RESUMO
Heterocyclic aromatic amines (HCAA) are listed by the US Food and Drug Administration (FDA) as harmful or potentially harmful constituents of tobacco smoke. However, quantifying HCAA exposure is challenging. In this study, we developed a sensitive, precise, and accurate isotope dilution, liquid chromatography-tandem mass spectrometry (LC-MS/MS) method to quantify urinary HCAAs in smokers and nonsmokers. The high-throughput robotic sample preparation system could handle a throughput of over 300 samples per day, while maintaining intra-day and inter-day imprecision and bias ≤10 %. The limits of detection of carcinogenic HCAAs ranged from 0.31 to 0.83 pg/mL. The validated method was applied to measure HCAAs in urine collected from smokers and non-smokers. This sensitive and efficient analytical method is ideal to support large-scale biomonitoring studies of HCAA exposure. Graphical Abstract LC/MS/MS and robotic sample preparation system for urinary HCAA analysis.
Assuntos
Aminas/urina , Compostos Heterocíclicos/urina , Ensaios de Triagem em Larga Escala/métodos , Robótica , Fumar/urina , Cromatografia Líquida , Desenho de Equipamento , Ensaios de Triagem em Larga Escala/instrumentação , Humanos , Técnicas de Diluição do Indicador , Limite de Detecção , Espectrometria de Massas em TandemRESUMO
2-Amino-9H-pyrido[2,3-b]indole (AαC) and 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) are carcinogenic heterocyclic aromatic amines (HAAs) formed during the combustion of tobacco and during the high-temperature cooking of meats. Human enzymes biotransform AαC and PhIP into reactive metabolites, which can bind to DNA and lead to mutations. We sought to understand the relative contribution of smoking and diet to the exposure of AαC and PhIP, by determining levels of AαC, its ring-oxidized conjugate 2-amino-9H-pyrido[2,3-b]indole-3-yl sulfate (AαC-3-OSO3H), and PhIP in urine of smokers on a free-choice diet before and after a six week tobacco smoking cessation study. AαC and AαC-3-OSO3H were detected in more than 90% of the urine samples of all subjects during the smoking phase. The geometric mean levels of urinary AαC during the smoking and cessation phases were 24.3 pg/mg creatinine and 3.2 pg/mg creatinine, and the geometric mean levels of AαC-3-OSO3H were 47.3 pg/mg creatinine and 3.7 pg/mg creatinine. These decreases in the mean levels of AαC and AαC-3-OSO3H were, respectively, 87% and 92%, after the cessation of tobacco (P < 0.0007). However, PhIP was detected in <10% of the urine samples, and the exposure to PhIP was not correlated to smoking. Epidemiological studies have reported that smoking is a risk factor for cancer of the liver and gastrointestinal tract. It is noteworthy that AαC is a hepatocellular carcinogen and induces aberrant crypt foci, early biomarkers of colon cancer, in rodents. Our urinary biomarker data demonstrate that tobacco smoking is a significant source of AαC exposure. Further studies are warranted to examine the potential role of AαC as a risk factor for hepatocellular and gastrointestinal cancer in smokers.
Assuntos
Aminoácidos Aromáticos/química , Aminoácidos Aromáticos/urina , Aminopiridinas/química , Compostos Heterocíclicos/urina , Indóis/química , Fumar , Aminopiridinas/urina , Cromatografia Líquida , Compostos Heterocíclicos/química , Humanos , Indóis/urina , Limite de Detecção , Espectrometria de Massas , Estrutura Molecular , Abandono do Hábito de FumarRESUMO
2-Amino-1-methylimidazo[4,5-b]pyridine (PhIP) and 2-amino-3,8-dimethylimidazo[4,5-f]quinoxaline (MeIQx) are carcinogenic heterocyclic aromatic amines (HAAs) formed in well-done cooked meats. Chemicals that induce cytochrome P450 (P450) 1A2, a major enzyme involved in the bioactivation of HAAs, also form in cooked meat. Therefore, well-done cooked meat may pose an increase in cancer risk because it contains both inducers of P450 1A2 and procarcinogenic HAAs. We examined the influence of components in meat to modulate P450 1A2 activity and the metabolism of PhIP and MeIQx in volunteers during a 4 week feeding study of well-done cooked beef. The mean P450 1A2 activity, assessed by caffeine metabolic phenotyping, ranged from 6.3 to 7.1 before the feeding study commenced and from 9.6 to 10.4 during the meat feeding period: the difference in means was significant (P < 0.001). Unaltered PhIP, MeIQx, and their P450 1A2 metabolites, N(2)-(ß-1-glucosiduronyl)-2-(hydroxyamino)-1-methyl-6-phenylimidazo[4,5-b]pyridine (HON-PhIP-N(2)-Gl); N3-(ß-1-glucosiduronyl)-2-(hydroxyamino)-1-methyl-6-phenylimidazo[4,5-b]pyridine (HON-PhIP-N3-Gl); 2-amino-3-methylimidazo-[4,5-f]quinoxaline-8-carboxylic acid (IQx-8-COOH); and 2-amino-8-(hydroxymethyl)-3-methylimidazo[4,5-f]quinoxaline (8-CH2OH-IQx) were measured in urine during days 2, 14, and 28 of the meat diet. Significant correlations were observed on these days between the levels of the unaltered HAAs and their oxidized metabolites, when expressed as percent of dose ingested or as metabolic ratios. However, there was no statistically significant correlation between the caffeine P450 1A2 phenotype and any urinary HAA biomarker. Although the P450 1A2 activity varied by greater than 20-fold among the subjects, there was a large intraindividual variation of the P450 1A2 phenotype and inconsistent responses to inducers of P450 1A2. The coefficient of variation of the P450 1A2 phenotype within-individual ranged between 1 to 112% (median = 40%) during the entire course of the study. The caffeine metabolic phenotype for P450 1A2 was a poor predictor of oxidative urinary metabolites of PhIP and MeIQx and may not be a reliable measure to assess the role of HAAs in cancer risk.
