p < .05). Wild-type gene (GG) constituted 14% of cases while mutant gene (GA + AA) constituted 86%. Allele mutation rate (A63.6%) was significantly higher among SLE patients (RR = 0.802; p = .0355). Furthermore, the variant rs1065852 genotype (GA + AA) demonstrated significant associations with lower CRP levels, higher HGB levels, and higher HDL-C levels (p < 0 0.05). CONCLUSION: The metabolic enzyme CYP2D6 may be used as susceptibility gene for predicting systemic lupus erythematosus and are correlated with CRP and other indicators.


Assuntos
Povo Asiático , Citocromo P-450 CYP2D6 , Predisposição Genética para Doença , Lúpus Eritematoso Sistêmico , Polimorfismo de Nucleotídeo Único , Humanos , Lúpus Eritematoso Sistêmico/genética , Lúpus Eritematoso Sistêmico/tratamento farmacológico , Feminino , Masculino , Adulto , Povo Asiático/genética , Estudos Prospectivos , Citocromo P-450 CYP2D6/genética , China , Pessoa de Meia-Idade , Genótipo , Frequência do Gene , Adulto Jovem , População do Leste Asiático
6.
Int J Mol Sci ; 25(16)2024 Aug 16.
Artigo em Inglês | MEDLINE | ID: mdl-39201627

RESUMO

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.


Assuntos
Analgésicos Opioides , Árabes , Citocromo P-450 CYP2D6 , Dor Pós-Operatória , Receptores Opioides mu , Tramadol , Adulto , Idoso , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Analgésicos Opioides/uso terapêutico , Árabes/genética , Citocromo P-450 CYP2D6/genética , Dor Pós-Operatória/tratamento farmacológico , Dor Pós-Operatória/genética , Farmacogenética/métodos , Polimorfismo de Nucleotídeo Único , Receptores Opioides mu/genética , Tramadol/uso terapêutico
7.
Eur J Clin Pharmacol ; 80(11): 1773-1785, 2024 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-39158690

RESUMO

BACKGROUND: There is insufficient replicated data to establish a relationship between the polymorphisms of SLC6A2 and CYP2D6 and the treatment responses of atomoxetine (ATX) in ADHD. We focused on evaluating the effect of top-line single nucleotide polymorphisms (SNPs) in SLC6A2 and CYP2D6 on the ATX treatment response in attention deficit and hyperactivity disorder (ADHD). METHODS: Of 160 patient records, 34 patients who met the inclusion criteria were evaluated to determine the relationship between genotypes of ten SNPs (six of SLC6A2 and four of CYP2D6) and ATX treatment response. Additionally, the connection between SNPs of CYP2D6 and the severity of side effects associated with ATX was analyzed in 37 patients, including the 34 study patients, and three patients discontinued because of ATX-dependent side effects. RESULTS: All six polymorphisms we studied in SLC6A2 were associated with the treatment response of ATX. Clinical improvement in oppositional defiant disorder symptoms of patients with ADHD was only observed in carriers of the homozygous "C" allele of rs3785143 (podd = 0.026). We detected an association between higher CGI-side-effect severity scores and the "TT" genotype of rs1065852 polymorphism in CYP2D6 (p = 0.043). CONCLUSIONS: The findings of this study suggest that genotypes of polymorphisms within the SLC6A2 and CYP2D6 may play an influential role in treatment response or the severity of side effects associated with ATX in ADHD patients.


Assuntos
Inibidores da Captação Adrenérgica , Cloridrato de Atomoxetina , Transtorno do Deficit de Atenção com Hiperatividade , Citocromo P-450 CYP2D6 , Genótipo , Polimorfismo de Nucleotídeo Único , Humanos , Cloridrato de Atomoxetina/uso terapêutico , Cloridrato de Atomoxetina/efeitos adversos , Transtorno do Deficit de Atenção com Hiperatividade/tratamento farmacológico , Transtorno do Deficit de Atenção com Hiperatividade/genética , Citocromo P-450 CYP2D6/genética , Masculino , Feminino , Inibidores da Captação Adrenérgica/uso terapêutico , Inibidores da Captação Adrenérgica/efeitos adversos , Criança , Adolescente , Proteínas da Membrana Plasmática de Transporte de Norepinefrina/genética , Resultado do Tratamento
8.
Cancer Chemother Pharmacol ; 94(4): 535-547, 2024 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-39110203

