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1.
J Vet Pharmacol Ther ; 43(2): 97-107, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31912519

RESUMO

Cyadox (CYX) is a synthetic antibacterial agent of quinoxaline with much lower toxic effects. A safety criterion of CYX for clinical use was established by studying the pharmacokinetics and metabolism of CYX after oral (PO), intramuscular (IM), and intravenous (IV) administration. CYX was administered in six domesticated cats (three males and three females) by PO (40 mg/kg.b.w.), IM (10 mg/kg.b.w.), and IV (10 mg/kg.b.w.) routes in a crossover pattern. Highly sensitive liquid chromatography with ultraviolet detection (HPLC-UV) method was developed for detection of CYX and its metabolites present in plasma, urine, and feces. The bioavailability of CYX after PO and IM routes was 4.37% and 84.4%. The area under curves (AUC), mean resident time (MRT), and clearance (CL) of CYX and its metabolites revealed that CYX quickly metabolized into its metabolites. The total recovery of CYX and its main metabolites was >60% after each route. PO delivery suggesting first pass effect in cats that might make this route suitable for intestinal infection and IM injection could be better choice for systemic infections. Less ability of glucuronidation did not show any impact on CYX metabolism. The findings of present study provide detailed information for evaluation of CYX.


Assuntos
Gatos/sangue , Administração Intravenosa , Administração Oral , Animais , Antibacterianos/administração & dosagem , Antibacterianos/farmacocinética , Área Sob a Curva , Gatos/metabolismo , Estudos Cross-Over , Fezes/química , Feminino , Meia-Vida , Injeções Intramusculares , Masculino , Quinoxalinas/administração & dosagem , Quinoxalinas/sangue , Quinoxalinas/farmacocinética , Quinoxalinas/urina
2.
Eur J Drug Metab Pharmacokinet ; 45(1): 101-111, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31673875

RESUMO

BACKGROUND AND OBJECTIVES: Erdafitinib, an oral selective pan-fibroblast growth factor receptor (FGFR) kinase inhibitor, is primarily metabolized by cytochrome P450 (CYP) 2C9 and 3A4. The aim of this phase 1 study was to assess the pharmacokinetics and safety of erdafitinib in healthy participants when coadministered with fluconazole (moderate CYP2C9 and CYP3A inhibitor), and itraconazole (a strong CYP3A4 and P-glycoprotein inhibitor). The effect of CYP2C9 genotype variants (*1/*1, *1/*2, *1/*3) on the pharmacokinetics of erdafitinib was also investigated. METHODS: In this open-label, parallel-group, single-center study, eligible healthy adults were randomized by CYP2C9 genotype to receive Treatment A (single oral dose of erdafitinib 4 mg) on day 1, Treatment B (fluconazole 400 mg/day orally) on days 1-11, or Treatment C (itraconazole 200 mg/day orally) on days 1-11. Healthy adults randomized to Treatment B and C received a single oral 4-mg dose of erdafitinib on day 5. The pharmacokinetic parameters, including mean maximum plasma concentration (Cmax), area under the curve (AUC) from time 0 to 168 h (AUC168h), AUC from time 0 to the last quantifiable concentration (AUClast), and AUC from time 0 to infinity (AUC∞) were calculated from individual plasma concentration-time data using standard non-compartmental methods. RESULTS: Coadministration of erdafitinib with fluconazole increased Cmax of erdafitinib by approximately 21%, AUC168h by 38%, AUClast by 49%, and AUC∞ by 48% while coadministration with itraconazole resulted in no change in erdafitinib Cmax and increased AUC168h by 20%, AUClast by 33% and AUC∞ by 34%. Erdafitinib exposure was comparable between participants with CYP2C9 *1/*2 or *1/*3 and with wild-type CYP2C9 genotype. The ratio of total amount of erdafitinib excreted in the urine (inhibited to non-inhibited) was 1.09, the ratio of total amount of excreted metabolite M6 was 1.21, and the ratio of the metabolite to parent ratio in the urine was 1.11, when coadministration of erdafitinib with itraconazole was compared with single-dose erdafitinib. Treatment-emergent adverse events (TEAEs) were generally Grade 1 or 2 in severity; the most commonly reported TEAE was headache. No safety concerns were identified with single-dose erdafitinib when administered alone and in combination with fluconazole or itraconazole in healthy adults. CONCLUSION: Coadministration of fluconazole or itraconazole or other moderate/strong CYP2C9 or CYP3A4 inhibitors may increase exposure to erdafitinib in healthy adults and thus may warrant erdafitinib dose reduction or use of alternative concomitant medications with no or minimal CYP2C9 or CYP3A4 inhibition potential. TRIAL REGISTRATION: ClinicalTrials.gov identifier number: NCT03135106.


