RESUMEN

Aromatic amines are a large group of chemical compounds that have attracted the attention of researchers due to their toxicity and carcinogenicity. This study aimed to develop an efficient method for sampling and analysis of aromatic amines (Aniline, N, N-dimethylaniline, 2-chloroaniline, and 3-chloroaniline) from the vapour phase (headspace) of urine samples. For the implementation of this plan, a needle trap device packed with the three-component adsorbent consisting of nano-Hydroxy Apatite (nHA), Zeolite (Ze), and Metal-Organic Framework (MOF) equipped with GC-FID was employed for the first phase. Examination of the prepared adsorbents was performed by FT-IR, PXRD, and FE-SEM techniques. The optimal value of considerable parameters such as time and temperature of extraction, salt content, and pH were established using the Response Surface Methodology-Central Composite Design (RMS-CCD) method. In this way, the optimal extraction of targeted analytes was accomplished in 41 min at 41 °C with NaCl content of 33.0% (w/v) and pH: 13.0, respectively. Also, the repeatability and reproducibility of the method were calculated to be in the range of 2.2-7.1% and 3.9-8.1%, respectively, which indicates the acceptable precision of the method. Also, the limit of detection (LOD) and limit of quantification (LOQ) were determined in the range of 0.3-32.0 ng.L-1 and 0.8-350.0 ng.L-1, respectively, which proves the high sensitivity of the proposed method. Furthermore, the recovery percent of the extracted analytes was concluded in the range of 97.0-99.0% after 6 and 30 days of the sampling and storage at 25 °C and 4 °C, respectively. Finally, the designed procedure was employed in the analysis of the above-mentioned aromatic amines in the real urine samples. The achieved results illustrate that the three-component absorbent system (nHA;Ze;MOF@NTD) can be introduced as an efficient, fast-response, sensitive, and versatile procedure for trace analysis of the different aromatic amine compounds in public and occupational health.

Asunto(s)

Compuestos de Anilina , Urinálisis , Compuestos de Anilina/orina , Urinálisis/métodos , Estructuras Metalorgánicas , Proyectos Piloto , Espectroscopía Infrarroja por Transformada de Fourier , Humanos

RESUMEN

Aromatic amines are widely used in personal care products and human exposure to this class of chemicals is widespread. Bioanalytical methods to determine trace levels of aromatic amines in human urine are scarce. In this study, a liquid chromatography-tandem mass spectrometry (LC-MS/MS) method was developed to determine 39 primary aromatic amines (AAs) along with nicotine and cotinine in human urine. Chromatographic separation of the 41 analytes was achieved on an Ultra Biphenyl (100 mm × 2.1 mm, 5 µm) column. Mass spectrometry was operated in electrospray ionization positive ion multiple reaction monitoring (MRM) mode. The method exhibited excellent linear dynamic range (0.1-50 ng/mL) with correlation coefficients (r) > 0.999 for all analytes. Urine samples (2 mL) were hydrolyzed using 10 M NaOH at 95 °C for 15 h and target analytes were extracted using methyl-tert-butyl ether (MTBE). Addition of 15 µL of 0.25 M HCl to the sample extracts improved the recoveries of several target analytes. The method was validated through the analysis of fortified quality control (QC) samples and a certified standard reference material (SRM). Relative recoveries (%) of target analytes fortified in QC samples were in the range of 75-114% for 37 of the 41 analytes while the other analytes exhibited lower recoveries (16-74%). The limits of detection (LOD) and limits of quantification (LOQ) of target analytes were in the range of 0.025-0.20 ng/mL and 0.1-1.0 ng/mL, respectively. Intra-day and inter-day precision of the method assessed through the analysis of fortified urine QC samples at three different concentrations were < 11.7% and < 15.9% (measured as RSD), respectively. The method was applied in the analysis of urine samples from the general population and known smokers; aniline, para-anisidine, para-toluidine, ortho/meta-toluidine, 3-chloroaniline, 4-chloroaniline, 3,4-dichloroaniline, and 4,4'-methylenedianiline were found in all smoker's urine at sum concentrations ranging from 0.04 to 9.16 ng/mL.

Asunto(s)

Compuestos de Anilina/orina , Cromatografía Liquida/métodos , Espectrometría de Masas en Tándem/métodos , Compuestos de Anilina/química , Monitoreo Biológico , Humanos , Límite de Detección , Modelos Lineales , Reproducibilidad de los Resultados , Fumar

RESUMEN

Aim: Osimertinib (Tagrisso, AZD9291) has been approved for the treatment of patients with metastatic EGFRm T790M non-small-cell lung cancer. Results: Rapid and sensitive LC-MC/MS methods were developed for osimertinib and its metabolites, AZ13597550 and AZ13575104, in human plasma (low- and high-range), urine and cerebrospinal fluid. We discuss the challenges of these multi-analyte and multiple matrix assays. The methods have been successfully validated and used for the analysis of over 20,000 clinical samples, with successful incurred sample reproducibility. Conclusion: The assays have been shown to be selective, accurate and robust, providing high-throughput analysis during the clinical development of osimertinib.

