Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 1.161
Filtrar
2.
Xenobiotica ; 51(1): 5-14, 2021 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-32662714

RESUMO

MGV354 was being developed as a novel ocular therapy for lowering of intraocular pressure, a key modifiable risk factor for glaucoma. MGV354 is an activator of soluble guanylate cyclase, an enzyme known to be involved in the regulation of IOP. MGV354 has been shown to robustly lower IOP over 24 h after a single topical ocular drop in rabbit and monkey pharmacology models. However, MGV354 failed to produce similar results in patients with ocular hypertension or open-angle glaucoma. With an objective of explaining the lack of efficacy in the clinic, we attempted to study whether human metabolism was significantly different from animal metabolism. The present study documents the investigation of metabolism of MGV354 in an effort to understand potential differences in biotransformation pathways of MGV354 in rabbits, monkeys, and humans. Overall twenty-six metabolites, formed via oxidative and conjugative pathways, were identified in vitro and in vivo. In vitro hepatic metabolism was qualitatively similar across species, with minor but distinct differences. There were no observable interspecies differences in the hepatic and ocular metabolism of MGV354. Although ocular metabolism was not as extensive as hepatic, the results do not explain the lack of efficacy of MGV354 in clinical studies.


Assuntos
Anti-Hipertensivos/metabolismo , Piperidinas/metabolismo , Pirazóis/metabolismo , Piridinas/metabolismo , Animais , Anti-Hipertensivos/uso terapêutico , Glaucoma de Ângulo Aberto/tratamento farmacológico , Humanos , Pressão Intraocular/efeitos dos fármacos , Hipertensão Ocular/tratamento farmacológico , Piperidinas/uso terapêutico , Pirazóis/uso terapêutico , Piridinas/uso terapêutico , Coelhos
3.
Nat Commun ; 11(1): 4659, 2020 09 16.
Artigo em Inglês | MEDLINE | ID: mdl-32938936

RESUMO

The αvß6 integrin plays a key role in the activation of transforming growth factor-ß (TGFß), a pro-fibrotic mediator that is pivotal to the development of idiopathic pulmonary fibrosis (IPF). We identified a selective small molecule αvß6 RGD-mimetic, GSK3008348, and profiled it in a range of disease relevant pre-clinical systems. To understand the relationship between target engagement and inhibition of fibrosis, we measured pharmacodynamic and disease-related end points. Here, we report, GSK3008348 binds to αvß6 with high affinity in human IPF lung and reduces downstream pro-fibrotic TGFß signaling to normal levels. In human lung epithelial cells, GSK3008348 induces rapid internalization and lysosomal degradation of the αvß6 integrin. In the murine bleomycin-induced lung fibrosis model, GSK3008348 engages αvß6, induces prolonged inhibition of TGFß signaling and reduces lung collagen deposition and serum C3M, a marker of IPF disease progression. These studies highlight the potential of inhaled GSK3008348 as an anti-fibrotic therapy.


Assuntos
Butiratos/farmacologia , Fibrose Pulmonar Idiopática/tratamento farmacológico , Integrinas/antagonistas & inibidores , Naftiridinas/farmacologia , Pirazóis/farmacologia , Pirrolidinas/farmacologia , Administração por Inalação , Animais , Antígenos de Neoplasias/metabolismo , Bleomicina/toxicidade , Butiratos/administração & dosagem , Butiratos/metabolismo , Butiratos/farmacocinética , Colágeno/metabolismo , Modelos Animais de Doenças , Células Epiteliais/efeitos dos fármacos , Humanos , Fibrose Pulmonar Idiopática/induzido quimicamente , Fibrose Pulmonar Idiopática/patologia , Integrinas/metabolismo , Masculino , Camundongos Endogâmicos C57BL , Simulação de Acoplamento Molecular , Naftiridinas/administração & dosagem , Naftiridinas/metabolismo , Naftiridinas/farmacocinética , Pirazóis/administração & dosagem , Pirazóis/metabolismo , Pirazóis/farmacocinética , Pirrolidinas/administração & dosagem , Pirrolidinas/metabolismo , Pirrolidinas/farmacocinética , Bibliotecas de Moléculas Pequenas/química , Bibliotecas de Moléculas Pequenas/farmacologia , Tomografia Computadorizada de Emissão de Fóton Único , Fator de Crescimento Transformador beta/metabolismo , Pesquisa Médica Translacional
5.
Bull Cancer ; 107(5): 574-585, 2020 May.
Artigo em Francês | MEDLINE | ID: mdl-32252973

