RESUMEN
Exposure of firefighting instructors to polycyclic aromatic hydrocarbons (PAHs) such as naphthalene is unavoidable during live fire training. The study aimed to investigate naphthalene uptake by measuring the urinary excretion of the naphthalene metabolite 1,2-dihydroxynaphthalene (DHN), to describe the DHN elimination kinetics and to evaluate the results by comparison to further biomarkers of PAH exposure. N = 6 male non-smoking firefighting instructors completed five training sessions each in a residential fire simulation unit under respiratory protection. All participants provided two urine samples before and another seven samples within an 18-h-interval after each session. DHN was detected by gas chromatography/tandem mass spectrometry (GC-MS/MS) in all samples (n = 237) with median concentrations ranging from 3.3 µg/g crea. (range 0.9-10.2) before exposure to 134.2 µg/g crea. (43.4-380.4) post exposure. Maximum elimination found 3.3 h (median) after onset of exposure decreased with a mean half-life of 6.6 h to 27.1 µg/g crea. (15.7-139.5) 18 h after training. DHN sensitively indicated a presumed dermal naphthalene intake during training, showing similar elimination kinetics like other naphthalene metabolites. Internal exposure of the participants transiently exceeded exposures determined for non-smokers in the general population, but was lower than at other workplaces with PAH exposure. Despite limited uptake, accumulation is possible with daily exposure.
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Bomberos , Naftoles , Exposición Profesional , Hidrocarburos Policíclicos Aromáticos , Humanos , Masculino , Exposición Profesional/análisis , Adulto , Hidrocarburos Policíclicos Aromáticos/orina , Hidrocarburos Policíclicos Aromáticos/análisis , Naftoles/orina , Naftalenos/orina , Naftalenos/farmacocinética , Naftalenos/análisis , Eliminación Renal , Cromatografía de Gases y Espectrometría de Masas , Biomarcadores/orina , Persona de Mediana Edad , IncendiosRESUMEN
AC-262536 is one of a number of selective androgen receptor modulators that are being developed by the pharmaceutical industry for treatment of a range of clinical conditions including androgen replacement therapy. Though not available therapeutically, selective androgen receptor modulators are widely available to purchase online as (illegal) supplement products. The growth- and bone-promoting effects, along with fewer associated negative side effects compared with anabolic-androgenic steroids, make these compounds a significant threat with regard to doping control in sport. The aim of this study was to investigate the metabolism of AC-262536 in the horse following in vitro incubation and oral administration to two Thoroughbred horses, in order to identify the most appropriate analytical targets for doping control laboratories. Urine, plasma and hair samples were collected and analysed for parent drug and metabolites. Liquid chromatography-high-resolution mass spectrometry was used for in vitro metabolite identification and in urine and plasma samples. Nine phase I metabolites were identified in vitro; four of these were subsequently detected in urine and three in plasma, alongside the parent compound in both matrices. In both urine and plasma samples, the longest detection window was observed for an epimer of the parent compound, which is suggested as the best target for detection of AC-262536 administration. AC-262536 and metabolites were found to be primarily glucuronide conjugates in both urine and plasma. Liquid chromatography-tandem mass spectrometry analysis of post-administration hair samples indicated incorporation of parent AC-262536 into the hair following oral administration. No metabolites were detected in the hair.
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Compuestos de Azabiciclo/metabolismo , Caballos/metabolismo , Naftalenos/metabolismo , Sustancias para Mejorar el Rendimiento/metabolismo , Administración Oral , Animales , Compuestos de Azabiciclo/administración & dosificación , Compuestos de Azabiciclo/sangre , Compuestos de Azabiciclo/orina , Cromatografía Liquida , Cabello/química , Caballos/sangre , Caballos/orina , Naftalenos/administración & dosificación , Naftalenos/sangre , Naftalenos/orina , Sustancias para Mejorar el Rendimiento/administración & dosificación , Sustancias para Mejorar el Rendimiento/sangre , Sustancias para Mejorar el Rendimiento/orina , Receptores Androgénicos/metabolismo , Detección de Abuso de Sustancias , Espectrometría de Masas en TándemRESUMEN
This study aimed to optimize a new sample preparation method using N-doped mesoporous carbon sorbent for simultaneous measurement of 1-naphthol and 2-naphthol, the biomarkers of exposure to naphthalene. The samples were analyzed using high-performance liquid chromatography supplied with ultraviolet detector (HPLC-UV). N-doped mesoporous carbon sorbent was obtained via the hard template procedure. The synthesized nanosorbent was then characterized by transmission electron microscopy (TEM), Brunauer-Emmett-Teller (BET), and elemental analysis (CHN). The effective factors in the extraction of the studied biomarkers were examined by the Box-Behnken (BBD) methodology. Regarding the optimum conditions, the sketched calibration curve for naphthols was linear in the concentration levels of 1-600⯵g L-1 for human urine samples. The accuracy and reproducibility of the introduced method were determined using the relative recovery (RR %) and relative standard deviation (RSD %) tests on the fortified urine samples. RR% and RSD% were found to be 97.0-101.2% and 3.1-9.0%, respectively. The calculated method detection limit of the optimized procedure was 0.3⯵g L-1 and 0.5⯵g L-1 for 1-naphthol and 2-naphthol, respectively.