Asunto(s)

Acrilamidas/análisis , Compuestos de Anilina/análisis , Análisis Químico de la Sangre/métodos , Urinálisis/métodos , Acrilamidas/sangre , Acrilamidas/líquido cefalorraquídeo , Acrilamidas/orina , Compuestos de Anilina/sangre , Compuestos de Anilina/líquido cefalorraquídeo , Compuestos de Anilina/orina , Hemólisis , Humanos , Límite de Detección

RESUMEN

RATIONALE: 4,4'-Methylene diphenyl diisocyanate (MDI) is a highly reactive isocyanate used in the production of polyurethanes. Workers exposed to these products may develop sensitization to the diisocyanate compounds, leading to occupational asthma. Quantifying MDI levels is necessary to ensure workplace safety. MDI is metabolized by acetylation and/or conjugation to macromolecules for excretion into urine. All metabolites can be chemically hydrolyzed to form the free diamine 4,4'-methylenedianiline (MDA) as a urinary biomarker of MDI exposure. Current methods involve long sample preparation, or have been designed using costly automation. There is therefore a need to develop a new practical method for assessing exposure to MDI. METHODS: Urine samples were acidified and heated to form MDA, followed by neutralization and liquid-liquid extraction. Extracts were separated by reversed-phase chromatography on a HSS T3 column followed by analysis on a triple quadrupole mass spectrometer in multiple reaction monitoring (MRM) mode. RESULTS: 13 C15 N-MDA was selected as the internal standard (IS) of choice following an investigation of internal standard stability. The hydrolysis efficiency, forming free MDA from conjugated metabolites in vivo, was evaluated using 4,4'-methylenebis(acetanilide) spiked into urine and complete hydrolysis occurred after 1 h. A dynamic range of 5 to 500 nM was achieved, and was useful for monitoring MDI exposure considering the biological guidance value (BGV) of 10 µg/L (~50 nM) proposed by the German Research Foundation (DFG). The limit of detection (LOD) and limit of quantification (LOQ) of the method were 0.8 and 2.7 nM, respectively. The intra-day and inter-day precisions were 4.33% and 4.27%, respectively. Finally, the method was tested with inter-laboratory samples from the German External Quality Assessment Scheme (G-EQUAS) program and the results submitted were all within the allowable tolerance range. CONCLUSIONS: A practical and validated method for the analysis of small- to medium-sized batches of samples has been developed for the biological monitoring of MDI exposure in human urine.

Asunto(s)

Compuestos de Anilina/orina , Cromatografía Liquida/métodos , Isocianatos , Exposición Profesional/análisis , Espectrometría de Masas en Tándem/métodos , Calibración , Cromatografía Liquida/normas , Humanos , Hidrólisis , Límite de Detección , Extracción Líquido-Líquido , Espectrometría de Masas en Tándem/normas

RESUMEN

Objective: To develop a method for determination of metabolites of diphenylmethane diisocyanate (MDI) in urine, i.e. methylenedianiline (MDA) by high performance liquid chromatography-tandem mass (LC-MS-MS) . Methods: Urine samples were prepared by hydrolyzation with sulfuric acid and extraction by acetonitrile, and then separated on a Shim-pack XR-ODS column, analyzed with high-performance liquid chromatography-tandem mass spectrometry (LC-MS/MS) . The external solvent standard calibration were tested. Results: The linearity ranges were 0.05~20.00 µg/L, The related coefficients were 0.999 5. The limit of detection was 0.02 µg/L. The rats of recovery were 91.0%~103.4%. The relative standard deviations were between 2.7%~7.3%. Conclusion: The method was sensitive, accurate and suitable for the MDA determination in urine of MDI exposed population.

Asunto(s)

Compuestos de Anilina/análisis , Compuestos de Anilina/orina , Cromatografía Líquida de Alta Presión/métodos , Espectrometría de Masas en Tándem/métodos , Animales , Calibración , Cromatografía Liquida , Humanos , Ratas , Sensibilidad y Especificidad , Análisis Espectral

RESUMEN

Phenylamine has been recognized as one of the most important industrially relevant ingredient and a crucial intermediate in chemical products. Yet, its internal exposure detection in human remains largely elusive due to the lack of potent monitoring method. Hereby this issue is addressed with a probe based on lanthanide functionalized organic-inorganic hybrid material Al(OH)(bpydc) (1) through post-synthetically modified metal-organic framework. The as-synthesized Tb3+@1 exhibits the strong luminescence of Tb3+ originated from efficient energy transfer from the ligand, which can sense the biological metabolite p-aminophenol (PAP) of the phenylamine in the human urine. Linear correlation between the integrated fluorescence intensity and the concentration of PAP was investigated, enabling quantitative analysis of PAP in physiologically ranges (0.005-5 mg mL-1) with low detection limit (5 µg mL-1). This probe demonstrates excellent sensitivity, high selectivity, good reusability and quick response to PAP. Furthermore, a simple and rapid smartphone-based medical portable test paper was developed, whose quantitative color change can be easily distinguished visually. Hence, the PAP sensing platform can serve as a potential diagnostic tool for home monitoring of PAP.