RESUMO

Direct oral anticoagulants, anti-IIa or anti-Xa, are widely used in the treatment and prevention of venous thromboembolic disease as well as in nonvalvular atrial fibrillation. Direct oral anticoagulants are characterized by a rapid onset of activity, a predictable response and a relatively wide therapeutic window. Nevertheless, theoretical drug interactions exist since direct oral anticoagulants are substrates of the transport protein P-glycoprotein and/or of isoforms of cytochromes P450 pathway. Direct oral anticoagulants do not have a marketing authorization for the treatment of cancer-associated thrombosis unlike low-molecular-weight heparins which remain the gold standard treatment today. However, recent studies have compared low-molecular-weight heparins to direct oral anticoagulants in the treatment of cancer-associated thrombosis. Results of these studies showed a non-inferiority of direct oral anticoagulants in the prevention of recurrent thromboembolic events but at the cost of an increased hemorrhagic risk, in particular for patients with gastrointestinal and urogenital cancers. Thus, international guidelines, unlike French guidelines, integrate them in first line of the therapeutic strategy of cancer patients. We are certainly entering an era of personalized therapy for cancer-associated thrombosis, considering cancer type and also the theoretical risk of drug interactions with anti-cancer treatments or supportive care.


Assuntos
Inibidores do Fator Xa/uso terapêutico , Neoplasias/complicações , Trombose/tratamento farmacológico , Subfamília B de Transportador de Cassetes de Ligação de ATP/metabolismo , Membro 2 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/metabolismo , Anticoagulantes/uso terapêutico , Antineoplásicos/metabolismo , Antineoplásicos/uso terapêutico , Sistema Enzimático do Citocromo P-450/metabolismo , Dabigatrana/metabolismo , Dabigatrana/uso terapêutico , Interações Medicamentosas , Inibidores do Fator Xa/efeitos adversos , Inibidores do Fator Xa/metabolismo , Hemorragia/induzido quimicamente , Heparina de Baixo Peso Molecular/uso terapêutico , Humanos , Proteínas de Neoplasias/metabolismo , Neoplasias/sangue , Neoplasias/tratamento farmacológico , Pirazóis/metabolismo , Pirazóis/uso terapêutico , Piridinas/metabolismo , Piridinas/uso terapêutico , Piridonas/metabolismo , Piridonas/uso terapêutico , Recidiva , Rivaroxabana/metabolismo , Rivaroxabana/uso terapêutico , Prevenção Secundária , Tiazóis/metabolismo , Tiazóis/uso terapêutico , Trombose/etiologia , Tromboembolia Venosa/prevenção & controle
6.
Life Sci ; 253: 117600, 2020 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-32234492

RESUMO

BACKGROUND: Skin cutaneous melanoma (SKCM) is the most common subtype of skin malignancy, with ever-increasing incidence, mortality, and disease burden. Dysregulation of JAK-STATs signaling pathway is involved in the pathogenesis and progression of cancers, thus affecting the prognosis of cancer patients. The function of JAKs in SKCM is still not clarified. METHODS: A total of five online portal (GEPIA, TIMER, GeneMANIA, LinkedOmics, and GSCALite) is used to mine the expression and gene regulation network JAK2 in SKCM. RESULTS: JAK2 expression was downregulated in SKCM and significantly associated with pathological stage and the prognosis of patients. The functions of JAK2 and associated genes were primarily involved in the DNA recombination, cell cycle checkpoint, metabolic process, NOD-like receptor signaling pathways, p53 signaling pathway and apoptosis. JAK2 level was significantly correlated with the abundance of immune cells and the level of immune biomarkers. Low expression of JAK2 were resistant to QL-VIII-58, TL-1-85, Ruxolitinib, TG101348 and Sunitinib. CONCLUSIONS: Our results reveal the expression and gene regulation network of JAK2 in skin cutaneous melanoma, providing more evidences about the role of JAK2 in carcinogenesis.


Assuntos
Antineoplásicos/farmacologia , Janus Quinases/metabolismo , Melanoma/metabolismo , Pirazóis/farmacologia , Neoplasias Cutâneas/tratamento farmacológico , Sunitinibe/farmacologia , Antineoplásicos/metabolismo , Bases de Dados de Ácidos Nucleicos , Bases de Dados de Proteínas , Regulação Neoplásica da Expressão Gênica , Redes Reguladoras de Genes/efeitos dos fármacos , Humanos , Janus Quinases/genética , MicroRNAs/metabolismo , Modelos Biológicos , Prognóstico , Pirazóis/metabolismo , Transdução de Sinais , Neoplasias Cutâneas/metabolismo , Sunitinibe/metabolismo
7.
J Med Chem ; 63(7): 3538-3551, 2020 04 09.
Artigo em Inglês | MEDLINE | ID: mdl-32134266