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Carbono/química , Cromatografía Líquida de Alta Presión/métodos , Nanopartículas/química , Naftalenos/orina , Microextracción en Fase Sólida/métodos , Biomarcadores/orina , Exposición a Riesgos Ambientales/análisis , Humanos , Límite de Detección , Modelos Lineales , Naftalenos/química , Naftalenos/aislamiento & purificación , Reproducibilidad de los Resultados , SonicaciónRESUMEN
Background and Objectives: The use of synthetic cannabinoids has increased around the world. As a result, the implementation of accurate analysis in human biological matrices is relevant and fundamental. Two different analytical technologies, ultra-high-performance liquid chromatography-high-resolution mass spectrometry (UHPLC-HRMS) and high-sensitivity gas chromatography-mass spectrometry (GC-MS) were used for the determination of three synthetic cannabinoids JWH-122, JWH 210, UR-144 and their metabolites in urine of consumers. Materials and Methods: Sample preparation included an initial hydrolysis with ß-glucuronidase and liquid-liquid extraction. The UHPLC-HRMS method included a Kinetex 2.6 u Biphenyl 100A (100 × 2.1 mm, 2.6 µm) (Phenomenex, Italy) column with a gradient mobile phase consisting of mobile phase A (ammonium formate 2mM in water, 0.1% formic acid) and mobile phase B (ammonium formate 2mM in methanol/acetonitrile 50:50 (v/v), 0.1% formic acid) and a full-scan data-dependent MS2 (ddMS2) mode was used (mass range 100-1000 m/z). The GC-MS method employed an ultra-Inert Intuvo GC column (HP-5MS UI, 30 m × 250 µm i.d, film thickness 0.25 µm; Agilent Technologies, Santa Clara, CA, USA) and electron-impact (EI) mass spectra were recorded in total ion monitoring mode (scan range 40-550 m/z). Results: Both methods have been successfully used for screening of parent synthetic cannabinoids and their metabolites in urine samples of consumers. Conclusions: The screening method applied JWH-122, JWH-210, UR-144 and their metabolites in urine of consumers can be applied to other compounds of the JWH family.
Asunto(s)
Cromatografía Líquida de Alta Presión/métodos , Cromatografía de Gases y Espectrometría de Masas/métodos , Drogas Ilícitas/orina , Indoles/orina , Naftalenos/orina , Humanos , Reproducibilidad de los ResultadosRESUMEN
Polycyclic aromatic hydrocarbons (PAH) are well-established environmental carcinogens likely to be causative agents for some human cancers. Bay-region diol epoxides are ultimate carcinogenic metabolites of multiple PAH. Dihydrodiols are the important intermediate products of this pathway and can be further oxidized to form diol epoxides. We quantified two dihydrodiol metabolites of phenanthrene (Phe), the simplest PAH with a bay-region, in the 6 h urine of smokers (N = 25) and non-smokers (N = 25) using a newly developed and validated analytical method. After hydrolysis by ß-glucuronidase and sulfatase, and solid phase extraction, the sample was silylated and analyzed by gas chromatography-negative ion chemical ionization-tandem mass spectrometry (GC-NICI-MS/MS). Levels (nmol/6h urine) of Phe-1,2-dihydrodiol (Phe-1,2-D) and Phe-3,4-dihydrodiol (Phe-3,4-D) were 2.04 ± 1.52 and 0.51 ± 0.35 , respectively, in smokers, significantly higher than those in non-smokers (1.35 ± 1.11 of Phe-1,2-D, p < 0.05; 0.27 ± 0.25 of Phe-3,4-D, p < 0.005). Cigarette smoking also influenced the regioselective metabolism of Phe, presenting as a significant difference in the urinary distribution pattern of Phe-1,2-D and Phe-3,4-D between smokers and non-smokers: the ratio Phe-3,4-D: Phe-1,2-D increased from 0.20 in non-smokers to 0.28 in smokers (p < 0.01), which can be explained by the induction of the phenanthrene metabolizing enzymes CYP1A2 and CYP1B1 by cigarette smoke. The method described here is the first example of facile quantitation of an intact human dihydrodiol metabolite of any PAH with three or more aromatic rings and will be applicable in clinical and molecular epidemiology studies of PAH metabolism and cancer susceptibility.
