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1.
Chem Biol Interact ; 313: 108840, 2019 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-31585114

RESUMO

BACKGROUND AND OBJECTIVES: Clonidine has been clinically used to treat Tourette's syndrome for decades. There was research finding that clonidine possessed the best risk-benefit ratio, especially for patients associated with attention deficit hyperactivity disorder. CYP2D6 is a significant member of Cytochrome P450 enzymes. The genetic polymorphisms of CYP2D6 greatly affect the clinical effects of drugs even lead to side effects and medical malpractice. Our goal is to research the effect of CYP2D6 genetic polymorphism on the metabolism of clonidine and evaluate the functions of 22 CYP2D6 allelic variants in vitro, which were discovered in Chinese Han population recently. METHODS: This study was carried out through a mature incubation system. The wild-type CYP2D6*1 and 24 variants (CYP2D6*2, CYP2D6*10 and 22 novel CYP2D6 variants) were expressed in insect cells, and the catalytic activity of all the variants were assessed by substrate clonidine. Metabolite 4-OH clonidine was accurately detected via ultra-performance liquid-chromatography tandem mass spectrometry to evaluate the effect of CYP2D6 genetic polymorphism on the clonidine. RESULT: Among the 22 novel CYP2D6 variants, the intrinsic clearance (Vmax/Km) of 21 variants were significantly decreased (from 1.53% to 83.25%) compared to the wild-type. In particular, the following seven variants (CYP2D6* 2, CYP2D6* 10, CYP2D6* 93, CYP2D6* 95, E215K, V327 M and R497C) attract more attention, of which the intrinsic clearance decreased more than 70% compared to the wild-type. Because the variants with significantly reduced intrinsic clearance are more likely to cause adverse reactions than the variants with increased or little changed intrinsic clearance. In addition, the related pharmacokinetic parameters of CYP2D6*92 and CYP2D6*96 could not be acquired for the defect of CYP2D6 nucleotide. CONCLUSION: We comprehensively evaluated the effect of 22 novel CYP2D6 variants on the metabolism of clonidine for the first time and hoped corresponding data provide a reference for metabolism of clonidine for further studies in vivo, and extend our understanding of the clinical drug toxicity or ineffectiveness by CYP2D6 genetic polymorphism.


Assuntos
Clonidina/farmacocinética , Citocromo P-450 CYP2D6/genética , Grupo com Ancestrais do Continente Asiático/genética , Clonidina/metabolismo , Citocromo P-450 CYP2D6/metabolismo , Humanos , Polimorfismo Genético
2.
Chem Biol Interact ; 314: 108825, 2019 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-31553897

RESUMO

The World Health Organization (WHO) and other worldwide health agencies have recently taken initiatives to encourage the use of traditional medicine and/or complementary/alternative medicine in order to promote well-being and public health. In this way, one of the WHO's concerns is the safe use of these therapies. Phytotherapy is a strategy consisting of the use of medicinal plants (MP) and/or herbal medicinal products (HMP) for medicinal purposes. The use of phytotherapy concomitantly with drugs may cause interactions compromising the expected pharmacological action or generating toxic effects. These interactions are complex processes that may occur with multiple medications targeting different metabolic pathways, and involving different compounds present in MP and HMP. Thus, the aim of this review was to summarize the main MP- and HMP-drug interactions that involve specific transporters (P-glycoprotein and BCRP) and CYP450 enzymes (CYP3A4 and CYP2D6), which play relevant roles in the mechanisms of interactions. Firstly, multiple databases were used to search studies describing in vitro or in vivo MP and HMP-drug interactions and, after that, a systematic note-taking and appraisal of the literature was conducted. It was observed that several MP and HMP, metabolic pathways and transcription factors are involved in the transporters and enzymes expression or in the modulation of their activity having the potential to provide such interactions. Thus, the knowledge of MP- and HMP-drug interaction mechanisms could contribute to prevent harmful interactions and can ensure the safe use of these products to help the establishment of the therapeutic planning in order to certify the best treatment strategy to be used.


Assuntos
Membro 2 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/metabolismo , Citocromo P-450 CYP2D6/metabolismo , Citocromo P-450 CYP3A/metabolismo , Animais , Interações Ervas-Drogas , Humanos , Plantas Medicinais/química , Plantas Medicinais/metabolismo
3.
BMC Infect Dis ; 19(1): 704, 2019 Aug 09.
Artigo em Inglês | MEDLINE | ID: mdl-31399061