RESUMO

The overaccumulation of glycogen appears as a hallmark in various glycogen storage diseases (GSDs), including Pompe, Cori, Andersen, and Lafora disease. Accumulating evidence suggests that suppression of glycogen accumulation represents a potential therapeutic approach for treating these GSDs. Using a fluorescence polarization assay designed to screen for inhibitors of the key glycogen synthetic enzyme, glycogen synthase (GS), we identified a substituted imidazole, (rac)-2-methoxy-4-(1-(2-(1-methylpyrrolidin-2-yl)ethyl)-4-phenyl-1H-imidazol-5-yl)phenol (H23), as a first-in-class inhibitor for yeast GS 2 (yGsy2p). Data from X-ray crystallography at 2.85 Å, as well as kinetic data, revealed that H23 bound within the uridine diphosphate glucose binding pocket of yGsy2p. The high conservation of residues between human and yeast GS in direct contact with H23 informed the development of around 500 H23 analogs. These analogs produced a structure-activity relationship profile that led to the identification of a substituted pyrazole, 4-(4-(4-hydroxyphenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl)pyrogallol, with a 300-fold improved potency against human GS. These substituted pyrazoles possess a promising scaffold for drug development efforts targeting GS activity in GSDs associated with excess glycogen accumulation.


Assuntos
Inibidores Enzimáticos/química , Glicogênio Sintase/antagonistas & inibidores , Imidazóis/química , Pirazóis/química , Animais , Caenorhabditis elegans/enzimologia , Cristalografia por Raios X , Descoberta de Drogas , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/metabolismo , Glicogênio Sintase/química , Glicogênio Sintase/metabolismo , Células HEK293 , Humanos , Imidazóis/síntese química , Imidazóis/metabolismo , Cinética , Estrutura Molecular , Ligação Proteica , Pirazóis/síntese química , Pirazóis/metabolismo , Saccharomyces cerevisiae/enzimologia , Relação Estrutura-Atividade
8.
J Med Chem ; 63(8): 4090-4106, 2020 04 23.
Artigo em Inglês | MEDLINE | ID: mdl-32202425

RESUMO

Fatty-acid binding protein 4 (FABP4) is a promising therapeutic target for immunometabolic diseases, while its potential for systemic inflammatory response syndrome treatment has not been explored. Here, a series of 2-(phenylamino)benzoic acids as novel and potent FABP4 inhibitors are rationally designed based on an interesting fragment that adopts multiple binding poses within FABP4. A fusion of these binding poses leads to the design of compound 3 with an ∼460-fold improvement in binding affinity compared to the initial fragment. A subsequent structure-aided optimization upon 3 results in a promising lead (17) with the highest binding affinity among all the inhibitors, exerting a significant anti-inflammatory effect in cells and effectively attenuating a systemic inflammatory damage in mice. Our work therefore presents a good example of lead compound discovery derived from the multiple binding poses of a fragment and provides a candidate for development of drugs against inflammation-related diseases.


Assuntos
Anti-Inflamatórios/administração & dosagem , Anti-Inflamatórios/metabolismo , Descoberta de Drogas/métodos , Proteínas de Ligação a Ácido Graxo/antagonistas & inibidores , Proteínas de Ligação a Ácido Graxo/metabolismo , Células 3T3 , Administração Oral , Animais , Anti-Inflamatórios/química , Compostos de Bifenilo/administração & dosagem , Compostos de Bifenilo/química , Compostos de Bifenilo/metabolismo , Células CACO-2 , Relação Dose-Resposta a Droga , Humanos , Inflamação/tratamento farmacológico , Inflamação/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos ICR , Ligação Proteica/efeitos dos fármacos , Ligação Proteica/fisiologia , Estrutura Secundária de Proteína , Estrutura Terciária de Proteína , Pirazóis/administração & dosagem , Pirazóis/química , Pirazóis/metabolismo , Resultado do Tratamento
9.
Enzyme Microb Technol ; 134: 109488, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-32044035

RESUMO

5-Methylpyrazine-2-carboxylic acid (MPCA) is an important pharmaceutical intermediate and is used in the production of hypoglycemic agents and lipid-lowering drugs. This work aimed to develop a whole-cell biocatalytic process for the efficient synthesis of MPCA from 2, 5-dimethylpyrazine (DMP). Firstly, a whole-cell biocatalyst Escherichia coli strain was constructed by plasmid-based expression of xylene monooxygenase (XMO), benzyl alcohol dehydrogenase (BADH), and benzaldehyde dehydrogenase (BZDH) from Pseudomonas putida ATCC 33015, resulting in MPCA titer of 5.0 g/L. Then, the reaction conditions were optimized and the MPCA titer was further increased to 9.1 g/L. Next, the Ribosome Binding Site (RBS) Calculator v2.0 was used to predict and compare the translation initiation rates of the RBS sequences preceding xylM and xylA genes, encoding the two subunits of XMO. By optimizing the RBS sequences preceding xylA, the MPCA titer was increased to 10.2 g/L and the yield of MPCA on DMP reached 0.665 mol/mol. Finally, to achieve plasmid-free production of MPCA, we integrated the genes encoding for XMO, BADH and BZDH in the genome by using CRISPR/Cas9 and further fine-tuned the copy number ratios of xylM and xylA in the genome, improving the MPCA titer to 15.6 g/L and the yield of MPCA on DMP to 1.0 mol/mol. This work developed a high-yield and plasmid-free biocatalysis process for the environmentally friendly production of MPCA with 100% substrate conversion, and paved the way for the commercial production of MPCA in the future.


