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1.
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
2.
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 , 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
3.
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
4.
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
5.
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
6.
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
7.
Zhonghua Yu Fang Yi Xue Za Zhi ; 53(12): 1242-1246, 2019 Dec 06.
Artigo em Chinês | MEDLINE | ID: mdl-31795580

RESUMO

Objective: To understand the status and health risk assessment of dietary fipronil contamination among 20 provinces of China. Methods: A total of 13 kinds of dietary samples in Chinese total diet study include cereals, legumes, potatoes, meats, eggs, aquatics, dairies, vegetables, fruits, sugars, beverages and water, alcohols, condiments and their corresponding products. Among them, condiments were used in the preparation of 12 other sample categories; thus, the actual mixed dietary samples of each province covered 12 groups. A total of 240 mixed dietary samples were collected from 20 provinces in China from 2009 to 2013. After the sample extraction and cleanup, dietary samples were analyzed for the residues of fipronil and its metabolites to obtain the contamination levels of fipronil residues using liquid chromatography-high resolution mass spectrometry. The dietary intake of adult residents was estimated based on food consumption of general population of China. Results: Among the 240 dietary samples, the detection rate of fipronil was 10.4% (25 samples), and the detection rates of fipronil metabolites, i.e. fipronil desulfinyl, fipronil sulfone and fipronil sulfide were 20.4% (49 samples), 40.0% (96 samples) and 8.8% (21 samples), respectively. According to the dietary exposure analysis, the average lower and upper dietary exposure levels of fipronil residues in adult residents of China were 11.34 and 12.35 ng·kg(-1)·d(-1), accounting for 5.7% and 6.2% of acceptable daily intake (ADI), respectively. The highest adult dietary intake of fipronil residues was found in Hunan province, with a value of 72.98 ng·kg(-1)·d(-1), accounting for 36.5% of ADI. Vegetables were the main dietary source of fipronil residues, which contributed to 71.0% of the total intake dose. Conclusion: Fipronil residues were detected in varying degrees in dietary samples, yet the health risk caused by the dietary intake of adult residents among 20 provinces of China is low.


Assuntos
Poluentes Ambientais/análise , Análise de Alimentos/métodos , Contaminação de Alimentos/análise , Cromatografia Gasosa-Espectrometria de Massas/métodos , Resíduos de Praguicidas/análise , Pirazóis/química , Verduras/química , Adulto , China , Cromatografia Líquida , Dieta , Humanos , Inseticidas/química , Inseticidas/metabolismo , Pirazóis/metabolismo , Medição de Risco
8.
Artigo em Inglês | MEDLINE | ID: mdl-31677523

RESUMO

Fipronil is a broad-spectrum insecticide belonging to the phenylpyrazole chemical family, classified by the U.S. EPA as a group C (possible human) carcinogen. It is highly toxic to crustaceans, insects and zooplankton as well as to termites, rabbits and certain groups of gallinaceous birds. In European Union and Greece, fipronil is authorized only for the control of termites and cockroaches and not as a plant protection product or as a veterinary drug. The definition of residue of fipronil comprises of the sum of fipronil and its sulfone metabolite expressed as fipronil and is set at 5 µg kg-1. In this study, a sensitive and reliable modified QuEChERS method, proposed by the European Reference Laboratory for animal origin products, has been validated and applied to the residue analysis of fipronil and its metabolites (sulfone and desulfinyl) in chicken eggs and other egg products by LC-MS/MS and GC-ECD analysis. The two analytical systems performed almost equally concerning validation process and with regard to the analysis of real samples, results from both systems were in agreement: out of 11 samples analysed, 4 samples showed measurable residues of fipronil sulfone with 3 samples exceeding the MRL limit.