RESUMO

BACKGROUND: Plasmodium vivax transmission in West Africa, dominant for the Duffy-negative blood group, has been increasingly recognized from both local residents as well as international travelers who contracted P. vivax malaria there. However, the relapsing pattern and sensitivity to antimalarial treatment of P. vivax strains originated from this region are largely unknown. There is evidence that the efficacy of primaquine for radical cure of relapsing malaria depends on host factors such as the hepatic enzyme cytochrome P450 (CYP) 2D6. CASE PRESENTATION: A 49-year-old Chinese man was admitted to the Shanglin County Hospital in Guangxi Province, China, on December 19, 2016, 39 days after he returned from Ghana, where he stayed for one and a half years. He was diagnosed by microscopy as having uncomplicated P. vivax malaria. Treatment included 3 days of intravenous artesunate (420 mg total), and 3 days of chloroquine (1550 mg total), and 8 days of primaquine (180 mg total). Although parasites and symptoms were cleared rapidly and he was malaria-negative for almost two months, he suffered four relapses with relapse intervals ranging from 58 to 232 days. The last relapse occurred at 491 days from his first vivax attack. For the first three relapses, he was treated similarly with chloroquine and primaquine, sometimes supplemented with additional artemisinin combination therapies (ACTs). For the last relapse, he was treated with intravenous artesunate, 3 days of an ACT, and 7 days of azithromycin, and had remained healthy for 330 days. Molecular studies confirmed P. vivax infections for all the episodes. Although this patient was diagnosed to have normal glucose-6-phosphate dehydrogenase (G6PD) activity, his CYP2D6 genotype corresponded to a *2A/*36 allele variant suggesting of an impaired primaquine metabolizer phenotype. CONCLUSIONS: This clinical case suggests that P. vivax malaria originating from West Africa may produce multiple relapses extending beyond one year. The failures of primaquine as an anti-relapse therapy may be attributed to the patient's impaired metabolizer phenotype of the CYP2D6. This highlights the importance of knowing the host G6PD and CYP2D6 activities for effective radical cure of relapsing malaria by primaquine.


Assuntos
Citocromo P-450 CYP2D6/metabolismo , Malária Vivax/tratamento farmacológico , Malária Vivax/parasitologia , Plasmodium vivax/patogenicidade , Antimaláricos/farmacocinética , Antimaláricos/uso terapêutico , Artemisininas/uso terapêutico , Artesunato/uso terapêutico , Cloroquina/uso terapêutico , Citocromo P-450 CYP2D6/genética , Gana , Humanos , Inativação Metabólica , Masculino , Pessoa de Meia-Idade , Plasmodium vivax/genética , Primaquina/farmacocinética , Primaquina/uso terapêutico , Recidiva
4.
Nat Commun ; 10(1): 3226, 2019 07 19.
Artigo em Inglês | MEDLINE | ID: mdl-31324806

RESUMO

Primaquine (PQ) is an essential antimalarial drug but despite being developed over 70 years ago, its mode of action is unclear. Here, we demonstrate that hydroxylated-PQ metabolites (OH-PQm) are responsible for efficacy against liver and sexual transmission stages of Plasmodium falciparum. The antimalarial activity of PQ against liver stages depends on host CYP2D6 status, whilst OH-PQm display direct, CYP2D6-independent, activity. PQ requires hepatic metabolism to exert activity against gametocyte stages. OH-PQm exert modest antimalarial efficacy against parasite gametocytes; however, potency is enhanced ca.1000 fold in the presence of cytochrome P450 NADPH:oxidoreductase (CPR) from the liver and bone marrow. Enhancement of OH-PQm efficacy is due to the direct reduction of quinoneimine metabolites by CPR with the concomitant and excessive generation of H2O2, leading to parasite killing. This detailed understanding of the mechanism paves the way to rationally re-designed 8-aminoquinolines with improved pharmacological profiles.


Assuntos
Antimaláricos/farmacologia , Plasmodium falciparum/efeitos dos fármacos , Primaquina/metabolismo , Primaquina/farmacologia , Aminoquinolinas/farmacologia , Medula Óssea/metabolismo , Citocromo P-450 CYP2D6/metabolismo , Sistema Enzimático do Citocromo P-450 , Relação Dose-Resposta a Droga , Humanos , Peróxido de Hidrogênio/metabolismo , Fígado/metabolismo , Malária Falciparum/tratamento farmacológico , NADP , Farmacocinética
5.
Phytomedicine ; 60: 153010, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31301970

RESUMO

BACKGROUND: Moringa oleifera Lam. is known as a drumstick tree that is widely cultivated in various subtropical and tropical provinces. Previous studies indicated that both aqueous and methanolic extracts of M. oleifera leaves have potent inhibitory effects on two major drug metabolizing Cytochrome P450 enzymes, namely, CYP3A4 and CYP2D6. PURPOSE: The current study was aimed to isolate the secondary metabolites from M. oleifera and investigate their cytotoxicity and inhibitory effects on CYP3A4 and CYP2D6 to assess their herb-drug interaction (HDI) potential. METHODS: Chemical structure elucidation was achieved by interpreting the spectroscopic data (UV, IR, 1D, and 2D NMR experiments), confirming by HR-ESI-MS, and comparing with the previously reported data in the literature. All the isolates were evaluated for their cytotoxicity against a panel of cell lines (SK-MEL, KB, BT-549, SK-OV-3, VERO, LLC-PK1, and HepG2) and inhibition of two principal CYP isozymes (CYP3A4 and CYP2D6). RESULTS: Phytochemical investigation of M. oleifera leaves resulted in the isolation and characterization of one new compound, namely omoringone (1), along with twelve known secondary metabolites (2-13) belonging to several chemical classes including flavonoids, terpenoids, lignans, and phenylalkanoids. A plausible biosynthetic pathway for compound 1 was provided. Because of the low isolation yield and limited supply, omoringone (1) and niazirin (12) were successively synthesized. No cytotoxicity was observed on any of the tested cell lines up to 50 µM. The extract exhibited an inhibitory effect on CYP3A4 isoform (IC50 = 52.5 ±â€¯2.5 µg/ml). Among the isolates, 1-4 and 7-9 inhibited CYP3A4 with the IC50 values ranging from 41.5 to 100 µM with no remarkable effect on CYP2D6 isozyme. CONCLUSION: This work aided in ascertaining components of M. oleifera contributing to CYP3A4 inhibition exhibited by the extract using an in vitro assay. Nonetheless, further studies are warranted to determine the bioavailability of the phytochemicals and extrapolate these findings in more physiologically relevant conditions to further establish the clinical relevance of in vitro observations.