Assuntos
Ácidos Carboxílicos/metabolismo , Escherichia coli/genética , Genoma Bacteriano , Engenharia Metabólica/métodos , Pirazóis/metabolismo , Biocatálise , Sistemas CRISPR-Cas , Oxigenases/metabolismo , Especificidade por Substrato
10.
J Agric Food Chem ; 68(7): 1966-1973, 2020 Feb 19.
Artigo em Inglês | MEDLINE | ID: mdl-31986037

RESUMO

Pesticide pollution of surface water represents a considerable risk for algae and thus affects the structure and stability of aquatic ecosystems. To investigate the risk of flufiprole to phytoplankton, the digestion and uptake of flufiprole as well as the toxic effects of flufiprole enantiomers and the six metabolites to Chlorella pyrenoidosa were investigated. Flufiprole enantiomers were mainly metabolized to flufiprole amide and detrifluoromethylsulfinyl flufiprole in culture medium, while various metabolites were formed in algae, notably the amide derivative and fipronil. Chlorella pyrenoidosa showed a strong absorption capacity for the flufiprole series. The EC50 values (96 h) indicated that fipronil was the most toxic compound, approximately 5 times as toxic as rac-flufiprole. R-flufiprole was more toxic than S-flufiprole. The contents of chlorophylls, malondialdehyde (MDA), reactive oxygen species (ROS), and total antioxidant capacity (T-AOC) were significantly altered by the chemicals in most cases, especially fipronil. Our results supported the potential detrimental effect of the metabolites of flufiprole on algae.


Assuntos
Chlorella/metabolismo , Inseticidas/metabolismo , Inseticidas/toxicidade , Pirazóis/metabolismo , Pirazóis/toxicidade , Biodegradação Ambiental , Biotransformação , Chlorella/efeitos dos fármacos , Clorofila/metabolismo , Inseticidas/química , Cinética , Malondialdeído/metabolismo , Pirazóis/química , Espécies Reativas de Oxigênio/metabolismo , Estereoisomerismo , Poluentes Químicos da Água/química , Poluentes Químicos da Água/metabolismo , Poluentes Químicos da Água/toxicidade
11.
Nat Commun ; 11(1): 577, 2020 Jan 29.
Artigo em Inglês | MEDLINE | ID: mdl-31996669

RESUMO

The Bruton tyrosine kinase (BTK) inhibitor ibrutinib provides effective treatment for patients with chronic lymphocytic leukemia (CLL), despite extensive heterogeneity in this disease. To define the underlining regulatory dynamics, we analyze high-resolution time courses of ibrutinib treatment in patients with CLL, combining immune-phenotyping, single-cell transcriptome profiling, and chromatin mapping. We identify a consistent regulatory program starting with a sharp decrease of NF-κB binding in CLL cells, which is followed by reduced activity of lineage-defining transcription factors, erosion of CLL cell identity, and acquisition of a quiescence-like gene signature. We observe patient-to-patient variation in the speed of execution of this program, which we exploit to predict patient-specific dynamics in the response to ibrutinib based on the pre-treatment patient samples. In aggregate, our study describes time-dependent cellular, molecular, and regulatory effects for therapeutic inhibition of B cell receptor signaling in CLL, and it establishes a broadly applicable method for epigenome/transcriptome-based treatment monitoring.


Assuntos
Tirosina Quinase da Agamaglobulinemia/efeitos dos fármacos , Cromatina/genética , Leucemia Linfocítica Crônica de Células B/tratamento farmacológico , Pirazóis/antagonistas & inibidores , Pirazóis/metabolismo , Pirazóis/uso terapêutico , Pirimidinas/antagonistas & inibidores , Pirimidinas/metabolismo , Pirimidinas/uso terapêutico , Epigenoma , Epigenômica , Perfilação da Expressão Gênica , Heterogeneidade Genética/efeitos dos fármacos , Humanos , Leucemia Linfocítica Crônica de Células B/imunologia , Aprendizado de Máquina , Receptores de Antígenos de Linfócitos B/efeitos dos fármacos , Análise de Sequência de RNA , Fatores de Transcrição , Transcriptoma
12.
J Biol Chem ; 295(10): 2916-2931, 2020 03 06.
Artigo em Inglês | MEDLINE | ID: mdl-31964715