Assuntos
Aminas/metabolismo , Citocromo P-450 CYP1A2/genética , Citocromo P-450 CYP1A2/metabolismo , Compostos Heterocíclicos/metabolismo , Fenótipo , Aminas/urina , Animais , Cafeína/metabolismo , Bovinos , Cromatografia Líquida de Alta Pressão , Culinária , Citocromo P-450 CYP1A2/análise , Ingestão de Alimentos , Feminino , Voluntários Saudáveis , Compostos Heterocíclicos/urina , Ensaios de Triagem em Larga Escala , Humanos , Masculino , CarneRESUMO
The renal localization of gallium-67 or gallium-68 ((67/68)Ga)-labeled low molecular weight (LMW) probes such as peptides and antibody fragments constitutes a problem in targeted imaging. Wu et al. previously showed that (67)Ga-labeled S-2-(4-isothiocyanatobenzyl)-1,4,7-triazacyclononane-1,4,7-triacetic acid (SCN-Bz-NOTA)-conjugated methionine ((67)Ga-NOTA-Met) was rapidly excreted from the kidney in urine following lysosomal proteolysis of the parental (67)Ga-NOTA-Bz-SCN-disulfide-stabilized Fv fragment (Bioconjugate Chem., (1997) 8, 365-369). In the present study, a new (67/68)Ga-labeling reagent for LMW probes that liberates (67/68)Ga-NOTA-Met was designed, synthesized, and evaluated using longer-lived (67)Ga in order to reduce renal radioactivity levels. We employed a methionine-isoleucine (MI) dipeptide bond as the cleavable linkage. The amine residue of MI was coupled with SCN-Bz-NOTA for (67)Ga-labeling, while the carboxylic acid residue of MI was derivatized to maleimide for antibody conjugation in order to synthesize NOTA-MI-Mal. A Fab fragment of the anti-Her2 antibody was thiolated with iminothiolane, and NOTA-MI-Mal was conjugated with the antibody fragment by maleimide-thiol chemistry. The Fab fragment was also conjugated with SCN-Bz-NOTA (NOTA-Fab) for comparison. (67)Ga-NOTA-MI-Fab was obtained at radiochemical yields of over 95% and was stable in murine serum for 24 h. In the biodistribution study using normal mice, (67)Ga-NOTA-MI-Fab registered significantly lower renal radioactivity levels from 1 to 6 h postinjection than those of (67)Ga-NOTA-Fab. An analysis of urine samples obtained 6 h after the injection of (67)Ga-NOTA-MI-Fab showed that the majority of radioactivity was excreted as (67)Ga-NOTA-Met. In the biodistribution study using tumor-bearing mice, the tumor to kidney ratios of (67)Ga-NOTA-MI-Fab were 4 times higher (6 h postinjection) than those of (67)Ga-NOTA-Fab. Although further studies including the structure of radiometabolites and/or cleavable linkages are required, the results of the present study indicate that the current chemical design is applicable to the development of (67)Ga-labeled Fabs for low renal radioactivity levels.