Assuntos
Citocromo P-450 CYP2D6/efeitos dos fármacos , Citocromo P-450 CYP3A/efeitos dos fármacos , Interações Ervas-Drogas , Moringa oleifera/química , Extratos Vegetais/farmacologia , Citocromo P-450 CYP2D6/metabolismo , Citocromo P-450 CYP3A/metabolismo , Inibidores do Citocromo P-450 CYP3A , Humanos , Isoenzimas/efeitos dos fármacos , Extratos Vegetais/química , Folhas de Planta/química , Árvores
6.
Toxicol Lett ; 313: 196-204, 2019 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-31278966

RESUMO

Fipronil is a chiral insecticide employed worldwide in crops, control of public hygiene and control of veterinary pests. Humans can be exposed to fipronil through occupational, food, and environmental contamination. Therefore, the risk assessment of fipronil in humans is important to protect human health. Fipronil sulfone is the major metabolite formed during fipronil metabolism by humans. Since the CYP450 enzymes are the main ones involved in drug metabolism, the evaluation of their inhibition by fipronil and its main metabolite is important to predict drug-pesticide interactions. The aim of this work was to investigate the inhibition effects of rac-fipronil, S-fipronil, R-fipronil and fipronil sulfone on the main human CYP450 isoforms. The results showed that CYP2D6 is the only CYP450 isoform inhibited by these xenobiotics. In addition, no enantioselective differences were observed in the inhibition of CYP450 isoforms by fipronil and its individuals' enantiomers. Rac-fipronil, S-fipronil and R-fipronil are moderate CYP2D6 inhibitors showing a competitive inhibition profile. On the other hand, the metabolite fipronil sulfone showed to be a strong inhibitor of CYP2D6 also by competitive inhibition. These results highlight the importance of metabolite evaluation on pesticide safety since the metabolism of fipronil into fipronil sulfone increases the risk of pesticide-drug interactions for drugs metabolized by CYP2D6.


Assuntos
Inibidores do Citocromo P-450 CYP2D6/toxicidade , Citocromo P-450 CYP2D6/metabolismo , Praguicidas/toxicidade , Pirazóis/toxicidade , Citocromo P-450 CYP2D6/química , Inibidores do Citocromo P-450 CYP2D6/química , Relação Dose-Resposta a Droga , Interações de Medicamentos , Humanos , Microssomos Hepáticos/efeitos dos fármacos , Microssomos Hepáticos/enzimologia , Modelos Biológicos , Praguicidas/química , Conformação Proteica , Pirazóis/química , Medição de Risco , Relação Estrutura-Atividade
7.
J Pharm Biomed Anal ; 174: 479-485, 2019 Sep 10.
Artigo em Inglês | MEDLINE | ID: mdl-31228851

RESUMO

Specific study about the effect of cytochrome P450 2D6 (CYP2D6) polymorphisms on the metabolism of clinic drugs is of great significance for drug safety investigation. Here, the interaction between CYP2D6 variants (*1, *2, *10, *39) and metoprolol (MET) was intensively researched in vitro from the aspect of drug-enzyme kinetic study. To obtain quantitative data, α-hydroxymetoprolol (main metabolite of MET) was selected as an ideal analyte and an LC-MS/MS method was adopted for sample determination. Firstly, by selecting suitable internal standard and optimizing separation condition, the LC-MS/MS method was established and validated. Then, the drug-enzyme incubation system was optimized by two parameters: incubation time and amount of enzyme. Lastly, the interaction between CYP2D6 allelic variants and MET was characterized by Km, Vmax and CLint. As a result, four CYP2D6 enzymes displayed diverse Km or Vmax towards MET and the values of CLint showed a wide range from 8.91 to 100%. Relative to CYP2D6*1 (CLint*1 = 100%), CYP2D6*2 demonstrated the second high catalytic activity (CLint*2/*1 = 74.87%) while CYP2D6*39 (CLint*39/*1 = 29.65%) and CYP2D6*10 (CLint*10/*1 = 8.91%) showed minimal catalytic activity. This comprehensive in vitro data suggested the prominent influence of CYP2D6 polymorphisms on the metabolism of MET, which could offer valuable information for personalized administration of MET in clinic.