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Cromatografía de Gases y Espectrometría de Masas/métodos , Naftalenos/orina , Fenantrenos/orina , Fumar/orina , Espectrometría de Masas en Tándem/métodos , Femenino , Humanos , Límite de Detección , Modelos Lineales , Masculino , Reproducibilidad de los Resultados , FumadoresRESUMEN
To examine the association between urinary metabolites of polycyclic aromatic hydrocarbons (OH-PAHs) and diabetes, online databases, including PubMed, Scopus, and Web of Science, were searched on July 17, 2019. Of the 668 articles identified through searching, six cross-sectional studies involving 24,406 participants were included. The pooled odds ratio (OR) and 95% confidence interval (CI) were calculated using a random-effect model. Heterogeneity was measured by reporting the I-square index. Moreover, subgroup analysis according to types of metabolites was performed. We found a significantly higher odds of diabetes in the highest versus the lowest category of urinary naphthalene (NAP), fluorine (FLU), phenanthrene (PHEN), and total OH-PAH metabolites. The pooled OR (95% CI) was estimated at 1.47 (1.17, 1.78), 1.50 (1.29, 1.71), 1.41 (1.21, 1.60), and 1.61 (1.01, 2.21), respectively. We also found a significant association per 1-fold increase in FLU (OR = 1.09, 95% CI [1.00, 1.19]) and PHEN (OR = 1.19, 95% CI [1.08, 1.30]) metabolites. In subgroup analysis stratified by types of OH-PAH metabolites, A significant stronger odds of diabetes was observed in the highest versus the lowest category of 2-PHEN (OR = 1.66, 95% CI [1.32, 2.00]), 2-NAP (OR = 1.66, 95% CI [1.16, 2.17]), 2-FLU (OR = 1.62, 95% CI [1.28, 1.97]), and 9-FLU (OR = 1.62, 95% CI [1.21, 2.04]) metabolites. Furthermore, there was a meaningfully greater likelihood of diabetes per 1-fold increase in 2-FLU (OR = 1.34, 95% CI [1.10, 1.57]), 2-PHEN (OR = 1.33, 95% CI [1.14, 1.51]), and 3-PHEN (OR = 1.19, 95% CI [1.04, 1.34]) metabolites. In conclusion, our study suggests the significant odds of association between urinary OH-PAH metabolites and diabetes.
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Diabetes Mellitus/orina , Hidrocarburos Policíclicos Aromáticos/orina , Femenino , Flúor/orina , Humanos , Hidroxilación , Masculino , Naftalenos/orina , Oportunidad Relativa , Fenantrenos/orina , Hidrocarburos Policíclicos Aromáticos/metabolismoRESUMEN
BACKGROUND: Cigarette smoking is a risk factor of osteoporosis and bone fracture. Tobacco smoke contains several polycyclic aromatic hydrocarbons. Thus, we hypothesized that environmental polycyclic aromatic hydrocarbon exposure is associated with bone loss and fracture risk. The present study examined the association between polycyclic aromatic hydrocarbon exposure and bone turnover in the general adult population. METHODS: A total of 1408 eligible participants from the National Health and Nutrition Examination Survey (NHANES 2001-2006) were included in this cross-sectional analysis. The levels of urinary N-telopeptide and serum bone-specific alkaline phosphatase, which are biomarkers of bone resorption and formation, respectively, were assessed. Meanwhile, polycyclic aromatic hydrocarbon exposure was evaluated using the concentrations of urinary polycyclic aromatic hydrocarbon metabolites. The association between polycyclic aromatic hydrocarbon exposures and N-telopeptide, and bone-specific alkaline phosphatase levels was assessed using a multivariate linear regression model. RESULTS: All polycyclic aromatic hydrocarbon metabolites except 3-phenanthrene were significantly associated with increased N-telopeptide levels (P < 0.05) after adjustment of relevant covariables. However, no significant relationship was observed between polycyclic aromatic hydrocarbon metabolites and bone-specific alkaline phosphatase levels. This relationship remained significant after the participants were assessed according to sex (P < 0.05). Additionally, all polycyclic aromatic hydrocarbon metabolites showed a positive association with N-telopeptide levels in participants aged <60 years (P < 0.05). CONCLUSION: Polycyclic aromatic hydrocarbon exposure is associated with increased bone resorption among the general adult population in the United States. Further studies must assess the potential mechanisms associated with the adverse effects of polycyclic aromatic hydrocarbon exposure on bone loss.