Assuntos
Compostos Heterocíclicos/metabolismo , Rim/efeitos da radiação , Lisossomos/metabolismo , Metionina/química , Peptídeos/química , Peptídeos/metabolismo , Proteólise , Animais , Linhagem Celular Tumoral , Estabilidade de Medicamentos , Radioisótopos de Gálio , Compostos Heterocíclicos/química , Compostos Heterocíclicos/farmacocinética , Compostos Heterocíclicos/urina , Compostos Heterocíclicos com 1 Anel , Fragmentos Fab das Imunoglobulinas/química , Marcação por Isótopo , Rim/metabolismo , Masculino , Camundongos , Peso Molecular , Radioatividade , Relação Estrutura-AtividadeRESUMO
Plerixafor is a selective antagonist of CXCR4 used for mobilization of hematopoietic stem cells (HSCs) for autologous stem cell transplantation (SCT) in patients with multiple myeloma (MM) and non-Hodgkin lymphoma (NHL). This Phase 1 open-label study in healthy subjects was conducted to evaluate the pharmacokinetic characteristics of plerixafor in subjects with renal impairment. All subjects received a single 0.24 mg/kg subcutaneous dose of plerixafor. Subjects were stratified into 4 cohorts based on creatinine clearance determined from a 24-hour urine collection: control (>90 mL/min), mild renal impairment (51-80 mL/min), moderate renal impairment (31-50 mL/min), and severe renal impairment (<31 mL/min, not requiring dialysis). Eleven female subjects (48%) and 12 male subjects (52%), ranging in age from 35 to 73 years, were enrolled. Plerixafor clearance was reduced in subjects with renal impairment and was positively correlated with creatinine clearance. The mean area under the concentration- versus-time curve from time 0 to 24 hours postdose of plerixafor in subjects with mild, moderate, and severe renal impairment was 7%, 32%, and 39% higher, respectively, than that in subjects with normal renal function. Renal impairment had no effect on maximal plasma concentrations. The safety profile was similar among subjects with renal impairment and controls. No renal impairment-related trends in the incidence of adverse events were apparent. A plerixaflor dose reduction to 160 microg/kg in patients with a creatinine clearance value Assuntos
Compostos Heterocíclicos/farmacocinética
, Receptores CXCR4/antagonistas & inibidores
, Insuficiência Renal/metabolismo
, Adulto
, Idoso
, Benzilaminas
, Estudos de Coortes
, Creatinina/metabolismo
, Creatinina/urina
, Ciclamos
, Feminino
, Mobilização de Células-Tronco Hematopoéticas
, Compostos Heterocíclicos/efeitos adversos
, Compostos Heterocíclicos/sangue
, Compostos Heterocíclicos/urina
, Humanos
, Testes de Função Renal
, Masculino
, Taxa de Depuração Metabólica
, Pessoa de Meia-Idade
, Insuficiência Renal/sangue
, Insuficiência Renal/fisiopatologia
, Insuficiência Renal/urina
RESUMO
A rapid and simple method for separation and detection of six heterocyclic aromatic amines (2-amino-1-methyl-6-phenylimidazo [4,5-b]-pyridine, 2-amino-1-methyl-imidazo [4,5-f]-quinoline, 2-amino-3,8-dimethyl-imidazo [4,5-f]-quinoxaline, 2-amino-3,7,8-trimethyl-imidazo [4,5-f]-quinoxaline, 2-amino-3,4,8-trimethyl-imidazo [4,5-f]-quinoxaline, and 2-amino-3,4-dimethyl-imidazo [4,5-f]-quinoline) in human urine samples is proposed to reflect daily intake and recent HAAs exposure. This method comprises previous clean-up and preconcentration of the analytes on Strata-X reversed phase extraction cartridges followed by capillary liquid chromatography (CLC) and evaporative light-scattering detection (ELSD). A mobile phase of acetonitrile and ammonium acetate 35 mM at pH 5.15 through a gradient of composition and a flow rate of 15 microL min(-1) resulted in good separations of the analytes. Temperature and gas pressure were optimized for detection. The CLC-ELSD allows the separation and quantification of HAAs with good resolution, precision, and sensitivity. The usefulness of the proposed method was demonstrated by the analysis of synthetic and natural human urine samples spiked with different concentration levels of heterocyclic amines.
Assuntos
Aminas/urina , Cromatografia Líquida , Compostos Heterocíclicos/urina , Espalhamento de Radiação , Humanos , Luz , Extração em Fase SólidaRESUMO
A novel method for the analysis of Gadolinium-based contrast agents in complex clinical matrices is presented. Three commonly applied ionic contrast agents for magnetic resonance imaging were separated by CE and detected by ESI-MS. Blank urine samples were spiked with Dotarem (Gd-DOTA, Gadolinium-1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid), Magnevist (Gd-DTPA, Gadolinium-diethylenetriaminepentaacetic acid) and Multihance (Gd-BOPTA, Gadolinium-benzyloxymethyl-diethylenetriaminepentaacetic acid) to determine the recovery rates. The figures of merit were determined with LODs as low as 2.0 x 10(-7) mol/L for Gd-DOTA, 5.0 x 10(-7) mol/L for Gd-DTPA and 1.0 x 10(-6) mol/L for Gd-BOPTA. The respective LOQs were 6.6 x 10(-7) mol/L for Gd-DOTA, 1.5 x 10(-6) mol/L for Gd-DTPA and 3.3 x 10(-6) mol/L for Gd-BOPTA. The linear working range comprised two orders of magnitude starting at the LOQ, with regression coefficients of R > or = 0.999 for all investigated analytes. Using this CE-MS method, Gd-DOTA was quantified in seven urine samples obtained at different times after delivery from a volunteer magnetic resonance imaging patient who was treated with Dotarem. Additionally, total Gd concentrations were determined by means of ICP-optical emission spectroscopy to validate the CE-MS data. To compensate for dietary dilution effects of the urine samples, creatinine was determined by HPLC with UV/Vis absorption detection. Gd-DOTA concentrations were normalized to urinary creatinine, illustrating the fast excretion kinetics of Gd-DOTA.