Assuntos
Citocromo P-450 CYP2D6/genética , Citocromo P-450 CYP2D6/metabolismo , Variação Genética , Metoprolol/análogos & derivados , Metoprolol/análise , Alelos , Cromatografia Líquida , Dabigatrana/análise , Deutério/química , Humanos , Cinética , Metoprolol/metabolismo , Mutação , Reprodutibilidade dos Testes , Espectrometria de Massas em Tandem
8.
Mol Med Rep ; 20(2): 1103-1112, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31173186

RESUMO

DL0410, a dual­action cholinesterase inhibitor and histamine­3 receptor antagonist with a novel structural scaffold, may be a potential candidate for the treatment of Alzheimer's disease (AD). To the best of the authors' knowledge, this is the first study to demonstrate a reliable method for the measurement of DL0410 in rat plasma, brain, bile, urine and feces samples, and identification of its primary metabolites. The pharmacokinetic properties of DL0410 were analyzed by liquid chromatography­mass spectrometry at oral doses of 25, 50 and 100 mg/kg and intravenous dose of 5 mg/kg. The investigation of the excretion and metabolism of DL0410 was determined following liquid­liquid extraction for biliary, urinary and fecal samples. Finally, the cytochrome (CY)P450 isoforms involved in the production of DL0410 metabolites with recombinant human cytochrome P450 enzymes were characterized. The results suggested that DL0410 was not well absorbed; however, was distributed to the entorhinal cortex and hippocampus of the brain. A total of two common metabolites of the reduction of DL0140 in the bile, urine and feces were identified and CYP2D6 was involved in this reaction. The pharmacokinetic results of DL0410 provided information for the illustration of its pharmacodynamic properties, mechanism of action and promoted its continued evaluation as a therapeutic agent for AD treatment.


Assuntos
Compostos de Bifenilo/farmacocinética , Inibidores da Colinesterase/farmacocinética , Citocromo P-450 CYP2D6/metabolismo , Antagonistas dos Receptores Histamínicos H3/farmacocinética , Piperidinas/farmacocinética , Doença de Alzheimer/tratamento farmacológico , Animais , Bile/metabolismo , Compostos de Bifenilo/análise , Compostos de Bifenilo/uso terapêutico , Líquidos Corporais/metabolismo , Encéfalo/metabolismo , Inibidores da Colinesterase/análise , Inibidores da Colinesterase/uso terapêutico , Fezes/química , Feminino , Antagonistas dos Receptores Histamínicos H3/análise , Antagonistas dos Receptores Histamínicos H3/uso terapêutico , Humanos , Masculino , Piperidinas/análise , Piperidinas/uso terapêutico , Ratos , Ratos Sprague-Dawley
9.
Int J Pharm ; 566: 391-399, 2019 Jul 20.
Artigo em Inglês | MEDLINE | ID: mdl-31158453

RESUMO

Chronic pain represents one of the most important public health problems, with a great prevalence of comorbidity with depression and cognitive decline. Antidepressants such as duloxetine, a serotonin-norepinephrine reuptake inhibitor, represent an essential part of the therapeutic strategy for chronic pain management in addition to classical analgesics. Duloxetine is endowed with good efficacy and a good profile of safety and tolerability. Yet, duloxetine is metabolized by the cytochrome P450 system 2D6 and 1A2 (CYP2D6 and CYP1A2) and it exhibits moderate inhibitory activity on CYP2D6, resulting in side effects and metabolic interactions that may occur on a long term therapeutic schedule. Cyclodextrins (CyDs) are used in pharmaceutical applications for numerous purposes, including the improvement of drug bioavailability. In order to evaluate their effects on the activity of duloxetine, we first spectrophotometrically studied the host-guest complexes obtained combining duloxetine and different ß-CyD derivatives (ß-CyD, ß-CyDen-c-(Glu-Glu), and succinyl-ß-CyD) and then performed in vivo and in vitro studies. Among duloxetine/CyDs complexes, succinyl-ß-CyD ameliorated the analgesic activity of duloxetine in the tail flick test and in the formalin test in mice and significantly protected the drug from CYP2D6 metabolism.


Assuntos
Analgésicos/administração & dosagem , Ciclodextrinas/administração & dosagem , Cloridrato de Duloxetina/administração & dosagem , Dor/tratamento farmacológico , Analgésicos/química , Animais , Células CACO-2 , Sobrevivência Celular/efeitos dos fármacos , Ciclodextrinas/química , Citocromo P-450 CYP2D6/metabolismo , Cloridrato de Duloxetina/química , Humanos , Masculino , Camundongos
10.
Clin Lab ; 65(5)2019 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-31115220