Assuntos
Cromatografia Gasosa/métodos , Ovos/análise , Inseticidas/análise , Pirazóis/análise , Espectrometria de Massas em Tandem/métodos , Animais , Galinhas , Cromatografia Líquida de Alta Pressão/métodos , Inseticidas/metabolismo , Limite de Detecção , Pirazóis/metabolismo
9.
J Agric Food Chem ; 67(51): 14019-14026, 2019 Dec 26.
Artigo em Inglês | MEDLINE | ID: mdl-31725274

RESUMO

Flufiprole is an insecticide used in the rice field and may pose a potential threat to aquatic organisms including loach. To investigate the transformation products of flufiprole in loach, the accumulation, elimination, and tissue distribution in vivo as well as the metabolism in vitro at the enantiomeric level were studied. Flufiprole enantiomers rapidly accumulated and were metabolized to flufiprole sulfone, fipronil, and flufiprole amide in the tissues. Enantiomeric fractions showed the preferential accumulation and degradation of S-flufiprole. The residue of the chiral metabolite flufiprole amide was also enantioselective. The individual enantiomer treatment indicated that S-flufiprole was preferentially metabolized to flufiprole sulfone and R-flufiprole to fipronil. The metabolites were more persistent than flufiprole with longer half-lives. The metabolism in liver microsomes also reached consistent conclusions. The dietary risk assessment indicated that flufiprole would not cause unacceptable threats to human health. However, the metabolites of flufiprole should be considered in the risk evaluation.


Assuntos
Cipriniformes/metabolismo , Inseticidas/química , Inseticidas/metabolismo , Pirazóis/química , Pirazóis/metabolismo , Animais , Resíduos de Drogas/química , Resíduos de Drogas/metabolismo , Peixes/metabolismo , Contaminação de Alimentos/análise , Microssomos Hepáticos/química , Microssomos Hepáticos/metabolismo , Estereoisomerismo , Distribuição Tecidual , Poluentes Químicos da Água/química , Poluentes Químicos da Água/metabolismo
10.
AAPS PharmSciTech ; 20(8): 326, 2019 Oct 28.
Artigo em Inglês | MEDLINE | ID: mdl-31659558

RESUMO

Present study was aimed to increase the oral bioavailability and reduce the fast fed variability of Ibrutinib by developing nanosuspension by simple precipitation-ultrasonication method. A three factor, three level, box-behnken design was used for formulation optimization using pluronic F-127 as stabilizer. Size and polydispersity index of the developed formulations were in the range of 278.6 to 453.2 nm and 0.055 to 0.198, respectively. Field emission scanning electron microscope (FESEM) revealed discrete units of nanoparticles. Further, differential scanning calorimetry (DSC) and powder X-ray diffraction (PXRD) studies confirmed the transformation of crystal drug to amorphous. The amorphous nature was retained after 6-month storage at room temperature. Size reduction to nano range and polymorphic transformation (crystalline to amorphous) increased the solubility of nanosuspension (21.44-fold higher as compared to plain drug). In vivo studies of plain drug suspension displayed a significant pharmacokinetic variation between fasting and fed conditions. The formulation had shown increased Cmax (3.21- and 3.53-fold), AUC0-t (5.21- and 5.83-fold) in fasting and fed states compared to that of values obtained for plain drug in fasting state (Cmax 48.59 ± 3.30 ng/mL and AUC0-t 137.20 ± 35.47 ng.h/mL). Significant difference was not observed in the pharmacokinetics of nanosuspension in fasting and fed states. The formulation had improved solubility in the intestinal pH, which might be the driving force behind the decreased precipitation and increased absorption at intestinal region. Optimistic results demonstrated nanosuspension as a promising approach for increasing the solubility, extent of absorption and diminishing the fast fed variability.