Assuntos
Meios de Contraste/análise , Meios de Contraste/química , Eletroforese Capilar/métodos , Imageamento por Ressonância Magnética , Espectrometria de Massas/métodos , Adulto , Gadolínio DTPA/química , Gadolínio DTPA/urina , Compostos Heterocíclicos/química , Compostos Heterocíclicos/urina , Humanos , Aumento da Imagem , Cinética , Masculino , Meglumina/análogos & derivados , Meglumina/química , Meglumina/urina , Compostos Organometálicos/química , Compostos Organometálicos/urinaRESUMO
Cigarette smoking significantly increases the risk of cancer and cardiovascular diseases as well as premature death. Aromatic amines (AAs) such as o-toluidine, 2-aminonaphthalene and 4-aminobiphenyl are found in cigarette smoke and are well-established human bladder carcinogens presumably acting via the formation of DNA adducts. These amines may be metabolized in the liver to acetylated or glucuronidated forms or oxidized to a hydroxylamine which may react with protein and DNA to form adducts. Free, acetylated and glucuronidated AAs are excreted in urine and can be measured as exposure biomarkers. Using isotope dilution GC-MS/MS, our laboratory quantifies six urinary AAs that are known or suspected carcinogens-o-toluidine, 2,6-dimethylaniline, o-anisidine, 1-aminonaphthalene, 2-aminonaphthalene and 4-aminobiphenyl-for large population studies such as the National Health and Nutrition Examination Survey (NHANES). We also monitor two additional corresponding structural isomers-2-aminobiphenyl and 3-aminobiphenyl-to verify isomer separation. A new and improved automated sample preparation method was developed to quantify these AAs, in which, sample cleanup was done via Supported Liquid Extraction (SLE+ ISOLUTE®) on a Hamilton STAR™ workstation. This automated method increased sample throughput by reducing sample cleanup time from 8 to 4 h while maintaining precision (intra and inter-run coefficient of variation <7%) and accuracy (±17%). Recent improvements in our GC/MS method have enhanced our assay sensitivity and specificity, resulting in longer analytical column life and maintaining or reducing the limit of detection for all six analytes. Indigo ASCENTTM software (3.7.1, Indigo BioAutomation, Inc.) is used for peak integration, calibration and quantification. A streamlined sample data flow was created in parallel with the automated method, in which samples can be tracked from receiving to final laboratory information management system output with minimal human intervention, minimizing potential human error. This newly validated, automated method and sample data flow are currently applied in biomonitoring of AAs in the US noninstitutionalized population NHANES 2013-2014 cycle.
Assuntos
Aminas/urina , Carcinógenos/análise , Fumar Cigarros/urina , Cromatografia Gasosa-Espectrometria de Massas/métodos , Compostos Heterocíclicos/urina , Espectrometria de Massas em Tandem , Automação Laboratorial , Biomarcadores/urina , Calibragem , Fumar Cigarros/efeitos adversos , Cromatografia Gasosa-Espectrometria de Massas/normas , Humanos , Técnicas de Diluição do Indicador , Exposição por Inalação/efeitos adversos , Limite de Detecção , Padrões de Referência , Reprodutibilidade dos Testes , Espectrometria de Massas em Tandem/normas , Poluição por Fumaça de Tabaco/efeitos adversos , Urinálise , Fluxo de TrabalhoRESUMO
A hollow-fibre supported liquid membrane (HF-SLM) extraction method has been developed for determination of 11 heterocyclic aromatic amines (HCAs) in human urine samples by using high performance liquid chromatography (HPLC) equipped with an ultraviolet (UV) absorbance detector. These compounds were extracted from an alkaline urine sample (donor phase) into the organic solvent residing in the pores of a polypropylene hollow fibre and then back extracted into an acidic solution (acceptor phase) inside the lumen of the hollow fibre. After extraction, HCAs were analyzed by injecting the analyte enriched acceptor phase into the HPLC. The analyte enrichment factors ranged between 241 and 339 obtained in a 90 min extraction time, and method detection limits (MDL) ranged between 0.1 and 0.5 microg L(-1) with relative standard deviation (RSD) values between 3.4% and 11%. The extraction technique employed in this work is easy to use and rapid as it involves only a few minutes manipulation of each sample. It is the most economical sample preparation/preconcentration technique to our knowledge as compared to other microextraction techniques.
Assuntos
Aminas/urina , Cromatografia Líquida de Alta Pressão/métodos , Compostos Heterocíclicos/urina , Adulto , Humanos , Masculino , Espectrofotometria UltravioletaRESUMO
A high through-put miniaturised separation-quantification method for the heterocyclic aromatic amine 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) in urine was developed. The limit of detection was of 0.65 fmol (0.14 pg) injected or 65 pM. Heterocyclic aromatic amines are mutagenic and carcinogenic compounds formed at low levels in protein-rich food during cooking. Due to the low concentrations and the high complexity of the matrix in which they exist (food, blood, and urine), and the often small sample volumes (capillary blood; urine, blood and milk from small animals), very sensitive and selective analytical methods are required for their detection. Miniaturization was accomplished by micro solid-phase extraction in capillaries with blue chitin as solid-phase, coupled on-line (in-capillary) to capillary electrophoresis with nanospray tandem mass spectrometric detection. This new technique provided a total analysis time of only 15 min, including extraction and separation, together with low sample and solvent consumption. Blue chitin showed high tolerance towards the urine matrix. Urine collected 12h after consumption of fried chicken contained 1.8 nmol L(-1) (0.40 pg microL(-1)) of PhIP.