Asunto(s)

Compuestos de Anilina/orina , Colorimetría , Estructuras Metalorgánicas/química , Sistemas de Atención de Punto , Terbio/química , Biomarcadores/orina , Humanos

RESUMEN

OBJECTIVES: We investigated the relationship between 4,4'-methylene-bis(2-chloroaniline) (MBOCA) exposure and micronucleus (MN) frequency, and how this association was affected by genetic polymorphism of the cytochrome P450 enzyme (CYP3A4). METHODS: We divided the study population into an exposed group (n=44 with total urine MBOCA ≥20 µg/g creatinine) and a control group (n=47 with total urine MBOCA <20 µg/g creatinine). Lymphocyte MN frequency (MNF) and micronucleated cell (MNC) frequency were measured by the cytokinesis-block MN assay method. MNF reported as the number of micronuclei in binucleated cells per 1000 cells, and MNC reported as the number of binucleated cells with the presence of MN per 1000 cells. CYP3A4 alleles were measured by PCR-based restriction fragment length polymorphism (PCR-RFLP). RESULTS: The mean MNF (6.11 vs 4.46 MN/1000 cells, p<0.001) and MNC (5.75 vs 4.15 MN/1000 cells, p<0.001) in the exposed workers was significantly higher than that in the controls. The CYP3A4 polymorphism A/A+A/G influenced the difference in the mean MNF (5.97 vs 4.38 MN/1000 cells, p<0.001) and MNC (5.60 vs 4.15 MN/1000 cells, p<0.001) between the MBOCA-exposed and control groups. After adjusting risk factors, the MNF level in the MBOCA-exposed workers was 0.520 MN cells/1000 cells (p<0.001) higher than the control group among the CYP3A4 A/A+A/G genotype. Similarly, the MNC level in the MBOCA-exposed workers was 0.593 MN/1000 cells (p<0.001) higher than the control group among the CYP3A4 A/A+A/G genotype. However, the difference in adjusted MNF and MNC between the exposed and control groups was not significant for the CYP3A4 polymorphism with the G/G genotype. CONCLUSIONS: We recommend that lymphocytes MNF and MNC are good indicators to evaluate MBOCA genotoxicity. Individuals with the CYP3A4 polymorphism A/A and A/G genotypes appear to be more susceptible to MBOCA genotoxicity.

Asunto(s)

Compuestos de Anilina/efectos adversos , Citocromo P-450 CYP3A/genética , Metilenobis (cloroanilina)/efectos adversos , Exposición Profesional/efectos adversos , Polimorfismo Genético , Adulto , Consumo de Bebidas Alcohólicas/epidemiología , Análisis de Varianza , Compuestos de Anilina/orina , Índice de Masa Corporal , Citocromo P-450 CYP3A/sangre , Citocromo P-450 CYP3A/orina , Sistema Enzimático del Citocromo P-450 , Femenino , Genotipo , Humanos , Linfocitos/química , Masculino , Metilenobis (cloroanilina)/análisis , Persona de Mediana Edad , Pruebas de Mutagenicidad , Reacción en Cadena de la Polimerasa , Factores de Riesgo , Fumar/epidemiología , Taiwán/epidemiología

RESUMEN

A study of the performance of reversed-phase chromatography with a programmable multiwavelength fluorimetric technique using either conventional hydro-organic or micellar eluent is established for the determination of xipamide (XIP) in the presence of its degradation product, 2,6-xylidine (XY). In conventional liquid chromatography (CLC), the analyses were carried out on a Promosil ODS 100 Å column (250 mm × 4.6 mm i.d., 5 µm) using a mobile phase consisting of methanol/0.1 M phosphate buffer (65: 35, v/v) at pH 4.0. For micellar liquid chromatography (MLC), a short Spherisorb column (150 mm × 4.6 mm i.d., 5 µm) was employed in conjunction with a greener mobile phase (pH 5.0) containing 0.1 M sodium dodecyl sulfate and 15% n-propanol. CLC proved to be superior to MLC in terms of sensitivity for the determination of the degradation product because it could detect trace amounts down to 10.0 ng/ml of XY as a degradation product in XIP. However, MLC represents an eco-friendly approach for the simultaneous determination of XIP and XY. In addition, the opportunity for the direct introduction of biological matrices into the chromatographic system is one of the distinctive benefits of MLC. The proposed methods were applied for the determination of XIP in its tablets, human urine and content uniformity testing. The results of the proposed methods were statistically compared with those obtained using the comparison fluorimetric method, revealing no significant differences in the performance of the methods regarding accuracy and precision.