Assuntos
Desenho de Drogas , Nanopartículas/química , Nanopartículas/metabolismo , Pirazóis/síntese química , Pirazóis/metabolismo , Pirimidinas/síntese química , Pirimidinas/metabolismo , Administração Oral , Animais , Disponibilidade Biológica , Varredura Diferencial de Calorimetria , Masculino , Nanopartículas/administração & dosagem , Tamanho da Partícula , Poloxâmero/química , Pirazóis/administração & dosagem , Pirimidinas/administração & dosagem , Ratos , Ratos Wistar , Solubilidade , Suspensões , Difração de Raios X/métodos
11.
J Agric Food Chem ; 67(46): 12904-12910, 2019 Nov 20.
Artigo em Inglês | MEDLINE | ID: mdl-31657925

RESUMO

In this study, a rapid, sensitive, and selective method was established for the detection of oxathiapiprolin and the metabolite IN-E8S72, as well as its glucose conjugate IN-SXS67 in cucumber using modified QuEChERS procedure combined with HPLC-MS/MS. The LOQs for all compounds were 0.02 mg kg-1, and the average recoveries were 77.4-111.3% with RSDs of 1.0-8.5%. Under the optimized conditions, the established method was successfully used to determine field samples in dissipation and terminal residue studies. The dissipation study results showed that oxathiapiprolin dissipated rapidly in cucumber with half-lives of 2.4-4.0 days. On the basis of the terminal residue results, the risk assessment was conducted, and both the international estimated daily intake (IEDI) or national estimated daily intake (NEDI) of oxathiapiprolin were much less than 100% which indicate a low health risk to consumers. This work provides guidance for establishing MRL of oxathiapiprolin in China and is of great significance for evaluating its dietary risk in cucumber.


Assuntos
Cucumis sativus/química , Fungicidas Industriais/análise , Hidrocarbonetos Fluorados/análise , Resíduos de Praguicidas/análise , Pirazóis/análise , China , Cromatografia Líquida de Alta Pressão , Qualidade de Produtos para o Consumidor , Cucumis sativus/metabolismo , Contaminação de Alimentos/análise , Fungicidas Industriais/metabolismo , Fungicidas Industriais/toxicidade , Humanos , Hidrocarbonetos Fluorados/metabolismo , Hidrocarbonetos Fluorados/toxicidade , Resíduos de Praguicidas/metabolismo , Resíduos de Praguicidas/toxicidade , Pirazóis/metabolismo , Pirazóis/toxicidade , Medição de Risco , Espectrometria de Massas em Tandem
12.
Expert Opin Drug Metab Toxicol ; 15(11): 975-984, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31619082

RESUMO

Objectives: Riociguat is a soluble guanylate cyclase stimulator licensed for the treatment of pulmonary arterial hypertension (PAH), a potentially fatal complication of human immunodeficiency virus infection. This study investigated the inhibitory potency of selected antiretroviral regimens on the metabolic clearance of riociguat.Methods: The inhibitory potential of the components of six antiretroviral combinations (ATRIPLA® (efavirenz/emtricitabine/tenofovir disoproxil), COMPLERA® (rilpivirine/emtricitabine/tenofovir disoproxil), STRIBILD® (elvitegravir/cobicistat/emtricitabine/tenofovir disoproxil), TRIUMEQ® (abacavir/dolutegravir/lamivudine), and two ritonavir-boosted regimens) on riociguat metabolism were evaluated in recombinant human CYP1A1 and CYP3A4 as well as in human hepatocytes exhibiting both CYP1A1 and CYP3A4 activity. In vitro-in vivo correlation was performed between calculated and observed increases in riociguat exposure in vivo.Results: Using both in vitro systems, the predicted increase in exposure of riociguat was highest with components of TRIUMEQ® followed by COMPLERA®, ATRIPLA®, STRIBILD®, and the ritonavir-boosted regimens. Further experiments in human hepatocytes confirmed CYP1A1 to be the predominant enzyme in the metabolic clearance of riociguat.Conclusion: Antiretroviral treatment containing the potent CYP1A1 inhibitor abacavir had the greatest impact on riociguat metabolic clearance. The impact of comedications containing only strong CYP3A4 inhibitors e.g. ritonavir was less pronounced, suggesting a benefit of riociguat over PAH-targeting medications with contraindications for use with strong CYP3A4 inhibitors.