RESUMO

Quorum sensing is a bacterial communication process whereby bacteria produce, release, and detect extracellular signaling molecules called autoinducers to coordinate collective behaviors. In the pathogen Vibrio cholerae, the quorum-sensing autoinducer 3,5-dimethyl-pyrazin-2-ol (DPO) binds the receptor and transcription factor VqmA. The DPO-VqmA complex activates transcription of vqmR, encoding the VqmR small RNA, which represses genes required for biofilm formation and virulence factor production. Here, we show that VqmA is soluble and properly folded and activates basal-level transcription of its target vqmR in the absence of DPO. VqmA transcriptional activity is increased in response to increasing concentrations of DPO, allowing VqmA to drive the V. cholerae quorum-sensing transition at high cell densities. We solved the DPO-VqmA crystal structure to 2.0 Å resolution and compared it with existing structures to understand the conformational changes VqmA undergoes upon DNA binding. Analysis of DPO analogs showed that a hydroxyl or carbonyl group at the 2'-position is critical for binding to VqmA. The proposed DPO precursor, a linear molecule, N-alanyl-aminoacetone (Ala-AA), also bound and activated VqmA. Results from site-directed mutagenesis and competitive ligand-binding analyses revealed that DPO and Ala-AA occupy the same binding site. In summary, our structure-function analysis identifies key features required for VqmA activation and DNA binding and establishes that, whereas VqmA binds two different ligands, VqmA does not require a bound ligand for folding or basal transcriptional activity. However, bound ligand is required for maximal activity.


Assuntos
Proteínas de Bactérias/metabolismo , Pirazóis/metabolismo , Percepção de Quorum , Transdução de Sinais , Fatores de Transcrição/metabolismo , Vibrio cholerae/metabolismo , Proteínas de Bactérias/química , Proteínas de Bactérias/genética , Sítios de Ligação , Cristalografia por Raios X , DNA/química , DNA/metabolismo , Regulação Bacteriana da Expressão Gênica , Ligantes , Simulação de Dinâmica Molecular , Mutagênese Sítio-Dirigida , Ligação Proteica , Pirazóis/química , Relação Estrutura-Atividade , Fatores de Transcrição/química , Fatores de Transcrição/genética
13.
Biochem Med (Zagreb) ; 30(1): 010702, 2020 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-31839722

RESUMO

Introduction: Clinical application of rivaroxaban and apixaban does not require therapeutic monitoring. Commercial anti-activated factor X (anti-FXa) inhibition methods for all anti-FXa drugs are based on the same principle, so there are attempts to evaluate potential clinical application of heparin-calibrated anti-FXa assay as an alternative method for direct FXa inhibitors. We aimed to evaluate relationship between anti-FXa methods calibrated with low molecular weight heparin (LMWH) and with drug specific calibrators, and to determine whether commercial LMWH anti-FXa assay can be used to exclude the presence of clinically relevant concentrations of rivaroxaban and apixaban. Materials and methods: Low molecular weight heparin calibrated reagent (Siemens Healthineers, Marburg, Germany) was used for anti-FXa activity measurement. Innovance heparin (Siemens Healthineers, Marburg, Germany) calibrated with rivaroxaban and apixaban calibrators (Hyphen BioMed, Neuville-sur-Oise, France) was used for quantitative determination of FXa inhibitors. Results: Analysis showed good agreement between LMWH calibrated and rivaroxaban calibrated activity (κ = 0.76) and very good agreement with apixaban calibrated anti-Xa activity (κ = 0.82), respectively. Low molecular weight heparin anti-FXa activity cut-off values of 0.05 IU/mL and 0.1 IU/mL are suitable for excluding the presence of clinically relevant concentrations (< 30 ng/mL) of rivaroxaban and apixaban, respectively. Concentrations above 300 ng/mL exceeded upper measurement range for LMWH anti-FXa assay and cannot be determined by this method. Conclusion: Low molecular weight heparin anti-FXa assay can be used in emergency clinical conditions for ruling out the presence of clinically relevant concentrations of rivaroxaban and apixaban. However, use of LMWH anti-FXa assay is not appropriate for their quantitative determination as an interchangeable method.