Assuntos
Aminas/urina , Compostos Heterocíclicos/urina , Eletroforese Capilar/métodos , Feminino , Humanos , Espectrometria de Massas/métodos , Estrutura Molecular , Reprodutibilidade dos TestesRESUMO
PURPOSE: To describe the clinical manifestations of presumed gadolinium toxicity in patients with normal renal function. MATERIALS AND METHODS: Participants were recruited from two online gadolinium toxicity support groups. The survey was anonymous and individuals were instructed to respond to the survey only if they had evidence of normal renal function, evidence of gadolinium in their system beyond 30days of this MRI, and no pre-existent clinical symptoms and/or signs of this type. RESULTS: 42 subjects responded to the survey (age: 28-69, mean 49.1±22.4years). The most common findings were: central pain (n=15), peripheral pain (n=26), headache (n=28), and bone pain (n=26). Only subjects with distal leg and arm distribution described skin thickening (n=22). Clouded mentation and headache were the symptoms described as persistent beyond 3months in 29 subjects. Residual disease was present in all patients. Twenty-eight patients described symptoms following administration of one brand of Gadolinium-Based Contrast Agent (GBCA), 21 after a single GBCA administration and 7 after multiple GBCA administrations, including: gadopentetate dimeglumine, n=9; gadodiamide, n=4; gadoversetamide, n=4; gadobenate dimeglumine, n=4; gadobutrol, n=1; gadoteridol, n=2; and unknown, n=4. CONCLUSIONS: Gadolinium toxicity appears to arise following GBCA administration, which appears to contain clinical features seen in Nephrogenic Systemic Fibrosis, but also features not observed in that condition.
Assuntos
Meios de Contraste/efeitos adversos , Gadolínio/efeitos adversos , Imageamento por Ressonância Magnética , Adulto , Idoso , Feminino , Gadolínio/urina , Gadolínio DTPA/efeitos adversos , Gadolínio DTPA/urina , Compostos Heterocíclicos/efeitos adversos , Compostos Heterocíclicos/urina , Humanos , Masculino , Meglumina/efeitos adversos , Meglumina/análogos & derivados , Meglumina/urina , Pessoa de Meia-Idade , Compostos Organometálicos/efeitos adversos , Compostos Organometálicos/urina , Dor/induzido quimicamente , Estudos ProspectivosRESUMO
OBJECTIVES: Gadolinium-based contrast agents (GBCAs) have been used for years for magnetic resonance imaging examinations. Because of their rapid blood clearance, they were considered as very safe products until some of them were shown to induce nephrogenic systemic fibrosis in patients with renal failure and hypersignals on T1-weighted unenhanced brain scans of patients with normal renal function. To date, these adverse effects have been related almost exclusively to the use of low-stability linear agents, which are more prone to release free gadolinium. The aim of the present meta-analysis was to ascertain the existence of a deep compartment for gadolinium storage in the body and to assess whether all the GBCAs present the same toxicokinetic profile. MATERIALS AND METHODS: Applying a systematic literature search methodology, all clinical and preclinical studies reporting time-dependent plasma concentrations and renal excretion data of gadolinium were identified and analyzed. Since the individual data were not available, the analysis focused on the average values per groups of subjects or animals, which had received a given GBCA at a given dose. The rate constants of the distribution phase (α), rapid elimination phase (ß), and residual excretion phase (γ) of gadolinium were determined in each group from the plasma concentration (Cp) time curves and the relative urinary excretion rate (rER) time curves, taking the 2-hour time point as a reference. Moreover, as bone may represent a reservoir for long-term gadolinium accumulation and slow release into the blood stream, the time curves of the relative concentration in the bone (rCB) of Gd-labeled GBCAs in mice or rats were analyzed taking day 1 concentrations as a reference. The ratio of gadolinium concentrations in the bone marrow (CBM) as compared with the bone (CB) was also calculated. RESULTS: The relative urinary excretion rate (rER) plots revealed a prolonged residual excretion phase of gadolinium in healthy volunteers, consistent with the existence of a deep compartment of distribution for the GBCAs. The rate constant γ of gadoterate meglumine (0.107 hour) is 5 times higher than that of the linear agents (0.020 ± 0.008 hour), indicating a much faster blood clearance for the macrocyclic GBCA. Similar results were obtained in the preclinical studies. A strong correlation was shown between the γ values of the different products and their respective thermodynamic stability constants (Ktherm). Greater clearance rates of Gd from murine bone were also found after gadoterate meglumine or gadoteridol injection (0.131-0.184 day) than after administration of the linear agents (0.004-0.067 day). The concentrations of Gd in the bone marrow (CBM) from animals exposed to either gadoterate meglumine or gadodiamide are higher than those in the bone (CB) for at least 24 hours. Moreover, the ratio of concentrations (CBM/CB) at 4 hours is significantly lower with the former agent than the latter (1.9 vs 6.5, respectively). CONCLUSIONS: Using a nonconventional pharmacokinetic approach, we showed that gadoterate meglumine undergoes a much faster residual excretion from the body than the linear GBCAs, a process that seems related to the thermodynamic stability of the different chelates. Gadolinium dissociation occurs in vivo for some linear chelates, a mechanism that may explain their long-term retention and slow release from bone. Potential consequences in terms of bone toxicity warrant further investigations.