Assuntos
Inibidores das Enzimas do Citocromo P-450/farmacologia , Interações Medicamentosas , Fluconazol/farmacologia , Itraconazol/farmacologia , Inibidores de Proteínas Quinases/farmacocinética , Pirazóis/farmacocinética , Quinoxalinas/farmacocinética , Adulto , Área Sob a Curva , Citocromo P-450 CYP2C9/genética , Combinação de Medicamentos , Feminino , Voluntários Saudáveis , Humanos , Masculino , Pessoa de Meia-Idade , Inibidores de Proteínas Quinases/efeitos adversos , Inibidores de Proteínas Quinases/sangue , Inibidores de Proteínas Quinases/urina , Pirazóis/efeitos adversos , Pirazóis/sangue , Pirazóis/urina , Quinoxalinas/efeitos adversos , Quinoxalinas/sangue , Quinoxalinas/urina , Receptores de Fatores de Crescimento de Fibroblastos/antagonistas & inibidores
3.
Chem Res Toxicol ; 29(3): 352-8, 2016 Mar 21.
Artigo em Inglês | MEDLINE | ID: mdl-26918625

RESUMO

Pancreatic cancer is the fourth leading cause of cancer death in the U.S. Once diagnosed, prognosis is poor with a 5-year survival rate of less than 5%. Exposure to carcinogenic heterocyclic amines (HCAs) derived from cooked meat has been shown to be positively associated with pancreatic cancer risk. To evaluate the processes that determine the carcinogenic potential of HCAs for human pancreas, 14-carbon labeled 2-amino-3,8-dimethylimidazo[4,5-f]quinoxaline (MeIQx), a putative human carcinogenic HCA found in well-done cooked meat, was administered at a dietary relevant dose to human volunteers diagnosed with pancreatic cancer undergoing partial pancreatectomy and healthy control volunteers. After (14)C-MeIQx exposure, blood and urine were collected for pharmacokinetic and metabolite analysis. MeIQx-DNA adducts levels were quantified by accelerator mass spectrometry from pancreatic tissue excised during surgery from the cancer patient group. Pharmacokinetic analysis of plasma revealed a rapid distribution of MeIQx with a plasma elimination half-life of approximately 3.5 h in 50% of the cancer patients and all of the control volunteers. In 2 of the 4 cancer patients, very low levels of MeIQx were detected in plasma and urine suggesting low absorption from the gut into the plasma. Urinary metabolite analysis revealed five MeIQx metabolites with 2-amino-3-methylimidazo[4,5-f]quinoxaline-8-carboxylic acid being the most abundant accounting for 25%-50% of the recovered 14-carbon/mL urine. There was no discernible difference in metabolite levels between the cancer patient volunteers and the control group. MeIQx-DNA adduct analysis of pancreas and duodenum tissue revealed adduct levels indistinguishable from background levels. Although other meat-derived HCA mutagens have been shown to bind DNA in pancreatic tissue, indicating that exposure to HCAs from cooked meat cannot be discounted as a risk factor for pancreatic cancer, the results from this current study show that exposure to a single dietary dose of MeIQx does not readily form measurable DNA adducts under the conditions of the experiment.