Asunto(s)

Cromatografía Liquida/métodos , Xipamida/orina , Adulto , Compuestos de Anilina/orina , Tampones (Química) , Calibración , Cromatografía Líquida de Alta Presión/métodos , Cromatografía Liquida/instrumentación , Femenino , Humanos , Concentración de Iones de Hidrógeno , Límite de Detección , Micelas , Concentración Osmolar , Reproducibilidad de los Resultados , Dodecil Sulfato de Sodio , Espectrometría de Fluorescencia , Comprimidos/análisis , Xipamida/análisis , Xipamida/metabolismo

RESUMEN

Urinary diamines are biomarkers of diisocyanate exposure. Diisocyanates are considered as skin and respiratory sensitizers and are the most frequently reported cause of occupational asthma. Herein we report on the development and validation of an ultraperformance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) method for the measurement of five aromatic diamines, 4,4'-methylenedianiline (MDA), 2,4-toluenediamine (4TDA), 2,6-toluenediamine (6TDA), 1,5-naphthalenediamine (NDA), and p-phenylenediamine (PPDA) in human urine. The method incorporates sample preparation steps, which include a 4 h acid hydrolysis followed by high-throughput solid-phase extraction prior to chromatographic separation. Chromatographic separation was achieved using a C18 reversed phase column with gradient elution of basic mobile phases (pH 9.2). The duty cycle of the method was less than 5 min, including both the column equilibration and autosampler movement. Analytical detection was performed using positive ion atmospheric pressure chemical ionization tandem mass spectrometry (APCI-MS/MS) in scheduled multiple reaction monitoring (sMRM) mode. Excellent linearity was observed over standard calibration curve concentration ranges of 3 orders of magnitude with method detection limit ranging from 10 to 100 pg/mL. The interday and intraday reproducibility and accuracy were within ±15%. This method is fast, accurate, and reproducible and is suitable for assessment of exposure to the most common aromatic diisocyanates within targeted groups as well as larger population studies such as the National Health and Nutrition Examination Survey (NHANES).

Asunto(s)

Compuestos de Anilina/orina , Diaminas/orina , Naftalenos/orina , Biomarcadores/orina , Isótopos de Carbono , Cromatografía Liquida/métodos , Humanos , Isocianatos/metabolismo , Isocianatos/toxicidad , Límite de Detección , Isótopos de Nitrógeno , Espectrometría de Masas en Tándem/métodos

RESUMEN

Aniline is an important source material in the chemical industry (e.g., rubber, pesticides, and pharmaceuticals). The general population is known to be ubiquitously exposed to aniline. Thus, assessment of aniline exposure is of both occupational and environmental relevance. Knowledge on human metabolism of aniline is scarce. We orally dosed four healthy male volunteers (two fast and two slow acetylators) with 5 mg isotope-labeled aniline, consecutively collected all urine samples over a period of 2 days, and investigated the renal excretion of aniline and its metabolites by LS-MS/MS and GC-MS. After enzymatic hydrolysis of glucuronide and sulfate conjugates, N-acetyl-4-aminophenol was the predominant urinary aniline metabolite representing 55.7-68.9 % of the oral dose, followed by the mercapturic acid conjugate of N-acetyl-4-aminophenol accounting for 2.5-6.1 %. Acetanilide and free aniline were found only in minor amounts accounting for 0.14-0.36 % of the dose. Overall, these four biomarkers excreted in urine over 48 h post-dose represented 62.4-72.1 % of the oral aniline dose. Elimination half-times were 3.4-4.3 h for N-acetyl-4-aminophenol, 4.1-5.5 h for the mercapturic acid conjugate, and 1.3-1.6 and 0.6-1.2 h for acetanilide and free aniline, respectively. Urinary maximum concentrations of N-acetyl-4-aminophenol were reached after about 4 h and maximum concentrations of the mercapturic acid conjugate after about 6 h, whereas concentrations of acetanilide and free aniline peaked after about 1 h. The present study is one of the first to provide reliable urinary excretion factors for aniline and its metabolites in humans after oral dosage, including data on the predominant urinary metabolite N-acetyl-4-aminophenol, also known as an analgesic under the name paracetamol/acetaminophen.

Asunto(s)

Compuestos de Anilina/metabolismo , Compuestos de Anilina/orina , Exposición a Riesgos Ambientales/análisis , Contaminantes Ambientales/metabolismo , Contaminantes Ambientales/orina , Administración Oral , Adulto , Compuestos de Anilina/toxicidad , Biotransformación , Cromatografía Líquida de Alta Presión , Relación Dosis-Respuesta a Droga , Contaminantes Ambientales/toxicidad , Cromatografía de Gases y Espectrometría de Masas , Voluntarios Sanos , Humanos , Masculino , Tasa de Depuración Metabólica , Espectrometría de Masas en Tándem , Toxicocinética