Assuntos
Fármacos Anti-HIV/farmacologia , Citocromo P-450 CYP1A1/metabolismo , Ativadores de Enzimas/metabolismo , Pirazóis/metabolismo , Pirimidinas/metabolismo , Fármacos Anti-HIV/administração & dosagem , Citocromo P-450 CYP1A1/antagonistas & inibidores , Citocromo P-450 CYP3A/efeitos dos fármacos , Citocromo P-450 CYP3A/metabolismo , Inibidores do Citocromo P-450 CYP3A/administração & dosagem , Inibidores do Citocromo P-450 CYP3A/farmacologia , Interações de Medicamentos , Ativadores de Enzimas/administração & dosagem , Hepatócitos/enzimologia , Hepatócitos/metabolismo , Humanos , Técnicas In Vitro , Pirazóis/administração & dosagem , Pirimidinas/administração & dosagem
14.
Artigo em Inglês | MEDLINE | ID: mdl-31254664

RESUMO

Spider mites are destructive arthropod pests on many crops and they have developed resistance to nearly all acaricides. In recent years, along with the application of high throughput sequencing, the molecular mechanisms of mite resistance had made a series of progress. But, the response in molecular level of mite exposure to acaricides, as well as the original mechanism of resistance development was still unclear. To disclose the deeply mechanisms, we used RNA sequencing to analyze the responses of mite exposure to a sublethal concentration (LC30) treatment of the three different action mode acaricides (Abamectin, Fenpropathrin, and Tebufenpyrad). A high number of differentially expressed genes may well be involved in detoxification and regulatory, with extensive overlap in differentially expressed genes between the three insecticide treatments. Two cytochrome P450 genes were co-up-regulated and one glutathione S-transferase genes were co-down-regulated in all the treatments, while carboxylesterase genes only had a response to abamectin. This interesting phenomenon revealed that P450 enzymes play an important role in the early stage of mite exposure to acaricide. Moreover, a P8 nuclear receptor gene was in response to stress caused by exposure to acaricides and RNA interference (RNAi) experiment indicated P8 nuclear receptor regulates the P450 enzyme activity and susceptibility of mites to acaricide. The differential response information of gene expression based on a large-scale sequence would provide some useful clues for studying the molecular mechanisms of mite resistance formation and development.


Assuntos
Acaricidas/toxicidade , Sistema Enzimático do Citocromo P-450/genética , Resistência a Medicamentos/genética , Receptores Citoplasmáticos e Nucleares/metabolismo , Tetranychidae/efeitos dos fármacos , Transcrição Genética/efeitos dos fármacos , Acaricidas/metabolismo , Animais , Proteínas de Artrópodes/metabolismo , Inativação Metabólica/genética , Ivermectina/análogos & derivados , Ivermectina/metabolismo , Ivermectina/toxicidade , Proteínas Nucleares/metabolismo , Pirazóis/metabolismo , Pirazóis/toxicidade , Piretrinas/metabolismo , Piretrinas/toxicidade , Receptores Citoplasmáticos e Nucleares/genética , Tetranychidae/genética
15.
Eur J Med Chem ; 178: 168-176, 2019 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-31181481

RESUMO

The androgen receptor (AR) is a steroid hormone receptor and its high expression and disruption of its regulation are strongly implicated in prostate cancer (PCa) development. One of the current therapies includes application of steroidal antiandrogens leading to blockade of the AR action by the abrogation of AR-mediated signaling. We introduced here novel 4,5,6,7-tetrahydropyrazolo[1,5-a]pyridine-fused steroidal compounds, described their synthesis based on [8π+2π] cycloaddition reactions of diazafulvenium methides with different steroidal scaffolds and showed their biological evaluation in different prostate cancer cell lines in vitro. Our results showed the ability of novel compounds to suppress the expression of known androgen receptor targets, Nkx3.1 and PSA in two prostate cell lines, 22Rv1 and VCaP. Candidate compound diminished the transcription of AR-regulated genes in the reporter cell line in a concentration-dependent manner. Antiproliferative activity of the most promising steroid was studied by clonogenic assay and induction of apoptosis in treated cells was documented by immunoblot detection of cleaved PARP.