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Fosfatasa Alcalina/sangre , Remodelación Ósea , Resorción Ósea/orina , Colágeno Tipo I/orina , Péptidos/orina , Hidrocarburos Policíclicos Aromáticos/orina , Adulto , Anciano , Resorción Ósea/epidemiología , Exposición a Riesgos Ambientales/estadística & datos numéricos , Femenino , Fluorenos/orina , Humanos , Masculino , Persona de Mediana Edad , Naftalenos/orina , Encuestas Nutricionales , Fenantrenos/orina , Pirenos/orina , Estados Unidos/epidemiologíaRESUMEN
Determination of the modulation of nitrite and nitrate levels in biological samples usually poses a major challenge, owing to their high background concentrations. To effectively investigate the variation of nitrite/nitrate in vivo, in this study, we developed a15N-labelled nitrite/nitrate tracer analysis using LC-MS/MS following the derivatization with 2,3-diaminonaphthalene. This method allows for the determination of 15N-labelled nitrite/nitrate as 15N-2,3-naphthotriazole (15N-NAT) that can efficiently differentiate newly introduced nitrite/nitrate from the background nitrite/nitrate in biological matrices. We also investigated the contribution of background 14N-NAT isotopomers to 15N-NAT, which has long been overlooked in the literature. Our results indicated that the contribution of background 14N-NAT isotopomers to 15N-NAT is significant. Such contribution is constant (~2.2% under positive ion mode and 1.1% under negative ion mode), and does not depend upon the concentration of 14N-NAT or the sample matrix measured. An equation has been therefore developed, for the first time, to correct the contribution of background 14N-NAT isotopomers to 15N-NAT. With the proposed 15N-labelled nitrite/nitrate tracer analysis, the amount and percentage distribution of 15NO2- and 15NO3-, both in urine and feces, after oral administration of 15N-labelled nitrite/nitrate are clearly demonstrated. The excretions of 15NO2- and 15NO3- were significantly increased with the increasing dose implying that the dietary nitrite/nitrate intake is an important source in urine/feces. The present method allows for the simple, reliable and accurate quantification of 15NO2- and 15NO3-, and it should also be useful to trace the biotransformation of nitrite and nitrate in vivo.
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Naftalenos/farmacocinética , Nitratos/metabolismo , Nitritos/metabolismo , Isótopos de Nitrógeno/farmacocinética , Triazoles/farmacocinética , Administración Oral , Animales , Transporte Biológico , Biotransformación , Cromatografía Liquida , Heces , Radicales Libres , Masculino , Ratones , Ratones Endogámicos ICR , Naftalenos/orina , Espectrometría de Masas en Tándem , Triazoles/administración & dosificación , Triazoles/orinaRESUMEN
OBJECTIVES: 1-Methylnaphthalene (1-MN) is a constituent of polycyclic aromatic hydrocarbons, the chemicals that have become ubiquitous in the environment as result of natural and industrial process. This paper reports a study on the distribution and excretion of 1-MN in rats after single and repeated inhalation exposure to 1-MN vapor. MATERIAL AND METHODS: Male Wistar rats were exposed to 1-MN vapor at nominal concentrations of 50 mg/m3 or 200 mg/m3 in the dynamic inhalation chambers (TSE Systems Head Nose Only Exposure) for 6 h (single exposure) or 5 days (6 h/day, repeated exposure). Blood, urine and tissue samples were collected during and after the exposure. Blood, urine and tissue concentrations of 1-MN were estimated by gas chromatography using the headspace technique. RESULTS: The elimination of 1-MN from blood followed an open 2-compartment model. The concentration in rat tissues was dependent on the magnitude and time of exposure. After repeated exposure, the concentration 1-MN in tissue decreased in comparison to single exposure. The elimination of 1-MN with urine after single and repeated exposure to 1-MN occurred mainly in the samples collected during the first day of collection. CONCLUSIONS: 1-Methylnaphthalene was rapidly eliminated from the blood and tissues of animals exposed by inhalation to 1-MN. In repeated exposure, there was probably a significant increase of 1-MN metabolism in rats exposed to low and high 1-MN doses. Under conditions of repeated 1-MN exposure, no significant systemic 1-MN accumulation could be observed. Int J Occup Med Environ Health 2018;31(6):763-770.
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Exposición a Riesgos Ambientales/efectos adversos , Contaminantes Ambientales/efectos adversos , Contaminantes Ambientales/metabolismo , Exposición por Inhalación/efectos adversos , Naftalenos/efectos adversos , Naftalenos/metabolismo , Toxicocinética , Animales , Relación Dosis-Respuesta a Droga , Contaminantes Ambientales/sangre , Contaminantes Ambientales/orina , Masculino , Naftalenos/sangre , Naftalenos/orina , Ratas , Ratas WistarRESUMEN
Zebrafish (Danio rerio) water tank (ZWT) approach was investigated as an alternative model for metabolism studies based on six different experiments with four model compounds. Sibutramine was applied for the multivariate optimization of ZWT conditions, also for the comparison of the metabolism among ZWT, humans and mice, beyond for the role of CYP2B6 in ZWT. After the optimization, 18 fish and 168 hours of experiments is the minimum requirement for a relevant panel of biotransformation products. A comparison among the species resulted in the observation of the same hydroxylated metabolites, with differences in metabolites concentration ratio. However, the ZWT allowed tuning of the conditions to obtain a specific metabolic profile, depending on the need. In addition, by utilizing CYP2B6 inhibition, a relevant ZWT pathway for the demethylation of drugs was determined. The stereospecificity of the ZWT metabolism was investigated using selegiline and no racemization or inversion transformations were observed. Moreover, the investigation of metabolism of cannabimimetics was performed using JWH-073 and the metabolites observed are the same described for humans, except for the hydroxylation at the indol group, which was explained by the absence of CYP2C9 orthologs in zebrafish. Finally, hexarelin was used as a model to evaluate studies by ZWT for drugs with low stability. As a result, hexarelin displays a very fast metabolization in ZWT conditions and all the metabolites described for human were observed in ZWT. Therefore, the appropriate conditions, merits, and relevant limitations to conduct ZWT experiments for the investigation of drug metabolism are described.