RESUMO

PURPOSE: Midostaurin, approved for FLT3-mutated acute myeloid leukemia and advanced systemic mastocytosis, is mainly metabolized by cytochrome P450 (CYP) 3A4. Midostaurin exhibited potential inhibitory effects on P-glycoprotein (P-gp), breast cancer resistance protein (BCRP), organic anion-transporting polyprotein 1B1, and CYP2D6 in in vitro studies. This study investigated the pharmacokinetic (PK) effects of midostaurin on P-gp (digoxin), BCRP (rosuvastatin) and CYP2D6 (dextromethorphan) substrates in healthy adults. METHODS: This was an open-label, single-sequence, phase I clinical study evaluating the effect of single-dose midostaurin (100 mg) on the PK of digoxin and rosuvastatin (Arm 1), and dextromethorphan (Arm 2). Participants were followed up for safety 30 days after last dose. In addition, the effect of midostaurin on the PK of dextromethorphan metabolite (dextrorphan) was assessed in participants with functional CYP2D6 genes in Arm 2. RESULTS: The effect of midostaurin on digoxin was minor and resulted in total exposure (AUC) and peak plasma concentration (Cmax) that were only 20% higher. The effect on rosuvastatin was mild and led to an increase in AUCs of approximately 37-48% and of 100% in Cmax. There was no increase in the primary PK parameters (AUCs and Cmax) of dextromethorphan in the presence of midostaurin. The study treatments were very well tolerated with no occurance of severe adverse events (AEs), AEs of grade ≥ 2, or deaths. CONCLUSION: Midostaurin showed only a minor inhibitory effect on P-gp, a mild inhibitory effect on BCRP, and no inhibitory effect on CYP2D6. Study treatments were well tolerated in healthy adults.


Assuntos
Membro 2 da Subfamília G de Transportadores de Cassetes de Ligação de ATP , Citocromo P-450 CYP2D6 , Dextrometorfano , Digoxina , Interações Medicamentosas , Proteínas de Neoplasias , Rosuvastatina Cálcica , Estaurosporina , Humanos , Estaurosporina/análogos & derivados , Estaurosporina/farmacocinética , Estaurosporina/farmacologia , Citocromo P-450 CYP2D6/genética , Citocromo P-450 CYP2D6/metabolismo , Membro 2 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/genética , Membro 2 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/metabolismo , Adulto , Masculino , Dextrometorfano/farmacocinética , Proteínas de Neoplasias/genética , Proteínas de Neoplasias/metabolismo , Proteínas de Neoplasias/antagonistas & inibidores , Feminino , Digoxina/farmacocinética , Digoxina/farmacologia , Pessoa de Meia-Idade , Rosuvastatina Cálcica/farmacocinética , Membro 1 da Subfamília B de Cassetes de Ligação de ATP/metabolismo , Membro 1 da Subfamília B de Cassetes de Ligação de ATP/genética , Adulto Jovem , Voluntários Saudáveis
9.
Biol Pharm Bull ; 47(8): 1422-1428, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-39111864

RESUMO

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.


Assuntos
Citocromo P-450 CYP2D6 , Hepatócitos , Humanos , Citocromo P-450 CYP2D6/genética , Citocromo P-450 CYP2D6/metabolismo , Células Hep G2 , Hepatócitos/metabolismo , Edição de Genes/métodos , Glucuronosiltransferase/genética , Glucuronosiltransferase/metabolismo , Polimorfismo de Nucleotídeo Único , Modelos Biológicos
10.
Clin Transl Sci ; 17(8): e13911, 2024 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-39123290

RESUMO

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.


Assuntos
Benchmarking , Citocromo P-450 CYP2D6 , Farmacogenética , Humanos , Citocromo P-450 CYP2D6/genética , Farmacogenética/normas , Farmacogenética/métodos , Citocromo P-450 CYP2C19/genética , Sequenciamento Completo do Genoma/normas , Sequenciamento Completo do Genoma/métodos , Técnicas de Genotipagem/métodos , Genótipo , Citocromo P-450 CYP2C9/genética , Citocromo P-450 CYP2A6/genética , Testes Farmacogenômicos/normas , Testes Farmacogenômicos/métodos , Sequenciamento de Nucleotídeos em Larga Escala/normas , Vitamina K Epóxido Redutases
12.
Clin Transl Sci ; 17(8): e70005, 2024 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-39177194

RESUMO

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.