Assuntos
Antineoplásicos/farmacologia , Neoplasias da Próstata/tratamento farmacológico , Pirazóis/farmacologia , Piridinas/farmacologia , Esteroides/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/metabolismo , Sítios de Ligação , Linhagem Celular Tumoral , Proteínas de Homeodomínio/metabolismo , Humanos , Masculino , Simulação de Acoplamento Molecular , Pirazóis/síntese química , Pirazóis/metabolismo , Piridinas/síntese química , Piridinas/metabolismo , Receptores Androgênicos/metabolismo , Esteroides/síntese química , Esteroides/metabolismo , Fatores de Transcrição/metabolismo
16.
Environ Pollut ; 246: 876-884, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31159137

RESUMO

Ecotoxicological studies show the association between pesticide pollution and transgenerational toxicity in aquatic organisms. However, a less considered risk is that many pesticides can be metabolized and transferred to offspring as new toxicants. In this study, we used zebrafish to evaluate the maternal transfer risk of fipronil (FIP), which is a great threat to aquatic organisms with toxic metabolite formation. After 28-day exposure to environmentally relevant concentrations (1.0, 5.0 and 10.0 µg/L) of FIP in adult female zebrafish (F0), the toxicants off-loading and transgenerational toxicity in offspring were studied. High burdens of FIP and its sulfone metabolite were found in both F0 and the embryos (F1), resulting in increased CYP450 activity. The residual levels of the metabolite were higher than those of the parent compound. Chiral analysis further showed a preferential accumulation of S-enantiomer of FIP in both F0 and F1. Maternal exposure to FIP increased the malformation rate and decreased the swim speed in larvae. Additionally, after exposure, the levels of thyroid hormones (THs), including triiodothyronine (T3) and thyroxine (T4), decreased in both generations, particularly in the F1. Gene transcription expression along the hypothalamic-pituitary-thyroid (HPT) axis was also significantly affected. Maternal exposure to FIP increased sulfone metabolite enrichment and cause multiple toxic effects in F1. Findings from this study highlight the key role of biologically active product formation in the maternal transfer of pollutants and associated risk assessment.


Assuntos
Exposição Materna/efeitos adversos , Praguicidas/toxicidade , Pirazóis/toxicidade , Sulfonas/toxicidade , Poluentes Químicos da Água/toxicidade , Animais , Disruptores Endócrinos/metabolismo , Disruptores Endócrinos/toxicidade , Feminino , Praguicidas/metabolismo , Pirazóis/metabolismo , Sulfonas/metabolismo , Hormônios Tireóideos/metabolismo , Poluentes Químicos da Água/metabolismo , Peixe-Zebra
17.
Pharm Res ; 36(7): 93, 2019 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-31044267

RESUMO

INTRODUCTION: In the HELIOS trial, bendamustine/rituximab (BR) plus ibrutinib (BR-I) improved disease outcomes versus BR plus placebo in previously treated chronic lymphocytic leukemia/small lymphocytic lymphoma. Here, we describe the pharmacokinetic (PK) observations, along with modeling to further explore the interaction between ibrutinib and rituximab. METHODS: 578 subjects were randomized to ibrutinib or placebo with BR (6 cycles). Ibrutinib PK samples and tumor measurements were obtained from all subjects; a subset was evaluated for bendamustine and rituximab PK. Population rituximab PK was assessed using nonlinear mixed-effects modeling. RESULTS: Dose-normalized plasma concentration-time bendamustine data were comparable between the arms. Systemic rituximab exposure was higher with BR-I versus BR; mean trough serum concentrations were 2- to 3-fold higher in the first three cycles and 1.2- to 1.7-fold higher subsequently. No relevant safety differences were observed. In the modeling, including treatment arm as a categorical covariate and tumor burden as a continuous time-varying covariate on overall rituximab clearance significantly improved fitting of the data. CONCLUSIONS: BR-I led to higher dose-normalized systemic rituximab exposure versus BR and more rapid steady-state achievement. The modeling data suggest that rituximab disposition is, at least in part, target mediated. Determining the clinical significance of these findings requires further assessments. TRIAL REGISTRATION: This study is registered at https://clinicaltrials.gov/ct2/show/NCT01611090 .