Assuntos
Meios de Contraste/farmacocinética , Gadolínio DTPA/farmacocinética , Compostos Heterocíclicos/farmacocinética , Meglumina/farmacocinética , Compostos Organometálicos/farmacocinética , Animais , Meios de Contraste/metabolismo , Gadolínio/sangue , Gadolínio/farmacocinética , Gadolínio/urina , Gadolínio DTPA/sangue , Gadolínio DTPA/urina , Compostos Heterocíclicos/sangue , Compostos Heterocíclicos/urina , Humanos , Meglumina/sangue , Meglumina/urina , Taxa de Depuração Metabólica , Camundongos , Modelos Animais , Compostos Organometálicos/sangue , Compostos Organometálicos/urina , Ratos , Valores de Referência , Distribuição TecidualRESUMO
Humans are exposed to a large number of environmental chemicals in their daily life, many of which are readily detectable in blood or urine. It remains uncertain if these chemicals can cause adverse health effects when present together at low doses. In this study we have tested whether a mixture of 27 chemicals administered orally to juvenile male rats for three months could leave a pathophysiological footprint. The mixture contained metals, perfluorinated compounds, PCB, dioxins, pesticides, heterocyclic amines, phthalate, PAHs and others, with a combined dose of 0.16 (Low dose), 0.47 (Mid dose) or 1.6 (High dose) mg/kg bw/day. The lowest dose was designed with the aim of obtaining plasma or urine concentrations in rats at levels approaching those observed in humans. Some single congeners were administered at doses representative of combined doses for chemical groups. With this baseline, we found effects on weight, histology and gene expression in the liver, as well as changes to the blood plasma metabolome in all exposure groups, including low-dose. Additional adverse effects were observed in the higher dosed groups, including enlarged kidneys and alterations to the metabolome. No significant effects on reproductive parameters were observed.
Assuntos
Dioxinas/toxicidade , Poluentes Ambientais/toxicidade , Compostos Heterocíclicos/toxicidade , Metais/toxicidade , Praguicidas/toxicidade , Ácidos Ftálicos/toxicidade , Bifenilos Policlorados/toxicidade , Animais , Peso Corporal/efeitos dos fármacos , Dioxinas/sangue , Dioxinas/urina , Poluentes Ambientais/sangue , Poluentes Ambientais/urina , Perfilação da Expressão Gênica , Regulação da Expressão Gênica , Compostos Heterocíclicos/sangue , Compostos Heterocíclicos/urina , Humanos , Rim/efeitos dos fármacos , Rim/metabolismo , Rim/patologia , Fígado/efeitos dos fármacos , Fígado/metabolismo , Fígado/patologia , Masculino , Metaboloma , Metais/sangue , Metais/urina , Praguicidas/sangue , Praguicidas/urina , Fosfolipídeos/sangue , Fosfolipídeos/urina , Ácidos Ftálicos/sangue , Ácidos Ftálicos/urina , Bifenilos Policlorados/sangue , Bifenilos Policlorados/urina , Ratos , Baço/efeitos dos fármacos , Baço/metabolismo , Baço/patologiaRESUMO
Heterocyclic amines (HCAs) and polycyclic aromatic hydrocarbons (PAHs) have been established as carcinogenic chemicals in Western diet. This study was performed to estimate HCA exposure levels in Korean daily life and to assess the ability of Chlorella vulgaris to detoxify carcinogenic HCAs in a randomized, double blind, placebo-controlled crossover study with chlorella supplement (N=6, all females, age: 27.17±7.73yr) for 2 weeks. We analyzed HCAs in hydrolyzed urine specimens using LC/TOF-MS. As results, urinary levels of MeIQx, PhIP, and IQx-8-COOH were 323.36±220.11ng/L, 351.59±254.93ng/L, and 130.85±83.22ng/L, respectively. Effects of chlorella to reduce urinary MeIQx were marginally significant (before, 430±226.86pg/mL vs. after, 174.45±101.65pg/mL: 0.05
Assuntos
Aminas/urina , Carcinógenos/análise , Chlorella vulgaris , Suplementos Nutricionais , Compostos Heterocíclicos/urina , Adulto , Povo Asiático , Estudos Cross-Over , Feminino , Humanos , Pirenos/urina , Adulto JovemRESUMO
The extensive use of environmental phenols (e.g., bisphenol A) and heterocyclic aromatic compounds (e.g., benzothiazole) in consumer products as well as widespread exposure of humans to these compounds have been well documented. Biomonitoring studies have used urinary measurements to assess exposures, based on the assumption that these chemicals are metabolized and eliminated in urine. Despite the fact that some of these chemicals are moderately lipophilic, the extent of their accumulation in adipose fat tissues has not been convincingly demonstrated. In this study, human adipose fat samples (N=20) collected from New York City, USA, were analyzed for the presence of environmental phenols, including bisphenol A (BPA), benzophenone-3 (BP-3), triclosan (TCS), and parabens, as well as heterocyclic aromatic compounds, including benzotriazole (BTR), benzothiazole (BTH), and their derivatives. BPA and TCS were frequently detected in adipose tissues at concentrations (geometric mean [GM]: 3.95ng/g wet wt for BPA and 7.21ng/g wet wt for TCS) similar to or below the values reported for human urine. High concentrations of BP-3 were found in human adipose tissues (GM: 43.4; maximum: 4940ng/g wet wt) and a positive correlation between BP-3 concentrations and donor's age was observed. The metabolite of parabens, p-hydroxybenzoic acid (p-HB), also was found at elevated levels (GM: 4160; max.: 17,400ng/g wet wt) and a positive correlation between donor's age and sum concentration of parabens and p-HB were found. The GM concentrations of BTR and BTH in human adipose tissues were below 1ng/g, although the methylated forms of BTR (i.e., TTR and XTR) and the hydrated form of BTH (i.e., 2-OH-BTH) were frequently detected in adipose samples, indicating widespread exposure to these compounds. Our results suggest that adipose tissue is an important repository for BP-3 and parabens, including p-HB, in the human body.