RESUMO

BACKGROUND: CYP2D6*10 is mainly responsible for the large pharmacokinetic variability of routinely administered metoprolol in middle-aged and elderly Asian patients. Utilizing an efficient method for identifying the CYP2D6*10 genotypes is clinically important for evaluating the pharmacokinetic effect of administration of metoprolol. This study attempted to evaluate the effectiveness of the two methods used to detect the rs1065852 and rs1135840 SNPs of the CYP2D6*10 gene. METHODS: Blood samples were processed for the collection of genomic DNA from 198 subjects across Chinese population, and detection of CYP2D6*10 (rs1065852 and rs1135840) was performed using the PyroMark Q24 pyrose-quencing and matrix-assisted laser desorption/ionization time-of-flight mass-spectrometry (MALDI-TOF MS). The discordant results were further validated with Sanger sequencing. We eventually attempted to assess some features of these two methods including reliability, rapidness, being appropriate, and cost-effectiveness. RESULTS: Genotyping of rs1065852 and rs1135840 detected by MALDI-TOF MS were concordant with those identified by PyroMark Q24 pyrosequencing in all 198 (100%) individuals. The hands-on-time and the turnaround time were shorter in the PyroMark Q24 pyrosequencing method than in the MALDI-TOF MS method for SNP of CYP2D6*10. In terms of being cost-effective and high-throughput, the MALDI-TOF MS method outperformed the PyroMark Q24 pyrosequencing method. CONCLUSIONS: CYP2D6*10 genotypes detected by PyroMark Q24 pyrosequencing and MALDI-TOF-MS showed that both methods were reliable, rapid, appropriate, and cost-effective methods. These methods are valuable for clinical applications.


Assuntos
Citocromo P-450 CYP2D6/genética , Técnicas de Genotipagem/métodos , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Polimorfismo de Nucleotídeo Único , Espectrometria de Massas por Ionização e Dessorção a Laser Assistida por Matriz/métodos , Idoso , Anti-Hipertensivos/sangue , Anti-Hipertensivos/metabolismo , Anti-Hipertensivos/uso terapêutico , Grupo com Ancestrais do Continente Asiático/genética , China , Análise Custo-Benefício , Citocromo P-450 CYP2D6/metabolismo , Feminino , Genótipo , Técnicas de Genotipagem/economia , Humanos , Hipertensão/sangue , Hipertensão/tratamento farmacológico , Hipertensão/genética , Masculino , Metoprolol/sangue , Metoprolol/metabolismo , Metoprolol/uso terapêutico , Pessoa de Meia-Idade , Reprodutibilidade dos Testes
11.
Medicina (Kaunas) ; 55(6)2019 May 28.
Artigo em Inglês | MEDLINE | ID: mdl-31141989

RESUMO

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.


Assuntos
Codeína/metabolismo , Citocromo P-450 CYP2D6/metabolismo , Dor/tratamento farmacológico , Fenótipo , Adulto , Idoso , Analgésicos/metabolismo , Analgésicos/uso terapêutico , Codeína/uso terapêutico , Citocromo P-450 CYP2D6/sangue , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Dor/fisiopatologia , Medição da Dor/métodos , Reino Unido
12.
Can J Physiol Pharmacol ; 97(8): 781-785, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31100205

RESUMO

The objective of the study was to investigate the effects of CYP2D6 activity on the efficacy and safety of mirtazapine in patients with depressive disorders and comorbid alcohol use disorder who received mirtazapine. The study included 109 Russian patients who received mirtazapine at a dose of 30.0 [15.0; 45.0] mg per day. Genotyping of CYP2D6*4 (1846G > A, rs3892097) was performed using real-time polymerase chain reaction with allele-specific hybridization. The activity of CYP2D6 was evaluated by determining the concentration of endogenous substrate of the enzyme and its urinary metabolite - pinoline to 6-hydroxy-1,2,3,4-tetrahydro-beta-carboline ratio, using high-performance liquid chromatography - mass spectrometry. The statistically significant differences between the scores on the Hamilton Depression Rating Scale (HAMD) in patients with different genotypes were revealed by day 16: (GG) 5.0 [3.0; 6.0], (GA) 1.5 [1.0; 3.2] (p < 0.001), and for the The UKU Side Effects Rating Scale (UKU): (GG) 6.0 [6.0; 7.0], (GA) 8.5 [8.0; 10.0] (p < 0.001). The calculation of correlation coefficients between the differences in scale scores and metabolic rate showed the presence of statistically significant weak inverse correlation with the efficacy indicator evaluated by HAMD (r = -0.278, p < 0.05), but not by UKU (r = 0.274, p > 0.05). This study demonstrated that an increased CYP2D6 activity reduces the efficacy of treatment with mirtazapine.


Assuntos
Alcoolismo/tratamento farmacológico , Citocromo P-450 CYP2D6/metabolismo , Transtorno Depressivo/tratamento farmacológico , Mirtazapina/efeitos adversos , Mirtazapina/farmacologia , Segurança , Adulto , Alcoolismo/enzimologia , Alcoolismo/epidemiologia , Alcoolismo/genética , Comorbidade , Citocromo P-450 CYP2D6/genética , Transtorno Depressivo/enzimologia , Transtorno Depressivo/epidemiologia , Transtorno Depressivo/genética , Feminino , Genótipo , Humanos , Masculino , Mirtazapina/uso terapêutico , Polimorfismo Genético
13.
Yakugaku Zasshi ; 139(5): 699-704, 2019.
Artigo em Japonês | MEDLINE | ID: mdl-31061338