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Preparaciones Farmacéuticas/metabolismo , Pez Cebra/metabolismo , Adulto , Animales , Antidepresivos/metabolismo , Antidepresivos/orina , Biotransformación , Ciclobutanos/metabolismo , Ciclobutanos/orina , Citocromo P-450 CYP2B6/metabolismo , Inhibidores del Citocromo P-450 CYP2B6/farmacología , Femenino , Humanos , Hidroxilación , Indoles/metabolismo , Indoles/orina , Masculino , Ratones , Modelos Animales , Naftalenos/metabolismo , Naftalenos/orina , Oligopéptidos/metabolismo , Oligopéptidos/orina , Preparaciones Farmacéuticas/orina , Selegilina/metabolismo , Selegilina/orina , Pez Cebra/orina , Proteínas de Pez Cebra/metabolismoRESUMEN
Naphthalene occurs together with polycyclic aromatic hydrocarbons (PAHs) at industrial workplaces and is ubiquitous in the environment. For biological monitoring of naphthalene exposures, up to now mainly 1- and 2-naphthol in urine have been used. Recently, we proposed 1,2-dihydroxynaphthalene (1,2-DHN) and the 1- and 2-naphthylmercapturic acid (1- and 2-NMA) as new urinary biomarkers to characterise a naphthalene exposure. In this study, in a collective of nine occupationally exposed workers handling with creosote the naphthalene metabolites 1,2-DHN, 1- and 2-NMA as well as 1- and 2-naphthol were analysed in order to evaluate the suitability of the different parameters for their application in biomonitoring studies. Additionally, air sampling was conducted to characterise the exposure in task related exposure situations at different workplaces. In the analysed 51 urine samples, 1,2-DHN was the main metabolite with concentrations ranging from 2.3 to 886⯵g/g creatinine (crea) (median 34⯵g/g crea). For the sum of 1- and 2-naphthol, concentrations in the range of 2.6-174⯵g/g crea (median 15⯵g/g crea) were observed. 1-NMA concentrations were in the range ofâ¯<â¯LOD-2.4⯵g/g crea (61% > LOD), while 2-NMA was not detected in the analysed urine samples. The biomarkers 1,2-DHN, 1- and 2-naphthol as well as 1-NMA showed significant correlations, which pointed out to naphthalene as the common exposure source. The poor correlations between naphthalene in the air and the biomarkers in urine may be a result of the varying exposure situations and may indicate not solely inhalative, but additional dermal uptake. 1,2-DHN was the most sensitive and, together with 1-NMA, the most specific parameter of the biological monitoring of naphthalene exposure at workplaces. Further studies with this parameter are needed for individuals at different workplaces as well as for persons of the general population without occupational PAH exposure to characterise 1,2-DHN levels as well as to establish their relationship with the naphthalene exposure.
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Contaminantes Ocupacionales del Aire/orina , Creosota/orina , Monitoreo del Ambiente/métodos , Exposición por Inhalación , Naftalenos/orina , Exposición Profesional , Acetilcisteína/análogos & derivados , Acetilcisteína/orina , Contaminantes Ocupacionales del Aire/efectos adversos , Biotransformación , Creosota/efectos adversos , Biomarcadores Ambientales , Humanos , Exposición por Inhalación/efectos adversos , Masculino , Naftalenos/efectos adversos , Naftoles/orina , Exposición Profesional/efectos adversos , Salud Laboral , Reproducibilidad de los Resultados , Medición de Riesgo , UrinálisisRESUMEN
BACKGROUND: `Herbal mixtures` containing synthetic cannabinoid receptor agonists (SCRAs) are promoted as legal alternative to marihuana and are easily available via the Internet. Keeping analytical methods for the detection of these SCRAs up-to-date is a continuous challenge for clinicians and toxicologists due to the high diversity of the chemical structures and the frequent emergence of new compounds. Since many SCRAs are extensively metabolized, analytical methods used for urine testing require previous identification of the major metabolites of each compound. OBJECTIVE: The aim of this study was to identify the in vivo major metabolites of nine SCRAs (AM- 694, AM-2201, JWH-007, JWH-019, JWH-203, JWH-307, MAM-2201, UR-144, XLR-11) for unambiguous detection of a drug uptake by analysis of urine samples. METHOD: Positive urine samples from patients of hospitals, detoxification and therapy centers as well as forensic-psychiatric clinics were analyzed by means of liquid chromatography-tandem mass spectrometry (LC-MS/MS) and liquid chromatography-quadrupole time-of-flight mass spectrometry (LCqToF- MS) for investigation of the major in vivo metabolites. RESULTS: For all investigated SCRAs, monohydroxylation, dihydroxylation and/or formation of the Nhexanoic/ pentanoic acid metabolites were among the most abundant metabolites detected in human urine samples. Substitution of the fluorine atom was observed to be an important metabolic reaction for compounds carrying an N-(5-fluoropentyl) side chain. N-Dealkylated metabolites were not detected in vivo. CONCLUSION: The investigated metabolites facilitate the reliable detection of drug uptake by analysis of urine samples. For distinction between uptake of the fluorinated and the non-fluorinated analogs, the N-(4-hydroxypentyl) metabolite of the non-fluorinated analog was identified as a useful analytical target and consumption marker.