Assuntos
Tecido Adiposo/química , Benzoatos/análise , Exposição Ambiental/análise , Poluentes Ambientais/análise , Compostos Heterocíclicos/análise , Fenóis/análise , Xenobióticos/análise , Adolescente , Adulto , Benzoatos/urina , Monitoramento Ambiental/métodos , Poluentes Ambientais/urina , Feminino , Compostos Heterocíclicos/urina , Humanos , Masculino , Pessoa de Meia-Idade , Cidade de Nova Iorque , Fenóis/urina , Xenobióticos/urina , Adulto JovemRESUMO
Many mutagenic heterocyclic amines (HAs) have been isolated from cooked foods and pyrolysates of amino acids and proteins, and the carcinogenicity of 10 of these HAs in rodents and of 1 in monkeys has been reported. Quantification of these carcinogenic HAs in various kinds of cooked foods indicated that the level of 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) was highest (0.56-69.2 ng/g), that of 2-amino-3,8-dimethylimidazo[4,5-f]quinoxaline (MeIQx) was second highest (0.64-6.44 ng/g), and those of other HAs were 0.03-2.50 ng/g. Heterocyclic amines were found in urine samples of 10 healthy volunteers consuming a normal diet, but HAs were not detectable in urine samples of three patients receiving parenteral alimentation. These results strongly suggest that humans are continuously exposed to HAs derived from food in the normal diet. Based on quantitative data on the levels of HAs in cooked foods and urine samples, the daily exposures to PhIP and MeIQx were estimated to be 0.1-13.8 micrograms and 0.2-2.6 micrograms per person, respectively. These levels of carcinogenic HAs are in the same range as those of other carcinogens such as N-nitrosodimethylamine and benzo[a]pyrene to which humans are exposed.
Assuntos
Aminas/efeitos adversos , Contaminação de Alimentos , Compostos Heterocíclicos/efeitos adversos , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Aminas/análise , Aminas/urina , Animais , Carcinógenos/análise , Feminino , Contaminação de Alimentos/análise , Compostos Heterocíclicos/análise , Compostos Heterocíclicos/urina , Humanos , Imidazóis/análise , Masculino , Pessoa de Meia-Idade , Mutagênicos/análise , Quinoxalinas/análiseRESUMO
Heterocyclic amines (HCAs) are mutagens/carcinogens to which humans are exposed on almost a daily basis. 2-Amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhlP) is the most abundant of the various carcinogenic HCAs (present at a level of 0.56 to 69.2 ng/g of cooked meat or fish), with 2-amino-3,8-dimethylimidazo[4,5-f]quinoxaline (MelQx) following it at 0.64 to 6.44 ng/g. HCAs have been found in the urine of healthy people who consume ordinary diets, while patients receiving parenteral alimentation lack, for example, PhlP and MelQx in their urine. Based on the concentrations of PhlP and MelQx in urine samples from 10 healthy volunteers, daily intake of MelQx in Japanese was calculated to be 0.3 to 3.9 micrograms/person, while that of PhlP was 0.005 to 0 micrograms. The Japanese consume more MelQx than Americans, whereas Japanese intake of PhlP was about one-third that of Americans. MelQx-DNA adducts have also detected in Japanese Kidney, colon, and rectum samples using the 32P-postlabeling method followed by identification using high-performance liquid chromatography (HPLC) analysis; the levels were 0.18, 1.8, and 1.4 per 10(9) nucleotides, respectively. In addition, we elucidated the mutational fingerprints of Phlp by analyzing Apc mutations in rat colon cancers induced by this carcinogen. Four of eight tumors had a total of five mutations in the Apc gene, four of which featured a guanine deletion from 5'-GTGGGAT-3' sequences. This specific mutation spectrum may be used as a fingerprint of PhlP in evaluating its risk potential for human colon carcinogenesis. Mutations were not found in similar 2-amino-3-methylimidazo[4,5-f]quinoline-induced colon lesions. Microsatellite instability was detected in both colon and mammary tumors induced by PhlP. The mechanisms involved in this development of microsatellite instability in PhlP. The mechanisms involved in this development of microsatellite instability in PhlP-induced cancers remain to be elucidated.