RESUMEN

Xylazine as veterinary medicine for sedation, but intoxication cases in humans were identified in the last few years. A highly sensitive method is required for analyzing xylazine and its metabolites in human blood and urine. This article presents an ultra high performance liquid chromatography coupled with quadrupole-time of flight mass spectrometry (UHPLC-QTOF) study for simultaneous determination of xylazine and 2,6-dimethylaniline (DMA) in human blood and urine. The samples were extracted and cleaned up by Oasis MCX solid-phase extraction. The analysis is performed using an UHPLC-QTOF. Analysis precision, accuracy, sensitivity, linear range, limit of detection (LOD) and limit of quantification (LOQ) were validated for the proposed method. In the blood and urine samples, the linear calibration curves with high linearity are obtained over the range of 2.0-1,000.0 ng/mL. The LOD for xylazine and DMA in blood are 0.2 and 0.1 ng/mL, in urine are 0.4 and 0.2 ng/mL; the LOQ for xylazine and DMA in blood are 0.6 and 0.3 ng/mL, in urine are 1.0 and 0.6 ng/mL, respectively. The intra- and interday precision is better than 8.6 and 11.9%. In conclusion, the proposed method is highly sensitive and reproducible, thus suitable for accurate quantification of xylazine and its metabolites in blood and urine.

Asunto(s)

Compuestos de Anilina/sangre , Compuestos de Anilina/orina , Xilazina/sangre , Xilazina/orina , Cromatografía Líquida de Alta Presión , Humanos , Límite de Detección , Extracción en Fase Sólida , Espectrometría de Masas en Tándem

RESUMEN

1. An excretion balance study was performed following i.p. administration of 4-bromoaniline (50 mg kg(-1)) to bile-cannulated rats, using bromine-detected ((79/81)Br) ICPMS for quantification. Approximately 90% of the dose was recovered in urine (68.9 ± 3.6%) and bile (21.4 ± 1.4%) by 48 h post-administration. 2. HPLC-ICPMS ((79/81)Br) was used to selectively detect and profile the major urinary and biliary-excreted metabolites and determined that the 0-12 h urine contained at least 21 brominated metabolites with 19 bromine-containing peaks observed in the 6-12 h bile samples. 3. The urinary and biliary metabolites were subsequently profiled using HPLC-oaTOFMS. By exploiting the distinctive bromine isotope pattern ca. 60 brominated metabolites were detected in the urine in negative electrospray ionisation (ESI) mode while bile contained ca. 21. 4. While a large number of bromine-containing metabolites were detected, the profiles were dominated by a few major components with the bulk of the 4-bromoaniline-related material in urine accounted for by 4-bromoanaline O-sulfate (∼75% of the total by ICPMS, 84% by TOFMS). In bile a hydroxylated N-acetyl compound was the major metabolite detected, forming some ∼65% of the 4-bromoaniline-related material by ICPMS (37% by TOFMS).

Asunto(s)

Compuestos de Anilina/metabolismo , Compuestos de Anilina/orina , Bilis/metabolismo , Bromo/orina , Animales , Cateterismo , Cromatografía Líquida de Alta Presión , Espectroscopía de Resonancia Magnética , Masculino , Espectrometría de Masas , Ratas , Ratas Wistar , Urinálisis

RESUMEN

A rapid, sensitive and high-throughput ultra-performance liquid chromatography method with tandem mass spectrometry (UPLC-MS/MS) has been developed for the determination of DAT-230 in rat plasma, urine, feces and tissues (heart, liver, spleen, lung, kidney, stomach, intestine and brain). The biological samples were prepared by protein precipitation, and separation was achieved on an ACQUITY™ UPLC BEH C18 column (50 mm × 2.1mm, 1.7 µm) with a mobile phase that consisted of methanol - 0.2% formic acid water (80:20, v/v) at a flow rate of 0.2 mL/min. The MS/MS ion transitions were monitored at m/z 372.17 → 357.17 for DAT-230 and m/z 406.08 → 345.16 for COH-203 (internal standard, IS). The calibration curve was linear in the range of 0.1-5200 ng/mL for all biological matrices (r(2) ≥ 0.996), and it had the same value for the lower limit of quantification. The validated method was successfully applied to the pharmacokinetics, tissue distribution and excretion study after intravenous administration of a 5mg/kg dose of DAT-230 to healthy Sprague-Dawley rats. The mean pharmacokinetic parameters of t1/2 and AUC0-12 were (1.1 ± 0.4)h and (861.0 ± 281.2) ng h/mL, respectively. Tissue distribution results indicated that DAT-230 exhibited rapid distribution and high liver, kidney, spleen, stomach and intestine uptake; these organs were indicated as the major target organs of the drug. In total, 5.3% of the administered DAT-230 was excreted in an unconverted form in urine, feces and bile, which implies that DAT-230 was excreted primarily in the form of metabolites.