Assuntos
Dieta , Mutagênicos/farmacocinética , Neoplasias Pancreáticas/metabolismo , Quinoxalinas/farmacocinética , Estudos de Casos e Controles , Adutos de DNA/sangue , Adutos de DNA/metabolismo , Adutos de DNA/urina , Dieta/efeitos adversos , Humanos , Mutagênicos/administração & dosagem , Mutagênicos/análise , Pancreatectomia , Neoplasias Pancreáticas/sangue , Neoplasias Pancreáticas/cirurgia , Neoplasias Pancreáticas/urina , Quinoxalinas/administração & dosagem , Quinoxalinas/sangue , Quinoxalinas/urina
4.
J Physiol ; 593(17): 3959-71, 2015 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-26148133

RESUMO

There is a long-standing concern that creatine supplementation could be associated with cancer, possibly by facilitating the formation of carcinogenic heterocyclic amines (HCAs). This study provides compelling evidence that both low and high doses of creatine supplementation, given either acutely or chronically, does not cause a significant increase in HCA formation. HCAs detection was unrelated to creatine supplementation. Diet was likely to be the main factor responsible for HCAs formation after either placebo (n = 6) or creatine supplementation (n = 3). These results directly challenge the recently suggested biological plausibility for the association between creatine use and risk of testicular germ cell cancer. Creatine supplementation has been associated with increased cancer risk. In fact, there is evidence indicating that creatine and/or creatinine are important precursors of carcinogenic heterocyclic amines (HCAs). The present study aimed to investigate the acute and chronic effects of low- and high-dose creatine supplementation on the production of HCAs in healthy humans (i.e. 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP), 2-amino-3,8-dimethylimidazo[4,5-f]quinoxaline (8-MeIQx), 2-amino-(1,6-dimethylfuro[3,2-e]imidazo[4,5-b])pyridine (IFP) and 2-amino-3,4,8-trimethylimidazo[4,5-f]quinoxaline (4,8-DiMeIQx)). This was a non-counterbalanced single-blind crossover study divided into two phases, in which low- and high-dose creatine protocols were tested. After acute (1 day) and chronic supplementation (30 days), the HCAs PhIP, 8-MeIQx, IFP and 4,8-DiMeIQx were assessed through a newly developed HPLC-MS/MS method. Dietary HCA intake and blood and urinary creatinine were also evaluated. Out of 576 assessments performed (from 149 urine samples), only nine (3 from creatine and 6 from placebo) showed quantifiable levels of HCAs (8-MeIQx: n = 3; 4,8-DiMeIQx: n = 2; PhIP: n = 4). Individual analyses revealed that diet rather than creatine supplementation was the main responsible factor for HCA formation in these cases. This study provides compelling evidence that both low and high doses of creatine supplementation, given either acutely or chronically, did not cause increases in the carcinogenic HCAs PhIP, 8-MeIQx, IFP and 4,8-DiMeIQx in healthy subjects. These findings challenge the long-existing notion that creatine supplementation could potentially increase the risk of cancer by stimulating the formation of these mutagens.


Assuntos
Carcinógenos/metabolismo , Creatina/farmacocinética , Furanos/urina , Imidazóis/urina , Quinoxalinas/urina , Adulto , Aminas , Creatina/sangue , Creatina/urina , Estudos Cross-Over , Dieta , Feminino , Humanos , Masculino , Método Simples-Cego
5.
Anal Chim Acta ; 826: 84-93, 2014 May 15.
Artigo em Inglês | MEDLINE | ID: mdl-24793857

RESUMO

A new highly advanced analytical approach, based on two-dimensional column coupled CE (ITP-CZE) hyphenated with tandem mass spectrometry (MS/MS, here triple quadrupole, QqQ) was developed, evaluated and applied in biomedical field in the present work. Capillary isotachophoresis (ITP) coupled on-line with capillary zone electrophoresis (CZE) used in hydrodynamically closed separation system was favorable for increasing the sample load capacity, increasing the analyte concentration, and removing the deteriorative highly conductive major matrix constituents. These factors considerably reduced the concentration limits of detection (cLOD) and external sample preparation (comparing to single column CZE), and, by that, provided favorable conditions for the mass spectrometry (enhanced signal to noise ratio, reproducibility of measurements, working life of MS). Here, the CZE-ESI combination provided more effective interfacing than ITP-ESI resulting in both a higher obtainable intensity of MS detection signal of the analyte as well as reproducibility of measurements of the analyte's peak area. The optimized ITP-CZE-ESI-QqQ method was successfully evaluated as for its performance parameters (LOD, LOQ, linearity, precision, recovery/accuracy) and applied for the direct identification and ultratrace (pgmL(-1)) determination of varenicline and, in addition, identification of its targeted metabolite, 2-hydroxy-varenicline, in unpretreated/diluted human urine. This application example demonstrated the real analytical potential of this new analytical approach and, at the same time, served as currently the most effective routine clinical method for varenicline.