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Agonistas de Receptores de Cannabinoides/orina , Indoles/orina , Detección de Abuso de Sustancias/métodos , Espectrometría de Masas en Tándem/métodos , Agonistas de Receptores de Cannabinoides/metabolismo , Cannabinoides/metabolismo , Cannabinoides/orina , Cromatografía Liquida/métodos , Humanos , Indoles/metabolismo , Naftalenos/metabolismo , Naftalenos/orina , Ácidos Pentanoicos/metabolismo , Ácidos Pentanoicos/orinaRESUMEN
Herein, we prepared a novel quartz crystal microbalance (QCM) sensor for synthetic cannabinoids (JWH-073, JWH-073 butanoic acid, JWH-018 and JWH-018 pentanoic acid,) detection. Firstly, the synthetic cannabinoid (SCs) imprinted (MIP) and non-imprinted (NIP) nanoparticles were synthesized by mini-emulsion polymerization system. The SCs-imprinted nanoparticles were first characterized by SEM, TEM, zeta-size and FTIR-ATR analysis and then were dropped onto the gold QCM surface. The SCs-imprinted QCM sensor was characterized by an ellipsometer, contact angle, and AFM. The limit of detection was found as 0.3, 0.45, 0.4, 0.2â¯pg/mL JWH-018, JWH-073, JWH-018 pentanoic acid and JWH-073 butanoic acid, respectively. The selectivity of the SCs-imprinted QCM sensor was shown by using JWH-018, JWH-018 pentanoic acid, JWH-073 and JWH-073 butanoic acid. According to the results, the SCs-imprinted QCM sensors show highly selective and sensitive in a broad range of synthetic cannabinoid concentrations (0.0005-1.0â¯ng/mL) in both aqueous and synthetic urine solutions.
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Cannabinoides/orina , Drogas Ilícitas/orina , Indoles/orina , Impresión Molecular/métodos , Naftalenos/orina , Polímeros/química , Tecnicas de Microbalanza del Cristal de Cuarzo/métodos , Humanos , Límite de Detección , Nanopartículas/química , Detección de Abuso de Sustancias/métodos , Propiedades de SuperficieRESUMEN
Each year, synthetic cannabinoids are occurring in high numbers on the illicit drug market but data obtained after controlled application are rare. The present study on pharmacokinetics in urine is part of a pilot study on adverse effects of JWH-018, which is one of the oldest and best known synthetic cannabinoids. Six subjects inhaled smoke from 2 and 3mg JWH-018. The drug and ten potential metabolites were analyzed in urine samples collected during 12h after inhalation by liquid chromatography-mass spectrometry (LC-MS/MS) without and with conjugate cleavage. The parent compound was not detectable, but 13 of its metabolites, all of which were conjugated. Concentrations of the predominant metabolite, JWH-018 pentanoic acid, were less than 5ng/ml, but in two subjects it was still detected up to 4 weeks after ingestion. Other major metabolites were 5- and 4-HOpentyl-JWH-018, JWH-073 butanoic acid and a hypothetically dihydroxylated and dehydrogenated metabolite of JWH-018. Occasionally, further hydroxylated metabolites were found. Generally, hydroxylated metabolites were detected in concentrations lower than 1ng/ml already 10h after inhalation. All concentrations were much lower than reported for urine samples of authentic JWH-018 users. The formation of the metabolite JWH-018 pentanoic acid was found to be slightly delayed, but its rather high concentrations and detection over several weeks after single dosing makes it a useful target for urine analysis. The different excretion of carboxylic acid and hydroxylated metabolites may aid in evaluation of time of use.