Asunto(s)

Compuestos de Anilina/farmacocinética , Cromatografía Liquida/métodos , Eliminación Hepatobiliar , Ensayos Analíticos de Alto Rendimiento , Eliminación Intestinal , Eliminación Renal , Espectrometría de Masas en Tándem/métodos , Tiofenos/farmacocinética , Moduladores de Tubulina/farmacocinética , Compuestos de Anilina/administración & dosificación , Compuestos de Anilina/sangre , Compuestos de Anilina/orina , Animales , Área Bajo la Curva , Bilis/metabolismo , Biotransformación , Calibración , Cromatografía Liquida/normas , Heces/química , Semivida , Ensayos Analíticos de Alto Rendimiento/normas , Inyecciones Intravenosas , Modelos Lineales , Masculino , Tasa de Depuración Metabólica , Ratas Sprague-Dawley , Estándares de Referencia , Reproducibilidad de los Resultados , Espectrometría de Masas en Tándem/normas , Tiofenos/administración & dosificación , Tiofenos/sangre , Tiofenos/orina , Distribución Tisular , Moduladores de Tubulina/administración & dosificación , Moduladores de Tubulina/sangre , Moduladores de Tubulina/orina

RESUMEN

PURPOSE: (18)F-Florbetaben is a positron emission tomography (PET) tracer indicated for imaging cerebral beta-amyloid deposition in adult patients with cognitive impairment who are being evaluated for Alzheimer's disease and other causes of cognitive decline. The present study examined ethnic comparability of the plasma pharmacokinetics, which is the input to the brain, between Caucasian and Japanese subjects. METHODS: Two identical phase I trials were performed in 18 German and 18 Japanese healthy volunteers to evaluate the plasma pharmacokinetics of a single dose of 300 MBq (18)F-florbetaben, either of low (≤5 µg, LD) or high (50-55 µg, HD) mass dose. Pharmacokinetic parameters were evaluated based on the total (18)F radioactivity measurements in plasma followed by metabolite analysis using radio-HPLC. RESULTS: The pharmacokinetics of (18)F-florbetaben was characterized by a rapid elimination from plasma. The dose-normalized areas under the curve of (18)F-florbetaben in plasma as an indicator of the input to the brain were comparable between Germans (LD: 0.38 min/l, HD: 0.55 min/l) and Japanese (LD: 0.35 min/l, HD: 0.45 min/l) suggesting ethnic similarity, and the mass dose effect was minimal. A polar metabolite fraction was the main radiolabelled degradation product in plasma and was also similar between the doses and the ethnic groups. CONCLUSION: Absence of a difference in the pharmacokinetics of (18)F-florbetaben in Germans and Japanese has warranted further global development of the PET imaging agent.

Asunto(s)

Compuestos de Anilina/sangre , Pueblo Asiatico , Tomografía de Emisión de Positrones , Radiofármacos/sangre , Estilbenos/sangre , Población Blanca , Anciano , Compuestos de Anilina/orina , Femenino , Voluntarios Sanos , Humanos , Japón , Masculino , Persona de Mediana Edad , Radiofármacos/orina , Estilbenos/orina

RESUMEN

Human biomonitoring (HBM) is frequently used for the analysis and assessment of exposure to chemicals under routine working conditions. In recent years, HBM has also been applied to monitor the exposure of the general population, and of emergency responders in the aftermath of chemical incidents. Two examples of targeted HBM programs in the chemical industry are described and discussed in this paper: (1) analysis and assessment of the exposure of firefighters and chemical workers after the spill of p-chloroaniline from a burning chemical barrel, and (2) biomonitoring of maintenance workers potentially exposed to benzene during regular turnarounds. The results of these investigations underline that human biomonitoring contributes substantially to comprehensive exposure analyses, human health risk assessments and communication. In addition, regular HBM surveillance and feedback can assist in the continuous improvement of workplace safety measures and exposure control. In conclusion, data on accidental or short-term exposure to hazardous chemicals are an important source of information for the further development of limit and assessment values, the validation of biomarkers and of targeted HBM programs for both routine monitoring and disaster management.

Asunto(s)

Compuestos de Anilina/orina , Benceno/análisis , Liberación de Peligros Químicos , Monitoreo del Ambiente/métodos , Bomberos , Sustancias Peligrosas/orina , Exposición Profesional/análisis , Biomarcadores/orina , Humanos , Exposición Profesional/efectos adversos