Assuntos
Anticoagulantes/química , Testes de Coagulação Sanguínea/métodos , Heparina de Baixo Peso Molecular/química , Pirazóis/química , Piridonas/química , Rivaroxabana/química , Anticoagulantes/metabolismo , Área Sob a Curva , Testes de Coagulação Sanguínea/normas , Calibragem , Compostos Cromogênicos/química , Fator Xa/química , Fator Xa/metabolismo , Inibidores do Fator Xa/química , Inibidores do Fator Xa/metabolismo , Heparina de Baixo Peso Molecular/metabolismo , Humanos , Pirazóis/metabolismo , Piridonas/metabolismo , Curva ROC
14.
Xenobiotica ; 50(7): 793-804, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31847673

RESUMO

The disposition and metabolism of prexasertib, a CHK-1 inhibitor was characterised over a 120 h period following a single 170-mg intravenous dose of [14C]prexasertib (50 µCi) to 6 patients with advanced/metastatic solid tumours.The prexasertib safety profile was consistent with prior studies. Plasma, urine, and faeces were analysed for radioactivity, prexasertib, and metabolites. Geometric mean t1/2 in plasma was 34.2 h for prexasertib and 73.8 h for total radioactivity. Unchanged prexasertib accounted for approximately 9% of plasma total radioactivity, indicating extensive metabolism by the presence of circulating metabolites. Both renal and faecal excretion were identified as important routes of elimination since 41.8% (±12.9%) of the total administered radioactivity was recovered in the renal excretions and 32.2% (±7.28%) in the faecal excretions. Mean renal clearance was approximately 15% of the total systemic clearance, while biliary clearance was also low. Prexasertib was cleared predominantly by metabolism with only 23% of the dose recovered in excreta as intact drug. Radioactivity was eliminated predominantly within 72 h in urine, but faecal elimination was protracted.The metabolism of prexasertib was complex while primary metabolic clearance pathways involved were oxidative deamination, O-dealkylation, mono-oxidation, and possibly direct glucuronide conjugation. Although prexasertib was the major component in plasma, up to 11 metabolites were observed. The most abundant metabolites identified in plasma were glucuronides and none of these are expected to contribute to the pharmacological activity or pose a safety concern.


Assuntos
Neoplasias , Pirazinas/metabolismo , Pirazóis/metabolismo , Administração Intravenosa , Humanos , Taxa de Depuração Metabólica , Pirazinas/administração & dosagem , Pirazóis/administração & dosagem
15.
Environ Pollut ; 257: 113499, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31706771

RESUMO

Production of chrysanthemum (Dendranthema grandiflora) in greenhouses often requires intensive pesticide use, which raises serious concerns over food safety and human health. This study investigated uptake, translocation and residue dissipation of typical fungicides (metalaxyl-M and fludioxonil) and insecticides (cyantraniliprole and thiamethoxam) in greenhouse chrysanthemum when applied in soils. Chrysanthemum plants could absorb these pesticides from soils via roots to various degrees, and bioconcentration factors (BCFLS) were positively correlated with lipophilicity (log Kow) of pesticides. Highly lipophilic fludioxonil (log Kow = 4.12) had the greatest BCFLS (2.96 ±â€¯0.41 g g-1), whereas hydrophilic thiamethoxam (log Kow = -0.13) had the lowest (0.09 ±â€¯0.03 g g-1). Translocation factors (TF) from roots to shoots followed the order of TFleaf > TFstem > TFflower. Metalaxyl-M and cyantraniliprole with medium lipophilicity (log Kow of 1.71 and 2.02, respectively) and hydrophilic thiamethoxam showed relatively strong translocation potentials with TF values in the range of 0.29-0.81, 0.36-2.74 and 0.30-1.03, respectively. Dissipation kinetics in chrysanthemum flowers followed the first-order with a half-life of 21.7, 5.5, 10.0 or 8.2 days for metalaxyl-M, fludioxonil, cyantraniliprole and thiamethoxam, respectively. Final residues of these four pesticides, including clothianidin (a primary toxic metabolite of thiamethoxam), in all chrysanthemum flower samples were below the maximum residue limit (MRL) values 21 days after two soil applications each at the recommended dose (i.e., 3.2, 2.1, 4.3 and 4.3 kg ha-1, respectively). However, when doubling the recommended dose, the metabolite clothianidin remained at concentrations greater than the MRL, despite that thiamethoxam concentration was lower than the MRL value. This study provided valuable insights on the uptake and residues of metalaxyl-M, fludioxonil, cyantraniliprole and thiamethoxam (including its metabolite clothianidin) in greenhouse chrysanthemum production, and could help better assess food safety risks of chrysanthemum contamination by parent pesticides and their metabolites.