Assuntos
Benzazepinas/urina , Eletroforese Capilar/métodos , Agonistas Nicotínicos/urina , Quinoxalinas/urina , Espectrometria de Massas em Tandem/métodos , Adulto , Benzazepinas/química , Benzazepinas/metabolismo , Eletroforese Capilar/instrumentação , Humanos , Estrutura Molecular , Agonistas Nicotínicos/química , Agonistas Nicotínicos/metabolismo , Quinoxalinas/química , Quinoxalinas/metabolismo , Sensibilidade e Especificidade , Espectrometria de Massas em Tandem/instrumentação , Vareniclina
6.
J Chromatogr A ; 1268: 1-8, 2012 Dec 14.
Artigo em Inglês | MEDLINE | ID: mdl-23122995

RESUMO

An ultrasound-assisted dispersive liquid-liquid microextraction (UADLLME) was developed as a simple, sensitive, and robust method for the simultaneous determination of quinocetone (QCT) and three of its synthesized desoxy metabolites in swine urine samples via high-performance liquid chromatography (HPLC). Experimental parameters were optimized using the one-factor-at-a-time approach and were followed using an orthogonal array design. The results indicate that ultrasonic irradiation significantly affects the DLLME extraction efficiency. Moreover, the intermolecular binding energies and octanol-water partition ratio (K(ow)) of the target analytes were calculated using the density functional theory and the atom-additive method, respectively. A high correlation was found between the extraction efficiency and the calculated results, which may serve as a scientific guideline in the determination of the target analyte selectivity of DLLME. The feasibility of UADLLME with HPLC for the simultaneous determination of QCT and its desoxy metabolites in blank swine urine samples was then investigated. Higher enrichment factors (118-175), low limits of detection (0.06-0.12 ng mL(-1)), and high precisions (relative standard deviation < 2.5%) were obtained. Calibration curves were performed in the 0.5-500 ng mL(-1) range and displayed good linearity. In addition, the proposed method was successfully applied to the pharmacokinetic study of QCT and its desoxy metabolites in real urine samples. The results show that UADLLME has a potential application in the pharmacokinetic and residue studies of quinoxaline-N-dioxides derivatives in biological fluid samples.


Assuntos
Microextração em Fase Líquida/métodos , Quinoxalinas/farmacocinética , Ultrassom/métodos , Animais , Cromatografia Líquida de Alta Pressão , Quinoxalinas/urina , Suínos
7.
Talanta ; 88: 330-7, 2012 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-22265507

RESUMO

A novel pretreatment method termed ultrasound-assisted dispersive liquid-liquid microextraction (UADLLME) coupled with high-performance liquid chromatography-ultraviolet detector (HPLC-UV) was applied for the detection of four synthesized metabolites of mequindox in pig urine samples. A total volume of 200 µL of methanol (dispersant) and 60 µL of 1,1,2,2-tetrachloroethane (extract) were injected into 5.0 mL of urine sample and then emulsified by ultrasound treatment for 4 min to form a cloudy solution. The effect of several factors on the recovery of each metabolite was investigated by a fitting derivation method for the first time. Under optimum conditions, the method yields a linear calibration curve in the concentration range from 0.5 to 500 µg/L and a limit of detection (LOD) of 0.16-0.28 µg/L for target analytes. The recoveries ranged from 72.0% to 91.3% with a relative standard deviation (RSD) of less than 5.2%. The enrichment factors for the four compounds ranged from 75 to 95. Two pig urine samples were successfully analyzed using the proposed method.