Assuntos
Aminas/toxicidade , Carcinógenos Ambientais/toxicidade , Exposição Ambiental , Compostos Heterocíclicos/toxicidade , Mutagênicos/toxicidade , Aminas/urina , Animais , Carcinógenos Ambientais/análise , Adutos de DNA , Contaminação de Alimentos , Compostos Heterocíclicos/urina , Humanos , Imidazóis/toxicidade , Imidazóis/urina , Mutagênicos/análise , Mutação , Neoplasias/induzido quimicamente , Neoplasias/genética , Quinoxalinas/toxicidade , Quinoxalinas/urinaRESUMO
Sibrafiban is a double prodrug that is converted to the inactive single prodrug and to the active IIb/IIIa antagonist following oral administration. Pharmacokinetics (PK) and pharmacodynamics (PD) of oral sibrafiban and its metabolites were evaluated in patients postacute coronary syndrome receiving once- or twice-daily sibrafiban for up to 28 days at several dose levels. Mean peak concentrations of sibrafiban were < 5 ng/mL. Peak single prodrug concentrations occurred 1.7 +/- 1.0 (mean +/- SD) hours after sibrafiban dosing. Total apparent plasma clearance of the single prodrug was 40 +/- 15 L/h, and the elimination half-life was 2.3 +/- 0.8 hours. Mean values of the steady-state pharmacokinetics for total concentrations of the active drug over all doses were: time to peak plasma concentration, 5.0 +/- 1.7 hours; apparent clearance, 13.9 +/- 3.9 L/h; and half-life, 11.0 +/- 2.8 hours. Once-daily dosing resulted in high peak-trough excursions in active drug concentrations: trough concentrations were 21% +/- 6% of peak. Twice-daily dosing resulted in an AUC for the active drug on Day 28 that was 168% +/- 36% of that on Day 1, and steady-state trough concentrations were 54% +/- 10% of peak with sustained inhibition of platelet aggregation. Dose-adjusted steady-state active drug concentrations increased with increasing age and with decreasing renal function and body weight.
Assuntos
Doença das Coronárias/tratamento farmacológico , Oximas/farmacocinética , Piperidinas/farmacocinética , Inibidores da Agregação Plaquetária/farmacocinética , Complexo Glicoproteico GPIIb-IIIa de Plaquetas/antagonistas & inibidores , Pró-Fármacos/farmacocinética , Doença Aguda , Administração Oral , Adulto , Fatores Etários , Idoso , Idoso de 80 Anos ou mais , Amidinas/sangue , Amidinas/urina , Área Sob a Curva , Peso Corporal , Doença das Coronárias/metabolismo , Método Duplo-Cego , Feminino , Taxa de Filtração Glomerular , Compostos Heterocíclicos/sangue , Compostos Heterocíclicos/urina , Humanos , Masculino , Taxa de Depuração Metabólica , Pessoa de Meia-Idade , Oximas/sangue , Oximas/urina , Piperidinas/sangue , Piperidinas/urina , SíndromeRESUMO
Heterocyclic amines (HAs), generated when proteinaceous food is cooked, are of special interest since they can be carcinogenic for humans. In this paper, the optimization of a clean-up procedure for the isolation and preconcentration of 15 heterocyclic amines in urine samples is described. The method proposed combines liquid extraction on a solid support of diatomaceous earth with solid-phase extraction in cartridges. Tests were performed on several cartridges containing graphitic carbon or mixed phases, i.e., combining reversed-phase and cation-exchange mechanism, and the best results were obtained with Oasis MCX. The optimized purification method was applied to the quantification of heterocyclic amines in hydrolyzed spiked human urine. The method was carried out by capillary electrophoresis (CE) coupled to mass spectrometry (MS) and applying field-amplified sample injection (FASI) as in-line preconcentration procedure. We obtained detection limits down to 0.3 ng/ml of urine and errors lower than 17%.
Assuntos
Aminas/urina , Eletroforese Capilar/métodos , Compostos Heterocíclicos/urina , Espectrometria de Massas/métodos , Espectrofotometria UltravioletaRESUMO
Zoledronic acid is a new, highly potent bisphosphonate drug under clinical evaluation. A radioimmunoassay has been developed to determine zoledronic acid concentration in human serum, plasma, and urine. The assay utilizes rabbit polyclonal antisera against a zoledronic acid-BSA conjugate and a [125I]zoledronic acid derivative as tracer in a competitive format adapted to microtiter plates. The assay shows a LLOQ 0.4 ng/ml in serum or plasma (interassay%CV=17%, accuracy 97%), 5 ng/ml in urine (21%, 98%). In 23 patients receiving 4, 8 or 16 mg of zoledronic acid, drug concentrations in plasma were dose proportional and showed a multiphasic profile, followed by a prolonged gradual decline to concentrations near the LLOQ. Zoledronic acid disposition in plasma and the recovery of only 40-50% of the dose in urine are consistent with the rapid and extensive uptake by and slow release from bone in parallel with renal clearance, typically shown by bisphosphonates.