Assuntos
Chrysanthemum/metabolismo , Praguicidas/metabolismo , Alanina/análogos & derivados , Alanina/metabolismo , Dioxóis/metabolismo , Fungicidas Industriais/análise , Guanidinas , Humanos , Inseticidas/análise , Neonicotinoides , Resíduos de Praguicidas/análise , Pirazóis/metabolismo , Pirróis/metabolismo , Solo/química , Poluentes do Solo/análise , Tiametoxam/metabolismo , Tiazóis , ortoaminobenzoatos/metabolismo
16.
J Nucl Med ; 61(4): 604-607, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-31562223

RESUMO

Neuroinflammation is important in amyotrophic lateral sclerosis (ALS). The P2X7 receptor (P2X7R) is a promising target for neuroinflammation. The objective of this study was to compare 18F-DPA714, a second-generation translocator protein tracer, with 11C-JNJ717, a novel P2X7R tracer, in vitro and in vivo in ALS. Methods: For the in vitro portion of the study, autoradiography with 18F-DPA714 and 11C-JNJ717 was performed on human ALS brain sections in comparison to immunofluorescence with Iba1 and GFAP. For the in vivo portion, 3 male patients with early-stage ALS (59.3 ± 7.2 y old) and 6 healthy volunteers (48.2 ± 16.5 y old, 2 men and 4 women) underwent dynamic PET/MR scanning with 18F-DPA714 and 11C-JNJ717. Volume-of-distribution images were calculated using Logan plots and analyzed on a volume-of-interest basis. Results: Autoradiography showed no difference in 11C-JNJ717 binding but did show increased 18F-DPA714 binding in the motor cortex correlating with Iba1 expression (glial cells). Similar findings were observed in vivo, with a 13% increase in 18F-DPA714 binding in the motor cortex. Conclusion: In symptomatic ALS patients, 18F-DPA714 showed increased signal whereas 11C-JNJ717 was not elevated.


Assuntos
Esclerose Amiotrófica Lateral/metabolismo , Tomografia por Emissão de Pósitrons/métodos , Receptores de GABA/metabolismo , Receptores Purinérgicos P2X7/metabolismo , Adulto , Esclerose Amiotrófica Lateral/diagnóstico por imagem , Feminino , Radioisótopos de Flúor , Humanos , Marcação por Isótopo , Masculino , Pessoa de Meia-Idade , Pirazóis/metabolismo , Pirimidinas/metabolismo
17.
Biomed Chromatogr ; 34(2): e4721, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31656058

RESUMO

Teneligliptin is a recently developed dipeptidyl peptidase-4 (DPP-4) inhibitor for the treatment of type 2 diabetes mellitus. To study simultaneous pharmacokinetics of teneligliptin and its major active metabolite, teneligliptin sulfoxide in human plasma, we developed and validated a LC-MS/MS method. The analytes were detected in the positive mode using multiple reaction monitoring (teneligliptin: m/z 427.2→243.1; teneligliptin-d8 : m/z 435.2→251.3; teneligliptin sulfoxide: m/z 443.2→68.2). The method demonstrated accuracy, precision, and linearity over the concentration range of 5 to 1000 ng/mL for teneligliptin and 2.5 to 500 ng/mL for teneligliptin sulfoxide. The developed method is the first fully validated method capable of simultaneous determination of teneligliptin and its active metabolite, teneligliptin sulfoxide in plasma. The suitability of the method was successfully demonstrated in terms of quantification of teneligliptin and teneligliptin sulfoxide pharmacokinetics in plasma samples collected from healthy volunteers. The measurement of plasma metabolite/parent ratio of teneligliptin was feasible by this method.


Assuntos
Cromatografia Líquida/métodos , Pirazóis/sangue , Espectrometria de Massas em Tandem/métodos , Tiazolidinas/sangue , Estabilidade de Medicamentos , Humanos , Limite de Detecção , Modelos Lineares , Pirazóis/química , Pirazóis/metabolismo , Pirazóis/farmacocinética , Reprodutibilidade dos Testes , Sulfóxidos/sangue , Sulfóxidos/química , Sulfóxidos/metabolismo , Sulfóxidos/farmacocinética , Tiazolidinas/química , Tiazolidinas/metabolismo , Tiazolidinas/farmacocinética
18.
Food Chem ; 309: 125748, 2020 Mar 30.
Artigo em Inglês | MEDLINE | ID: mdl-31699564

RESUMO

Herein, a cold-induced aqueous two-phase system (CI-ATPS)-based concurrent sample enrichment and cleanup strategy was developed for the analysis of fipronil and its metabolites in dietary samples by liquid chromatography-high resolution mass spectrometry. By optimizing the conditions in CI-ATPS, the analytes were extracted to a small volume acetonitrile-rich phase with the enrichment factor of three-folds. Additionally, the lipids could be efficiently precipitated between the lower and upper layer to complete the removal of lipids. In detection analysis, a target single ion monitoring mode was employed to enhance the detection capability of fipronil and its metabolites. Generally, this established method could detect the target analytes in dietary samples at ng/kg level. Finally, this method was validated and certificated by a proficiency test, then was also successfully applied to dietary samples in the Total Diet Study, and the results showed that 56.3% of samples were detected with fipronil or its metabolites.