RESUMEN

Aniline is an important starting material in the manufacture of polyurethane-based plastic materials. Aniline-derived methemoglobinemia (Met-Hb) is well described in exposed workers although information on the dose-response association is limited. We used an experimental design to study the association between aniline in air with the formation of Met-Hb in blood and the elimination of aniline in urine. A 6-h exposure of 2 ppm aniline in 19 non-smoking volunteers resulted in a time-dependent increase in Met-Hb in blood and aniline in urine. The maximum Met-Hb level in blood (mean 1.21 ± 0.29 %, range 0.80-2.07 %) and aniline excretion in urine (mean 168.0 ± 51.8 µg/L, range 79.5-418.3 µg/L) were observed at the end of exposure, with both parameters rapidly decreasing after the end of exposure. After 24 h, the mean level of Met-Hb (0.65 ± 0.18 %) returned to the basal level observed prior to the exposure (0.72 ± 0.19 %); whereas, slightly elevated levels of aniline were still present in urine (means 17.0 ± 17.1 vs. 5.7 ± 3.8 µg/L). No differences between males and females as well as between slow and fast acetylators were found. The results obtained after 6-h exposure were also comparable to those observed in four non-smoking volunteers after 8-h exposure. Maximum levels of Met-Hb and aniline in urine were 1.57 % and 305.6 µg/L, respectively. Overall, our results contribute to the risk assessment of aniline and as a result, the protection of workers from aniline-derived adverse health effects at the workplace.

Asunto(s)

Compuestos de Anilina/administración & dosificación , Metahemoglobina/metabolismo , Enfermedades Profesionales/prevención & control , Exposición Profesional/prevención & control , Adulto , Compuestos de Anilina/toxicidad , Compuestos de Anilina/orina , Femenino , Humanos , Masculino , Metahemoglobinemia/inducido químicamente , Metahemoglobinemia/prevención & control , Persona de Mediana Edad , Proyectos Piloto , Medición de Riesgo/métodos , Factores Sexuales , Factores de Tiempo , Adulto Joven

RESUMEN

Efaproxiral (RSR 13) is an experimental synthetic allosteric modifier of haemoglobin (Hb) that acts by increasing the release of oxygen from Hb to the surrounding tissues. It has been shown to increase maximum oxygen uptake (VO(2max)) in a canine skeletal muscle model. The ability to increase maximal muscle oxygen uptake makes efaproxiral a potential performance-enhancing agent and is therefore prohibited by the World Anti-Doping Agency. In this study, a method for the detection and elimination of efaproxiral in equine plasma and urine after a 2.5 g intravenous administration of efaproxiral is described. Post administration plasma and urine samples were collected up to 120 h. Efaproxiral was detected up to 120 h in urine and up to 78 h in plasma. In plasma, the peak concentration was 42 µg/ml and detected at 5 min post administration. In urine, the peak concentration was 2.8 mg/ml and detected at 0-1 h post administration. A validated liquid chromatography tandem mass spectrometry method was used for the quantitation of efaproxiral in equine plasma and urine. The limit of detection of the method is 0.05 ng/ml in plasma and 0.1 ng/ml in urine. The method is highly sensitive and specific with good precision, accuracy and recovery. The manuscript also describes the systematic identification of efaproxiral metabolites detected in post administration equine urine samples. The metabolites were identified by use of enhanced mass spectra and enhanced product ion scans. Both positive and negative mode ionizations were utilized for metabolite identification and plausible fragmentation pathways were proposed for the phase 1 metabolite identified. In addition to free efaproxiral, one phase 1 metabolite and two phase 2 metabolites were identified in post administration urine.

Asunto(s)

Compuestos de Anilina/sangre , Compuestos de Anilina/orina , Cromatografía Líquida de Alta Presión/métodos , Propionatos/sangre , Propionatos/orina , Espectrometría de Masas en Tándem/métodos , Compuestos de Anilina/química , Compuestos de Anilina/farmacocinética , Animales , Caballos , Análisis de los Mínimos Cuadrados , Propionatos/química , Propionatos/farmacocinética , Reproducibilidad de los Resultados , Sensibilidad y Especificidad

RESUMEN

Epidemiological studies suggest associations between the use of N-acetyl-4-aminophenol (paracetamol) during pregnancy and increased risks of reproductive disorders in the male offspring. Previously we have reported a ubiquitous urinary excretion of N-acetyl-4-aminophenol in the general population. Possible sources are (1) direct intake of paracetamol through medication, (2) paracetamol residues in the food chain and (3) environmental exposure to aniline or related substances that are metabolized into N-acetyl-4-aminophenol. In order to elucidate the origins of the excretion of N-acetyl-4-aminophenol in urine and to contribute to the understanding of paracetamol and aniline metabolism in humans we developed a rapid, turbulent-flow HPLC-MS/MS method with isotope dilution for the simultaneous quantification of N-acetyl-4-aminophenol and two other aniline related metabolites, N-acetyl-2-aminophenol and acetanilide. We applied this method to three sets of urine samples: (1) individuals with no known exposure to aniline and also no recent paracetamol medication; (2) individuals after occupational exposure to aniline but no paracetamol medication and (3) paracetamol users. We confirmed the omnipresent excretion of N-acetyl-4-aminophenol. Additionally we revealed an omnipresent excretion of N-acetyl-2-aminophenol. In contrast, acetanilide was only found after occupational exposure to aniline, not in the general population or after paracetamol use. The results lead to four preliminary conclusions: (1) other sources than aniline seem to be responsible for the major part of urinary N-acetyl-4-aminophenol in the general population; (2) acetanilide is a metabolite of aniline in man and a valuable biomarker for aniline in occupational settings; (3) aniline baseline levels in the general population measured after chemical hydrolysis do not seem to originate from acetanilide and hence not from a direct exposure to aniline itself and (4) N-acetyl-2-aminophenol does not seem to be related to aniline nor to N-acetyl-4-aminophenol in man.