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/farmacocinética , Cloridrato de Bendamustina/farmacocinética , Leucemia Linfocítica Crônica de Células B/tratamento farmacológico , Pirazóis/metabolismo , Pirimidinas/metabolismo , Rituximab/farmacocinética , Adulto , Idoso , Idoso de 80 Anos ou mais , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Cloridrato de Bendamustina/efeitos adversos , Cloridrato de Bendamustina/uso terapêutico , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Modelos Biológicos , Resultado do Tratamento
18.
Drug Metab Pers Ther ; 34(2)2019 05 30.
Artigo em Inglês | MEDLINE | ID: mdl-31145690

RESUMO

Ruxolitinib is mainly metabolized by cytochrome P450 (CYP) enzymes CYP3A4 and CYP2C9 followed by minor contributions of other hepatic CYP enzymes in vitro. A physiologically based pharmacokinetic (PBPK) model was established to evaluate the changes in the ruxolitinib systemic exposures with co-administration of CYP3A4 and CYP2C9 perpetrators. The fractions metabolized in the liver via oxidation by CYP enzymes (fm,CYP3A4 = 0.75, fm,CYP2C9 = 0.19, and fm,CYPothers = 0.06) for an initial ruxolitinib model based on in vitro data were optimized (0.43, 0.56, and 0.01, respectively) using the observed exposure changes of ruxolitinib (10 mg) with co-administered ketoconazole (200 mg). The reduced amount of fm,CYP3A4 was distributed to fm,CYP2C9. For the initial ruxolitinib model with co-administration of ketoconazole, the area under the curve (AUC) increase of 2.60-fold was over-estimated compared with the respective observation (1.91-fold). With the optimized fm values, the predicted AUC ratio was 1.82. The estimated AUC ratios of ruxolitinib by co-administration of the moderate CYP3A4 inhibitor erythromycin (500 mg) and the strong CYP3A4 inducer rifampicin (600 mg) were within a 20% error compared with the clinically observed values. The PBPK modeling results may provide information on the labeling, i.e. supporting a dose reduction by half for co-administration of strong CYP3A4 inhibitors. Furthermore, an AUC increase of ruxolitinib in the absence or presence of the dual CYP3A4 and CYP2C9 inhibitor fluconazole (100-400 mg) was prospectively estimated to be 1.94- to 4.31-fold. Fluconazole simulation results were used as a basis for ruxolitinib dose adjustment when co-administering perpetrator drugs. A ruxolitinib PBPK model with optimized fm,CYP3A4 and fm,CYP2C9 was established to evaluate victim DDI risks. The previous minimal PBPK model was supported by the FDA for the dose reduction strategy, halving the dose with the concomitant use of strong CYP3A4 inhibitors and dual inhibitors on CYP2C9 and CYP3A4, such as fluconazole at ≤200 mg. Fluconazole simulation results were used as supportive evidence in discussions with the FDA and EMA about ruxolitinib dose adjustment when co-administering perpetrator drugs. Thus, this study demonstrated that PBPK modeling can support characterizing DDI liabilities to inform the drug label and might help reduce the number of clinical DDI studies by simulations of untested scenarios, when a robust PBPK model is established.