Assuntos
Cromatografia Líquida/métodos , Contaminação de Alimentos/análise , Inseticidas/análise , Inseticidas/isolamento & purificação , Extração Líquido-Líquido/métodos , Espectrometria de Massas/métodos , Pirazóis/análise , Pirazóis/isolamento & purificação , Humanos , Inseticidas/metabolismo , Pirazóis/metabolismo
19.
J Agric Food Chem ; 68(4): 1022-1029, 2020 Jan 29.
Artigo em Inglês | MEDLINE | ID: mdl-31884791

RESUMO

Topramezone is a 4-hydroxyphenylpyruvate dioxygenase (HPPD) inhibitor. Due to its broad-spectrum, high efficiency, and low toxicity, topramezone is a candidate herbicide for the construction of genetically modified (GM) herbicide-resistant crops. In the present study, we screened a topramezone-resistant isolate Sphingobium sp. TPM-19 and cloned a topramezone-resistant HPPD gene (SphppD) from this isolate. SpHPPD shared the highest similarity (53%) with an HPPD from Vibrio vulnificus CMCP6. SpHPPD was synthesized in Escherichia coli BL21(DE3) and purified to homogeneity using Co2+-affinity chromatography. SpHPPD was found to be a monomer. The Km and kcat of SpHPPD for 4-hydroxyphenylpyruvate (4-HPP) were 82.8 µM and 15.0 s-1, respectively. SpHPPD showed high resistance to topramezone with half maximal inhibitory concentration (IC50) and Ki values of 5.2 and 2.5 µM, respectively. Additionally, SpHPPD also showed high resistance to isoxaflutole (DKN) (IC50: 8.7 µM; Ki: 6.0 µM) and mesotrione (IC50: 4.2 µM; Ki: 1.3 µM) and moderate resistance to tembotrione (IC50: 2.5 µM; Ki: 1.0 µM). The introduction of the SphppD gene into Arabidopsis thaliana enhanced obvious resistance against topramezone. In conclusion, this study provides a novel topramezone-resistant HPPD gene for the genetic engineering of GM herbicide-resistant crops.


Assuntos
4-Hidroxifenilpiruvato Dioxigenase/química , 4-Hidroxifenilpiruvato Dioxigenase/metabolismo , Proteínas de Bactérias/química , Proteínas de Bactérias/metabolismo , Inibidores Enzimáticos/química , Pirazóis/química , Sphingomonadaceae/enzimologia , 4-Hidroxifenilpiruvato Dioxigenase/genética , Arabidopsis/efeitos dos fármacos , Arabidopsis/genética , Arabidopsis/metabolismo , Proteínas de Bactérias/genética , Clonagem Molecular , Inibidores Enzimáticos/metabolismo , Inibidores Enzimáticos/farmacologia , Estabilidade Enzimática , Resistência a Herbicidas , Herbicidas/química , Herbicidas/metabolismo , Herbicidas/farmacologia , Cinética , Plantas Geneticamente Modificadas/efeitos dos fármacos , Plantas Geneticamente Modificadas/genética , Plantas Geneticamente Modificadas/metabolismo , Pirazóis/metabolismo , Pirazóis/farmacologia , Sphingomonadaceae/química , Sphingomonadaceae/genética
20.
Xenobiotica ; 50(2): 150-169, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31006307

RESUMO

Asciminib is a potent, specific BCR-ABL1 inhibitor being developed for the treatment of patients with chronic myelogenous leukemia (CML) and Philadelphia chromosome positive acute lymphoblastic leukemia (Ph + ALL).Here, we present the results of human oral absorption, distribution, metabolism, excretion (ADME) and in vitro studies that together provide an overall understanding of the metabolism, distribution and clearance of asciminib in humans.Asciminib was rapidly absorbed with a maximum plasma concentration at two hours post-dose. Total radioactivity and asciminib showed similar terminal half-lives in plasma.Oral asciminib absorption ranged between a minimum of 33%, and a maximum of 57% based on the metabolite profiles of late time-point feces collections.Asciminib was eliminated mainly through feces via unchanged asciminib excretion and metabolism.Direct glucuronidation and oxidation were major metabolic pathways in human that were catalyzed predominantly by UDP-glucuronosyltransferase (UGT)2B7 and cytochrome P450 (CYP)3A4, respectively.The relative contribution of the glucuronidation pathway to the total clearance of asciminib via metabolism is estimated to range ∼28-58%, whereas the relative contribution of the oxidative pathway is estimated to range ∼37-64%, based upon the maximum oral absorption in humans.


Assuntos
Niacinamida/análogos & derivados , Inibidores de Proteínas Quinases/metabolismo , Pirazóis/metabolismo , Adulto , Proteínas de Fusão bcr-abl/metabolismo , Humanos , Masculino , Niacinamida/metabolismo
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA
...