RESUMO

Human hepatocytes possess a wider range of phase I and II drug-metabolizing enzyme activities than other liver tissue-derived products, such as human liver microsomes. Thus, hepatocytes may be useful for predicting the in vivo metabolic fate of new drugs of abuse in humans. Recently, new types of human hepatocytes have been made commercially available for use in drug metabolism studies, such as a liver tumor-derived cell line (HepaRG), and a human induced pluripotent stem cell-derived hepatocyte (h-iPS-HEP). In our laboratory, HepaRG has been used to elucidate the metabolic pathways of XLR-11, a synthetic cannabinoid, and its thermal degradant. In addition, the potential of h-iPS-HEP to metabolize drugs was assessed using fentanyl as a model drug, and indeed, h-iPS-HEP exhibited a pattern for fentanyl metabolite formation similar to that observed in vivo. In addition, the phase I and II drug-metabolizing enzyme activities of HepaRG, h-iPS-HEP, liver-humanized mouse-derived hepatocytes (PXB-cellsTM), and human primary hepatocytes were evaluated and compared. HepaRG showed high phase I and II drug metabolism activities; however, the CYP2D6 activity in these cells was quite low, and therefore h-iPS-HEP lacked O-methylation and conjugation activities. PXB-cells provided optimal results, i.e., these cells are extremely easy to use, and they possess higher phase I and II drug-metabolizing enzyme activities than the other cells tested. Although PXB-cells are contaminated with mouse-derived cells up to a concentration of several percent, this cell system appears to be promising for the prediction of in vivo human metabolism of new drugs of abuse.


Assuntos
Canabinoides/metabolismo , Hepatócitos/enzimologia , Hepatócitos/metabolismo , Transtornos Relacionados ao Uso de Substâncias/metabolismo , Animais , Linhagem Celular , Citocromo P-450 CYP2D6/metabolismo , Fentanila/metabolismo , Humanos , Metilação , Camundongos
14.
Expert Rev Clin Pharmacol ; 12(6): 523-536, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31008668

RESUMO

Introduction: Tamoxifen dominates the anti-estrogenic therapy in the early and metastatic breast cancer setting. Tamoxifen has a complex metabolism, being mainly metabolized by CYP2D6 into its 30-100 times more potent metabolite, endoxifen. Recently, a phase I study in which endoxifen as an orally z-endoxifen hydrochloride has been successfully evaluated. Areas covered: the principal pharmacogenetic and non-genetic differences in the pharmacology of tamoxifen and endoxifen are evaluated. To this end, references from PubMed, Embase or Web of Science, among others, were reviewed As non-genetic factors, important differences and similarities such age, or adherence to tamoxifen therapy are comprehensively illustrated. Additionally, since CYP2D6 genotypes are considered the main limitation of tamoxifen, many studies have investigated the association between the worsened clinical outcomes in patients with non-functional CYP2D6 genotypes. In this review, an overview of the research on this field is presented. Also, a summary describing the literature about individualizing tamoxifen therapy with endoxifen concentrations and its limitations is listed. Expert opinion: z-endoxifen hydrochloride is only investigated in the metastatic setting, still more research is required before its place in therapeutics is known. Similarly, monitoring tamoxifen efficacy based on endoxifen concentrations might not be overall recommended due to the limited evidence available.


Assuntos
Antineoplásicos Hormonais/administração & dosagem , Neoplasias da Mama/tratamento farmacológico , Tamoxifeno/análogos & derivados , Administração Oral , Antineoplásicos Hormonais/farmacocinética , Neoplasias da Mama/patologia , Citocromo P-450 CYP2D6/genética , Citocromo P-450 CYP2D6/metabolismo , Feminino , Genótipo , Humanos , Adesão à Medicação , Metástase Neoplásica , Farmacogenética , Tamoxifeno/administração & dosagem , Tamoxifeno/farmacocinética
15.
Malar J ; 18(1): 140, 2019 Apr 18.
Artigo em Inglês | MEDLINE | ID: mdl-30999967

RESUMO

BACKGROUND: Primaquine, an 8-aminoquinoline with anti-hypnozoite activity against Plasmodium vivax, is metabolized by human cytochrome P450 2D6 (CYP2D6) to its active metabolite. Human CYP2D6 activities may influence the metabolism of primaquine and the risk of experiencing Plasmodium relapses following primaquine anti-relapse therapies (PART). In this study, the CYP2D6 profile and its relationship with outcomes of PART in Australian Defence Force (ADF) personnel is retrospectively investigated. METHODS: Genomic DNA was isolated from stored and de-identified serum or blood samples from ADF personnel deployed on peacekeeping duties to Papua New Guinea (PNG) (1999) and East Timor (1999-2000) who received PART before returning to Australia and after experiencing relapses. CYP2D6 allelic type was determined by PCR and Sanger sequencing. CYP2D6 allele frequency, predicted phenotypes and activity scores were compared among personnel who did not experience P. vivax (ADF-NR, n = 48) and those who experience at least one (ADF-R, n = 109) relapse, as well as between those who experienced 1 (n = 79), 2 (n = 21) and 3-5 (n = 9) relapses within the ADF-R group. RESULTS: 16 CYP2D6 alleles were observed in 157 ADF personnel. Alleles *1, *4, *2 and *41 were major alleles (> 5%). The CYP2D6 allele frequency profile in the ADF-NR group matched that of a European population. There was an increased proportion of non-functional CYP2D6 alleles in the ADF-R group compared to the European population and ADF-NR group. However, frequencies of predicted CYP2D6 phenotype and activity score were not different between the ADF-R and ADF-NR groups, nor among sub-groups experiencing multiple relapses within the ADF-R group. CONCLUSIONS: CYP2D6 phenotype or activity score based on the allele classification was not a major contributor to P. vivax relapse in this ADF cohort. Other factors such as adherence and/or parasite tolerance to primaquine are likely contributing factors to P. vivax relapses in this cohort.