Assuntos
Citocromo P-450 CYP2C9/metabolismo , Citocromo P-450 CYP3A/metabolismo , Modelos Biológicos , Pirazóis/metabolismo , Pirazóis/farmacocinética , Administração Oral , Células CACO-2 , Interações de Medicamentos , Eritromicina/administração & dosagem , Eritromicina/metabolismo , Eritromicina/farmacocinética , Humanos , Cetoconazol/administração & dosagem , Cetoconazol/metabolismo , Cetoconazol/farmacocinética , Pirazóis/administração & dosagem , Rifampina/administração & dosagem , Rifampina/metabolismo , Rifampina/farmacocinética
19.
J Chromatogr B Analyt Technol Biomed Life Sci ; 1114-1115: 125-133, 2019 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-30953840

RESUMO

Taking into consideration of the cytotoxicity and topo-IIα inhibitory activity of pyrazoline derivatives (1-3) against HCT15 cells, and known topo-IIα inhibitor, etoposide, respectively, the compounds were biotransformed in rat liver microsomes. LC-MS/MS and MALDI mass spectrometric techniques has been used for analysis. All three compounds were biotransformed into demethylated metabolites. Among three compounds, compounds 1 and 2 were biotransformed into mono-hydroxylated metabolites and compound 3 biotransformed into reduced and epoxidized metabolites. Reduced and reduced along with demethylation metabolites were identified from MALDI Orbitrap spectrometric analysis. Without NADPH or microsomes no compounds (1-3) were generated metabolites, it shows CYP450 enzymes involvement in the presence of NADPH in the metabolisms.


Assuntos
Metabolômica/métodos , Microssomos Hepáticos/metabolismo , Pirazóis/metabolismo , Espectrometria de Massas em Tandem/métodos , Inibidores da Topoisomerase/metabolismo , Animais , Linhagem Celular Tumoral , Cromatografia Líquida/métodos , Sistema Enzimático do Citocromo P-450/metabolismo , Humanos , NADP/metabolismo , Pirazóis/análise , Ratos , Espectrometria de Massas por Ionização e Dessorção a Laser Assistida por Matriz , Inibidores da Topoisomerase/análise
20.
Sci Total Environ ; 672: 335-341, 2019 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-30959300

RESUMO

Enantioselective degradation and biotransformation are critical processes affecting the bioaccumulation and toxicity of chiral pesticides in the environment. In the present study, enantioselective uptake, biotransformation and elimination of a current use pesticide, fipronil in a benthic invertebrate, Lumbriculus variegatus were assessed using a sediment bioaccumulation test. Toxicokinetic models were constructed to quantitatively describe kinetic processes of fipronil enantiomers. The degradation of fipronil in sediment significantly affected chemical uptake, thus degradation kinetic model was incorporated into toxicokinetic modeling. It was shown that S-(+)-fipronil degraded faster than R-(-)-fipronil in sediment, with dissipation rate constants being 0.090 ±â€¯0.008 and 0.023 ±â€¯0.006 1/d, respectively. As a result, R-(-)-enantiomer preferentially accumulated in sediment over time. Similarly, higher concentrations of R-(-)-fipronil were detected in L. variegatus compared with S-(+)-fipronil. Toxicokinetic modeling showed R-(-)-fipronil had larger uptake and elimination rate coefficients and apparent maximum reaction rate, but a smaller apparent half-saturation constant than S-(+)-fipronil. Preferential uptake of R-(-)-fipronil from sediment to L. variegatus was the main reason for greater R-(-)-fipronil concentrations in organism. Biotransformation of fipronil in L. variegatus was also enantioselective, yet it played fewer roles on enantioselective bioaccumulation than uptake. Overall, our findings highlight the importance of selective degradation, uptake and biotransformation of sediment-associated fipronil on its enantioselective bioaccumulation in benthic invertebrates, which helps to improve the accuracy for assessing aquatic toxicity of the chiral pesticide. CAPSULE: Enantioselective bioaccumulation of sediment-associated fipronil in Lumbriculus variegatus was quantitatively explained by selective degradation, uptake, biotransformation and elimination parameters using a combination of degradation and toxicokinetic modeling.


Assuntos
Oligoquetos/fisiologia , Pirazóis/metabolismo , Poluentes Químicos da Água/metabolismo , Animais , Biodegradação Ambiental , Oligoquetos/metabolismo , Pirazóis/toxicidade , Estereoisomerismo , Poluentes Químicos da Água/toxicidade
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