Assuntos
Analgésicos Opioides , Dor Crônica , Citocromo P-450 CYP2D6 , Adulto , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Analgésicos Opioides/uso terapêutico , Analgésicos Opioides/efeitos adversos , Dor Crônica/tratamento farmacológico , Citocromo P-450 CYP2D6/genética , Citocromo P-450 CYP2D6/metabolismo , Manejo da Dor/métodos , Medição da Dor , Testes Farmacogenômicos , Medicina de Precisão/métodos
13.
J Phys Chem B ; 128(29): 7188-7198, 2024 Jul 25.
Artigo em Inglês | MEDLINE | ID: mdl-39016537

RESUMO

Human cytochrome P450 (CYP) proteins metabolize 75% of small-molecule pharmaceuticals, which makes structure-based modeling of CYP metabolism and inhibition, bolstered by the current availability of X-ray crystal structures of CYP globular catalytic domains, an attractive prospect. Accounting for this broad metabolic capacity is a combination of the existence of multiple different CYP proteins and the capacity of a single CYP protein to metabolize multiple different small molecules. It is thought that structural plasticity and flexibility contribute to this latter property; therefore, incorporating diverse conformational states of a particular CYP is likely an important consideration in structure-based CYP metabolism and inhibition modeling. While all-atom explicit-solvent molecular dynamics simulations can be used to generate conformational ensembles under biologically relevant conditions, existing CYP crystal structures are of the globular domain only, whereas human CYPs contain N-terminal transmembrane and linker peptides that anchor the globular catalytic domain to the endoplasmic reticulum. To determine whether this can cause significant differences in the sampled binding site conformations, microsecond scale all-atom explicit-solvent molecular dynamics simulations of the CYP2D6 globular domain in an aqueous environment were compared with those of the full-length protein anchored in a POPC lipid bilayer. While bilayer-anchoring damped some structural fluctuations in the globular domain relative to the aqueous simulations, none of the affected residues included binding site pocket residues. Furthermore, clustering of molecular dynamics snapshots based on either pairwise binding site pocket RMSD or volume differences demonstrated a lack of separation of snapshots from the two simulation conditions into different clusters. These results suggest the substantially simpler and computationally cheaper aqueous simulation approach can be used to generate a relevant conformational ensemble of the CYP2D6 binding site for structure-based metabolism and inhibition modeling.


Assuntos
Citocromo P-450 CYP2D6 , Bicamadas Lipídicas , Simulação de Dinâmica Molecular , Humanos , Sítios de Ligação , Citocromo P-450 CYP2D6/química , Citocromo P-450 CYP2D6/metabolismo , Bicamadas Lipídicas/química , Bicamadas Lipídicas/metabolismo , Conformação Proteica
14.
J Chem Inf Model ; 64(15): 6026-6040, 2024 Aug 12.
Artigo em Inglês | MEDLINE | ID: mdl-38994927

RESUMO

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.


Assuntos
Citocromo P-450 CYP2D6 , Simulação de Dinâmica Molecular , Polimorfismo de Nucleotídeo Único , Citocromo P-450 CYP2D6/metabolismo , Citocromo P-450 CYP2D6/genética , Citocromo P-450 CYP2D6/química , Humanos , Conformação Proteica
15.
Pharm Res ; 41(8): 1613-1620, 2024 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-39044045

RESUMO

PURPOSE: The aim of this study was to examine the ability of sunscreen active ingredients to inhibit in vitro drug metabolism via cytochrome P450 (CYP) enzymes and drug uptake transporters. METHODS: Metabolism assays with human liver microsomes were conducted for CYP2C9, CYP2D6 and CYP3A4 using probe substrates warfarin, bufuralol and midazolam, respectively. Uptake transporter assays with transfected cell lines were conducted for OAT3, OCT2 and OATP1B1 with probe substrates estrone-3-sulfate, metformin and rosuvastatin, respectively. Six sunscreen active ingredients, avobenzone, enzacamene, oxybenzone, octinoxate, trolamine, and homosalate, were evaluated up to their aqueous solubility limits in the assays. RESULTS: None of the sunscreen active ingredients inhibited CYP2D6 or CYP3A4 activities in the microsomes at concentration ranges up to tenfold higher than their known clinical total plasma levels. Only enzacamene, oxybenzone and trolamine were found to be inhibitory to CYP2C9 activity with IC50 values of 14.76, 22.46 and 154.7 µM, respectively. Avobenzone, enzacamene, homosalate and octinoxate were not inhibitory to the uptake transporters at the evaluated concentrations. Oxybenzone was inhibitory to OAT3 and OCT2 with IC50 values of 39.93 and 42.77 µM, respectively. Trolamine also inhibited uptake in OAT3 and OCT2 transfected cells with IC50 values of 448.1 and 1376 µM, respectively. CONCLUSIONS: Although enzacamene, oxybenzone and trolamine inhibited CYP2C9 and the renal transporters OAT3 and OCT2 in vitro, their IC50 values exceeded total plasma levels found in clinical studies. Therefore, it is unlikely that these sunscreen active ingredients in sunscreen products will inhibit the metabolism or transport of co-administered drugs in consumers.