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Cannabinoides/orina , Indoles/orina , Naftalenos/orina , Eliminación Renal , Fumar Productos sin Tabaco , Biomarcadores/orina , Biotransformación , Butiratos/orina , Cannabinoides/administración & dosificación , Cannabinoides/síntesis química , Cannabinoides/farmacocinética , Cromatografía Liquida , Estudios Cruzados , Femenino , Humanos , Hidroxilación , Indoles/administración & dosificación , Indoles/síntesis química , Indoles/farmacocinética , Exposición por Inhalación , Masculino , Naftalenos/administración & dosificación , Naftalenos/síntesis química , Naftalenos/farmacocinética , Ácidos Pentanoicos/orina , Proyectos Piloto , Espectrometría de Masas en Tándem , Urinálisis , Adulto JovenRESUMEN
Exposure to Polycyclic Aromatic Hydrocarbons (PAHs) occurs by respiratory, digestive and dermal absorption. Biomonitoring takes all pathways into account but sensitive and specific biomarkers are required. Different gaseous PAHs metabolites were used due to their abundance in the atmospheric mixtures but none of them were selected as better biomarker than the others. To identify the best candidates for assessing occupational airborne exposure, relation between atmospheric levels of Naphtalene, Fluorene and Phenanthrene and urinary metabolites concentrations was studied in a carbon electrode workers group. Linear mixed effects models were built to select explanatory variables and estimate variance component. Urinary creatinine was a predictor of metabolites levels confirming the importance of diuresis for interpreting results. High significance of pre-shift sampling time combined with positive coefficients of post-shift indicated that urine should be sampled at the end of the workday in association with pre-shift urine to avoid misinterpretations. Among the 10 metabolites studied, urinary 2-hydroxyfluorene and 2-hydroxyphenanthrene showed the highest increase of variance explained by models after inclusion of individual atmospheric levels as explanatory variable. Priority could be given to 2-hydroxyfluorene due to higher excretion levels than 2-hydroxyphenanthrene.
Asunto(s)
Fluorenos/orina , Exposición por Inhalación/análisis , Naftalenos/orina , Exposición Profesional/análisis , Fenantrenos/orina , Adulto , Biomarcadores/orina , Humanos , Modelos Lineales , Estudios Longitudinales , Masculino , Persona de Mediana EdadRESUMEN
The knowledge of pharmacokinetic (PK) properties of synthetic cannabinoids (SCs) is important for interpretation of analytical results found for example in intoxicated individuals. In the absence of human data from controlled studies, animal models elucidating SC PK have to be established. Pigs providing large biofluid sample volumes were tested for prediction of human PK data. In this context, the metabolic fate of two model SCs, namely 4-ethylnaphthalen-1-yl-(1-pentylindol-3-yl)methanone (JWH-210) and 2-(4-methoxyphenyl)-1-(1-pentyl-indol-3-yl)methanone (RCS-4), was elucidated in addition to Δ9 -tetrahydrocannabinol (THC). After intravenous administration of the compounds, hourly collected pig urine was analyzed by liquid chromatography-high resolution mass spectrometry. The following pathways were observed: for JWH-210, hydroxylation at the ethyl side chain or pentyl chain and combinations of them followed by glucuronidation; for RCS-4, hydroxylation at the methoxyphenyl moiety or pentyl chain followed by glucuronidation as well as O-demethylation followed by glucuronidation or sulfation; for THC, THC glucuronidation, 11-hydroxylation, followed by carboxylation and glucuronidation. For both SCs, parent compounds could not be detected in urine in contrast to THC. These results were consistent with those obtained from human hepatocyte and/or human case studies. Urinary markers for the consumption of JWH-210 were the glucuronide of the N-hydroxypentyl metabolite (detectable for 3-4 h) and of RCS-4 the glucuronides of the N-hydroxypentyl, hydroxy-methoxyphenyl (detectable for at least 6 h), and the O-demethyl-hydroxy metabolites (detectable for 4 h). Copyright © 2016 John Wiley & Sons, Ltd.