Assuntos
Antimaláricos/uso terapêutico , Citocromo P-450 CYP2D6/genética , Malária Vivax/tratamento farmacológico , Primaquina/uso terapêutico , Alelos , Austrália , Citocromo P-450 CYP2D6/metabolismo , Humanos , Militares , Papua Nova Guiné , Recidiva , Estudos Retrospectivos , Timor-Leste , Resultado do Tratamento
16.
Drug Metab Dispos ; 47(6): 567-573, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-30952677

RESUMO

Rolapitant [(Varubi), 5S,8S)-8-[[(1R)-1-[3,5 bis(trifluoromethyl phenyl]ethoxy]methyl]-8-phenyl-1,7-diazaspiro[4.5]decan-2-one] is a high-affinity NK1 receptor antagonist that was approved in September 2015 as a treatment for nausea and vomiting caused by chemotherapy. In vivo rolapitant moderately inhibits CYP2D6 for at least 7 days after one 180 mg dose. Due to the long inhibition time, we investigated rolapitant as a possible mechanism-based inactivator of CYP2D6. Rolapitant docked in the active site of CYP2D6 and displayed type I binding to CYP2D6 with a K s value of 1.2 ± 0.4 µM. However, in NADPH-, time-, and concentration-dependent assays of CYP2D6 activity, no evidence for mechanism-based inactivation and no metabolites of rolapitant were observed. Stopped-flow binding studies yielded a kon /koff (K d) value of 6.2 µM. The IC50 value for rolapitant inhibition of CYP2D6 activity was 24 µM, suggesting that inhibition is not due to tight binding of rolapitant to CYP2D6. By Lineweaver-Burk analysis, rolapitant behaved as a mixed, reversible inhibitor. The K i values of 20 and 34 µM were determined by Dixon analysis, with bufuralol and dextromethorphan as reporter substrates, respectively, and drug-drug interaction modeling did not predict the reported in vivo inhibition. The interaction of rolapitant with CYP2D6 was also examined in 1 microsecond molecular dynamics simulations. Rolapitant adopted multiple low-energy binding conformations near the active site, but at distances not consistent with metabolism. Given these findings, we do not see evidence that rolapitant is a mechanism-based inactivator. Moreover, the reversible inhibition of CYP2D6 by rolapitant may not fully account for the moderate inhibition described in vivo.


Assuntos
Inibidores do Citocromo P-450 CYP2D6/uso terapêutico , Citocromo P-450 CYP2D6/metabolismo , Compostos de Espiro/uso terapêutico , Domínio Catalítico/fisiologia , Dextrometorfano/uso terapêutico , Interações de Medicamentos/fisiologia , Etanolaminas/uso terapêutico , Humanos
17.
Biol Pharm Bull ; 42(4): 623-630, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30930421

RESUMO

The metabolism of butyrylfentanyl, a new designer drug, was investigated using fresh human hepatocytes isolated from a liver-humanized mouse model. In the culture medium of hepatocytes incubated with butyrylfentanyl, the desphenethylated metabolite (nor-butyrylfentanyl), ω-hydroxy-butyrylfentanyl, (ω-1)-hydroxy-butyrylfentanyl, 4'-hydroxy-butyrylfentanyl, ß-hydroxy-butyrylfentanyl, 4'-hydroxy-3'-methoxy-butyrylfentanyl, and ω-carboxy-fentanyl were identified as the metabolites of butyrylfentanyl. Each metabolite was definitively identified by comparing the analytical data with those of authentic standards. The amount of the main metabolite, nor-butyrylfentanyl, reached 37% of the initial amount of butyrylfentanyl at 48 h. ω-Hydroxy-butyrylfentanyl and (ω-1)-hydroxy-butyrylfentanyl, formed by hydroxylation at the N-butyryl group of butyrylfentanyl, were the second and third largest metabolites, respectively. The majority of 4'-hydroxy-butyrylfentanyl and 4'-hydroxy-3'-methoxy-butyrylfentanyl was considered to be conjugated. CYP reaction phenotyping for butyrylfentanyl using human liver microsomes and various anti-CYP antibodies revealed that CYP3A4 was involved in the formation of nor-butyrylfentanyl, (ω-1)-hydroxy-butyrylfentanyl, and ß-hydroxy-butyrylfentanyl. In contrast, CYP2D6 was involved in the formation of ω-hydroxy-butyrylfentanyl.