Assuntos
Interações Medicamentosas , Microssomos Hepáticos , Protetores Solares , Humanos , Protetores Solares/farmacocinética , Protetores Solares/metabolismo , Protetores Solares/farmacologia , Microssomos Hepáticos/metabolismo , Células HEK293 , Citocromo P-450 CYP2D6/metabolismo , Inibidores das Enzimas do Citocromo P-450/farmacologia , Citocromo P-450 CYP3A/metabolismo
16.
Artigo em Inglês | MEDLINE | ID: mdl-39069248

RESUMO

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.


Assuntos
Encéfalo , Citocromo P-450 CYP2D6 , Ciclo Estral , Camundongos Transgênicos , Animais , Feminino , Citocromo P-450 CYP2D6/metabolismo , Citocromo P-450 CYP2D6/genética , Humanos , Encéfalo/metabolismo , Encéfalo/efeitos dos fármacos , Camundongos , Ciclo Estral/efeitos dos fármacos , Harmina/farmacologia , Propranolol/farmacologia , Masculino , Fígado/metabolismo , Fígado/efeitos dos fármacos , Inibidores do Citocromo P-450 CYP2D6/farmacologia , Hipotermia/induzido quimicamente , Hipotermia/metabolismo
17.
J Affect Disord ; 363: 542-551, 2024 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-39038621

RESUMO

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.


Assuntos
Antidepressivos , Transtorno Depressivo Maior , Herança Multifatorial , Humanos , Transtorno Depressivo Maior/tratamento farmacológico , Transtorno Depressivo Maior/genética , Antidepressivos/uso terapêutico , Masculino , Feminino , Adulto , Pessoa de Meia-Idade , Resultado do Tratamento , Citocromo P-450 CYP2D6/genética , Citocromo P-450 CYP2C19/genética , Estudos de Coortes , Variação Genética
18.
Eur J Clin Pharmacol ; 80(10): 1531-1541, 2024 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-38963454

RESUMO

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.


Assuntos
Antipsicóticos , Citocromo P-450 CYP2D6 , Haplótipos , Palmitato de Paliperidona , Polimorfismo de Nucleotídeo Único , Risperidona , Risperidona/farmacocinética , Risperidona/sangue , Humanos , Citocromo P-450 CYP2D6/genética , Citocromo P-450 CYP2D6/metabolismo , Masculino , Feminino , Adulto , Antipsicóticos/farmacocinética , Antipsicóticos/sangue , Palmitato de Paliperidona/farmacocinética , Palmitato de Paliperidona/sangue , Pessoa de Meia-Idade , Taxa de Depuração Metabólica , Alelos , Adulto Jovem , Genótipo , Modelos Biológicos
19.
Transl Psychiatry ; 14(1): 296, 2024 Jul 19.
Artigo em Inglês | MEDLINE | ID: mdl-39025838

RESUMO

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.


Assuntos
Antidepressivos , Citocromo P-450 CYP2C19 , Citocromo P-450 CYP2D6 , Feminino , Humanos , Masculino , Antidepressivos/uso terapêutico , Povo Asiático/genética , Citocromo P-450 CYP2C19/genética , Citocromo P-450 CYP2D6/genética , Citocromo P-450 CYP2D6/metabolismo , Transtorno Depressivo Maior/tratamento farmacológico , Transtorno Depressivo Maior/genética , Transtorno Depressivo Maior/metabolismo , Genótipo , Fenótipo , Resultado do Tratamento , População Branca/genética
20.
Angew Chem Int Ed Engl ; 63(41): e202409217, 2024 Oct 07.
Artigo em Inglês | MEDLINE | ID: mdl-38989537

RESUMO

Cytochrome P450 2D6 (CYP2D6) is a key enzyme that mediates the metabolism of various drugs and endogenous substances in humans. However, its biological role in drug-drug interactions especially mechanism-based inactivation (MBI), and various diseases remains poorly understood, owing to the lack of molecular tools suitable for selectively monitoring CYP2D6 in complex biological systems. Herein, using a tailored molecular strategy, we developed a fluorescent probe BDPM for CYP2D6. BDPM exhibits excellent specificity and imaging capability for CYP2D6, making it suitable for the real-time monitoring of endogenous CYP2D6 activity in living bio-samples. Therefore, our tailored strategy proved useful for constructing the highly selective and enzyme-activated fluorescent probes. BDPM as a molecular tool to explore the critical roles of CYP2D6 in the pathogenesis of diseases, high-throughput screening of inhibitors and intensive investigation of CYP2D6-induced MBI in natural systems.


Assuntos
Citocromo P-450 CYP2D6 , Corantes Fluorescentes , Humanos , Corantes Fluorescentes/química , Citocromo P-450 CYP2D6/metabolismo , Citocromo P-450 CYP2D6/química , Estrutura Molecular
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