Asunto(s)

Acetaminofén/orina , Acetanilidas/orina , Aminofenoles/orina , Compuestos de Anilina/orina , Acetaminofén/efectos adversos , Acetaminofén/química , Acetanilidas/química , Acetanilidas/toxicidad , Aminofenoles/química , Aminofenoles/toxicidad , Compuestos de Anilina/química , Compuestos de Anilina/toxicidad , Cromatografía Líquida de Alta Presión , Monitoreo del Ambiente , Cadena Alimentaria , Humanos , Espectrometría de Masas , Exposición Profesional

RESUMEN

Dispersive liquid-liquid microextraction based on solidification of floating organic drop (DLLME-SFO) was for the first time combined with field-amplified sample injection (FASI) in CE to determine four ß(2)-agonists (cimbuterol, clenbuterol, mabuterol, and mapenterol) in bovine urine. Optimum BGE consisted of 20 mM borate buffer and 0.1 mM SDS. Using salting-out extraction, ß(2)-agonists were extracted into ACN that was then used as the disperser solvent in DLLME-SFO. Optimum DLLME-SFO conditions were: 1.0 mL ACN, 50 µL 1-undecanol (extraction solvent), total extraction time 1.5 min, no salt addition. Back extraction into an aqueous solution (pH 2.0) facilitated direct injection of ß(2)-agonists into CE. Compared to conventional CZE, DLLME-SFO-FASI-CE achieved sensitivity enhancement factors of 41-1046 resulting in LODs in the range of 1.80-37.0 µg L(-1). Linear dynamic ranges of 0.15-10.0 mg L(-1) for cimbuterol and 15-1000 µg L(-1) for the other analytes were obtained with coefficients of determination (R(2)) ≥ 0.9901 and RSD% ≤5.5 (n = 5). Finally, the applicability of the proposed method was successfully confirmed by determination of the four ß(2)-agonists in spiked bovine urine samples and accuracy higher than 96.0% was obtained.

Asunto(s)

Agonistas de Receptores Adrenérgicos beta 2/orina , Electroforesis Capilar/métodos , Microextracción en Fase Líquida/métodos , 2-Hidroxifenetilamina/análogos & derivados , 2-Hidroxifenetilamina/orina , Compuestos de Anilina/orina , Animales , Bovinos , Clenbuterol/análogos & derivados , Clenbuterol/orina , Concentración de Iones de Hidrógeno , Sensibilidad y Especificidad , Solventes

RESUMEN

The disposition of 2-Methoxy-4-nitroaniline (MNA) was investigated in male and female Harlan Sprague Dawley rats and B6C3F(1)/N mice following oral, intravenous, and dermal exposure to [(14)C]MNA at 2, 15, or 150 mg/kg. Clearance of MNA was investigated in male and female rat, mouse, and human hepatocytes. MNA was cleared slowly in hepatocytes from rat (t(1/2) = 152-424 min) and human (t(1/2) = 118-403 min) but faster in mouse (t(1/2)= 70-106 min). MNA was well-absorbed in rats and mice following oral administration and eliminated chiefly in urine (rats, 75-79%; mice, 55-68%) 72 h post dosing. Less than 1% of the radioactivity remained in tissues at 72 h. MNA was poorly absorbed following dermal application in rats (5.5%) and mice (10%) over 24 h. The major pathway of metabolism of MNA was via hydroxylation of the phenyl ring to form 6-hydroxy MNA; major metabolites detected were sulfate and glucuronide conjugates of 6-hydroxy MNA. Following oral administration, the percent of total radioactivity bound in tissues bound was highest in liver (43%) and red blood cells (30%), whereas the radioactivity bound to DNA was highest in cecum (160 pmol/mg DNA).

Asunto(s)

Compuestos de Anilina/metabolismo , Compuestos de Anilina/farmacocinética , Nitrocompuestos/metabolismo , Nitrocompuestos/farmacocinética , Caracteres Sexuales , Compuestos de Anilina/administración & dosificación , Compuestos de Anilina/orina , Animales , Bilis/metabolismo , Radioisótopos de Carbono/administración & dosificación , Cromatografía Líquida de Alta Presión , ADN/metabolismo , Vías de Administración de Medicamentos , Femenino , Hepatocitos/metabolismo , Humanos , Espectroscopía de Resonancia Magnética , Masculino , Espectrometría de Masas , Redes y Vías Metabólicas , Metaboloma , Metabolómica , Ratones , Nitrocompuestos/administración & dosificación , Nitrocompuestos/orina , Radiactividad , Ratas , Ratas Sprague-Dawley , Distribución Tisular/efectos de los fármacos