Asunto(s)
Cannabinoides/orina , Dronabinol/orina , Drogas Ilícitas/orina , Indoles/orina , Naftalenos/orina , Psicotrópicos/orina , Porcinos/orina , Animales , Cannabinoides/metabolismo , Cromatografía Liquida/métodos , Dronabinol/metabolismo , Humanos , Drogas Ilícitas/metabolismo , Indoles/metabolismo , Naftalenos/metabolismo , Psicotrópicos/metabolismo , Detección de Abuso de Sustancias/métodos , Porcinos/metabolismo , Espectrometría de Masas en Tándem/métodosRESUMEN
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/métodosRESUMEN
One of the many issues of designer drugs of abuse like synthetic cannabinoids (SCs) such as JWH-018 is that details on their metabolism has yet to be fully elucidated and that multiple metabolites exist. The presence of isomeric compounds poses further challenges in their identification. Our group has previously shown the effectiveness of gas chromatography-electron ionization-tandem mass spectrometry (GC-EI-MS/MS) in the mass spectrometric differentiation of the positional isomers of the naphthoylindole-type SC JWH-081, and speculated that the same approach could be used for the metabolite isomers. Using JWH-018 as a model SC, the aim of this study was to differentiate the positional isomers of its hydroxyindole metabolites by GC-MS/MS. Standard compounds of JWH-018 and its hydroxyindole metabolite positional isomers were first analyzed by GC-EI-MS in full scan mode, which was only able to differentiate the 4-hydroxyindole isomer. Further GC-MS/MS analysis was performed by selecting m/z 302 as the precursor ion. All four isomers produced characteristic product ions that enabled the differentiation between them. Using these ions, MRM analysis was performed on the urine of JWH-018 administered mice and determined the hydroxyl positions to be at the 6-position on the indole ring. GC-EI-MS/MS allowed for the regioisomeric differentiation of the hydroxyindole metabolite isomers of JWH-018. Furthermore, analysis of the fragmentation patterns suggests that the present method has high potential to be extended to hydroxyindole metabolites of other naphthoylindole type SCs in identifying the position of the hydroxyl group on the indole ring. Copyright © 2016 John Wiley & Sons, Ltd.
Asunto(s)
Indoles/química , Naftalenos/química , Animales , Cannabinoides/metabolismo , Cromatografía de Gases y Espectrometría de Masas/métodos , Humanos , Drogas Ilícitas , Indoles/orina , Isomerismo , Masculino , Ratones , Naftalenos/orina , Espectrometría de Masas en Tándem/métodosRESUMEN
PURPOSE: Although exposure to polycyclic aromatic hydrocarbons (PAHs) is common in both environmental and occupational settings, few studies have compared PAH exposure among people with different professions. The purpose of this study was to investigate the variations in recent PAH exposure among different occupational groups over time using national representative samples. METHOD: The study population consisted of 4162 participants from the 2001 to 2008 National Health and Nutrition Examination Survey, who had both urinary PAH metabolites and occupational information. Four corresponding monohydroxy-PAH urine metabolites: naphthalene (NAP), fluorene (FLUO), phenanthrene (PHEN), and pyrene (PYR) among seven broad occupational groups were analyzed using weighted linear regression models, adjusting for creatinine levels, sociodemographic factors, smoking status, and sampling season. RESULTS: The overall geometric mean concentrations of NAP, FLUO, PHEN, and PYR were 6927, 477, 335, and 87 ng/L, respectively. All four PAH metabolites were elevated in the "extractive, construction, and repair (ECR)" group, with 21-42 % higher concentrations than those in the reference group of "management." Similar trends were seen in the "operators, fabricators, and laborers (OFL)" group for FLUO, PHEN, and PYR. In addition, both "service" and "support" groups had elevated FLUO. Significant (p < 0.001) upward temporal trends were seen in NAP and PYR, with an approximately 6-17 % annual increase, and FLUO and PHEN remained relatively stable. Race and socioeconomic status show independent effects on PAH exposure. CONCLUSIONS: Heterogeneous distributions of urinary PAH metabolites among people with different job categories exist at the population level. The upward temporal trends in NAP and PYR warrant reduction in PAH exposure, especially among those with OFL and ECR occupations.
Asunto(s)
Exposición Profesional/análisis , Ocupaciones/estadística & datos numéricos , Hidrocarburos Policíclicos Aromáticos/orina , Adolescente , Adulto , Estudios Transversales , Femenino , Fluorenos/orina , Humanos , Modelos Lineales , Masculino , Naftalenos/orina , Fenantrenos/orina , Pirenos/orina , Grupos Raciales/estadística & datos numéricos , Factores Socioeconómicos , Factores de Tiempo , Estados Unidos/epidemiología , Adulto JovenRESUMEN
Orteronel is newly identified as a selective 17,20-lyase inhibitor for an agent for castration resistant prostate cancer. The absorption and disposition of [(14)C]orteronel were investigated in rats and monkeys. Orteronel was extensively excreted into rat and monkey urine in an unchanged form after oral administration. The unbound based renal clearances in rats and monkeys were greater than the respective glomerular filtration rates (GFR), suggesting that urinary tubular secretion plays an important role in the renal excretion of orteronel. Therefore, the uptake of [(14)C]orteronel was investigated using rat kidney slices to estimate the contribution of carrier-mediated transport on the urinary tubular secretion. The uptake study using rat kidney slices suggested that the transport of orteronel from the blood circulation to the kidney was mediated by a digoxin sensitive transport system represented by Oatp4c1 and non-saturable components. Furthermore, the saturable component accounted for a limited fraction of the total renal uptake by rat kidney slices. These results suggested that non-saturable uptake mainly contributed to the renal excretion of orteronel in rats.