Assuntos
Fentanila/análogos & derivados , Hepatócitos/metabolismo , /metabolismo , Células Cultivadas , Citocromo P-450 CYP2D6/metabolismo , Citocromo P-450 CYP3A/metabolismo , Fentanila/metabolismo , Humanos , Microssomos Hepáticos/metabolismo , Padrões de Referência
18.
Int Clin Psychopharmacol ; 34(3): 124-130, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-30870237

RESUMO

High-dose antipsychotic(s) can induce dopamine supersensitivity psychosis in schizophrenia patients. The precise relationship between a drug's blood concentration and the occurrence of dopamine supersensitivity psychosis has not been established. We divided 36 patients with schizophrenia who had undergone treatment mainly with risperidone into two groups: one with normal metabolizing activity of CYP2D6 (n = 15), and the other with lower activity of its variant, CYP2D6*10 (n = 21). The patients' blood concentrations of risperidone and 9-OH-risperidone were measured, and we compared the occurrence of dopamine supersensitivity psychosis episodes between the groups. There was no significant difference in any concentration of risperidone, 9-OH-risperidone, or active moiety between the groups although the with-CYP2D6*10 group had greater variabilities of these parameters compared to the without-CYP2D6*10 group. There was a lower rate of dopamine supersensitivity psychosis episodes in the without-CYP2D6*10 group (4/15, 26.7%) compared to the with-CYP2D6*10 group (11/21, 52.4%), but the difference was not significant. Although our findings were negative, largely because of the small sample size, these results suggest that (1) patients with an impaired functional allele of CYP2D6 may have higher concentrations of risperidone and its active metabolite and that (2) these patients may experience more frequent dopamine supersensitivity psychosis episodes.


Assuntos
Citocromo P-450 CYP2D6/metabolismo , Dopamina/fisiologia , Psicoses Induzidas por Substâncias/tratamento farmacológico , Risperidona/metabolismo , Esquizofrenia/tratamento farmacológico , Alelos , Antipsicóticos/uso terapêutico , Citocromo P-450 CYP2D6/genética , Genótipo , Humanos , Palmitato de Paliperidona/sangue , Escalas de Graduação Psiquiátrica , Transtornos Psicóticos/tratamento farmacológico , Risperidona/sangue , Risperidona/uso terapêutico , Esquizofrenia/genética
19.
Yakugaku Zasshi ; 139(3): 415-417, 2019.
Artigo em Japonês | MEDLINE | ID: mdl-30828021

RESUMO

The Japanese Society for the Study of Xenobiotics has focused on drug development and clinical pharmacotherapy by applying cutting-edge technology and reviewing drugs. One specific area of focus has been the reverse-translational approach. This approach uses data from the investigation of clinical problems and from the detailed revisiting of preclinical studies to discover new pharmacotherapies and new methods to prevent drug-induced side effects. In 2017, the U.S. Food and Drug Administration restricted the use of prescription codeine cough-and-cold medicines in children. This decision was based on concerns about the effects of the extensive metabolite morphine in cytochrome P450 2D6 ultra-rapid metabolizers. However, there are few reports on the side effects of dihydrocodeine in Japanese children. Our laboratory measured serum concentrations of dihydrocodeine in a 1-month-old infant with respiratory depression who was given dihydrocodeine phosphate in a suspected case of overdosing. Levels of dihydrocodeine and its primary metabolite, dihydromorphine, were high in this infant. However, the molar ratios of glucuronide conjugates of dihydrocodeine and dihydromorphine were lower than those found in a 3-year-old and a 6-year-old child used as references. To support and facilitate reverse-translational research, the elimination of regional differences in the methodologies used for liquid chromatography to measure drug concentrations and for the genotyping of drug-metabolizing enzymes should become the focus in hospitals, laboratories, and doctoral programs.


Assuntos
Sociedades Científicas/organização & administração , Pesquisa Médica Translacional , Xenobióticos , Criança , Pré-Escolar , Codeína/administração & dosagem , Codeína/efeitos adversos , Codeína/análogos & derivados , Codeína/metabolismo , Citocromo P-450 CYP2D6/metabolismo , Di-Hidromorfina/sangue , Descoberta de Drogas , Tratamento Farmacológico , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/prevenção & controle , Humanos , Lactente , Japão
20.
Breast Cancer ; 26(5): 535-543, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-30734152

RESUMO

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


Assuntos
Neoplasias da Mama/metabolismo , Citocromo P-450 CYP2D6/genética , Citocromo P-450 CYP2D6/metabolismo , Genótipo , Moduladores Seletivos de Receptor Estrogênico/farmacocinética , Tamoxifeno/análogos & derivados , Toremifeno/farmacocinética , Adulto , Idoso , Idoso de 80 Anos ou mais , Neoplasias da Mama/tratamento farmacológico , Citocromo P-450 CYP2C19/genética , Inibidores do Citocromo P-450 CYP2D6/uso terapêutico , Feminino , Fogachos/etiologia , Humanos , Hidroxilação , Pessoa de Meia-Idade , Fenótipo , Polimorfismo Genético , Moduladores Seletivos de Receptor Estrogênico/administração & dosagem , Moduladores Seletivos de Receptor Estrogênico/efeitos adversos , Moduladores Seletivos de Receptor Estrogênico/uso terapêutico , Fumar , Tamoxifeno/análise , Toremifeno/administração & dosagem , Toremifeno/efeitos adversos , Toremifeno/uso terapêutico
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