Assuntos
Quinoxalinas/síntese química , Quinoxalinas/urina , Animais , Calibragem , Cromatografia Líquida de Alta Pressão , Emulsões , Etano/análogos & derivados , Etano/química , Hidrocarbonetos Clorados/química , Concentração de Íons de Hidrogênio , Limite de Detecção , Microextração em Fase Líquida , Metanol/química , Oxirredução , Reprodutibilidade dos Testes , Solventes , Sonicação , Suínos
8.
J Agric Food Chem ; 59(17): 9319-26, 2011 Sep 14.
Artigo em Inglês | MEDLINE | ID: mdl-21834531

RESUMO

A rapid immunochromatographic lateral flow test strip of competitive format has been developed for the specific determination of olaquindox (OLA) residues in pig urine and muscle tissues. The sensitivity of the test strip was found to be 1.58 ± 0.27 µg/kg and 1.70 ± 0.26 µg/kg of OLA in pig urine and muscle tissues, and the lower detection limit was 0.27 ± 0.08 µg/kg and 0.31 ± 0.07 µg/kg respectively. For negative pig urine and muscle samples spiked with 4, 12, and 36 µg/kg, the recovery range was 83.0-94.0% and 78.8-87.4% and the coefficient of variation scope [CV (%)] was 3.17-7.41% and 4.66-7.64% respectively. Parallel analysis of OLA samples from pig urine and muscle tissue showed comparable results from the test strip and HPLC. Each test requires 5-8 min, and the test strip can provide a useful screening method for quantitative, semiquantitative, or qualitative detection of OLA residues.


Assuntos
Coloide de Ouro , Imunoensaio/métodos , Quinoxalinas/análise , Drogas Veterinárias/análise , Animais , Anticorpos Monoclonais , Feminino , Camundongos , Camundongos Endogâmicos BALB C , Músculos/química , Quinoxalinas/urina , Fitas Reagentes , Sensibilidade e Especificidade , Suínos
9.
Rapid Commun Mass Spectrom ; 25(7): 889-98, 2011 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-21416525

RESUMO

Olaquindox (OLA), N-(2-hydroxyethyl)-3-methyl-2-quinoxalincarboxamide-1,4-dioxide, is an antimicrobial and growth-promoting agent for animals, which has been banned or allowed only limited use for its potential toxicity. To thoroughly understand the metabolic pathways, metabolism of OLA in rat was studied using ultra-performance liquid chromatography coupled to quadrupole time-of-flight mass spectrometry with MS(E) and mass defect filtering techniques. Twenty metabolites (M1-M20) were detected in rat feces and urine, of which nine phase I metabolites (M6, M7, M11-M16) and four phase II metabolites (M17-M20) were found in vivo for the first time. The structures of metabolites were reliably characterized on the basis of accurate mass and fragment ions in MS(E) spectra. The major metabolic pathways reported previously in pigs, including reduction of N→O groups, oxidation of the alcohol and hydrolysis, were also confirmed in this study. In addition, hydroxylation of the methyl group, N-dehydroxyethylation and glucuronidation were also proved to be the important metabolic pathways, which contribute to improving our knowledge about in vivo metabolism of OLA.


Assuntos
Cromatografia Líquida de Alta Pressão/métodos , Espectrometria de Massas/métodos , Quinoxalinas/análise , Animais , Fezes/química , Masculino , Quinoxalinas/metabolismo , Quinoxalinas/urina , Ratos , Ratos Sprague-Dawley
10.
Toxicol Lett ; 200(1-2): 24-33, 2011 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-20974235

RESUMO

Olaquindox is a growth-promoting feed additive for food-producing animals. Its toxicities were reported to be closely related to the metabolism. To provide the interpretation of toxicities in animals, this study explored the metabolism of olaquindox in rats, chickens and pigs of different genders by qualitative metabolite profiling. Animals were fed olaquindox in an oral dose, and then their urine, plasma, feces, liver, kidney and muscle were collected. Liquid chromatography combined with hybrid ion trap/time-of-flight mass spectrometry was used for structural investigation and identification of metabolites. The structures of metabolites were elucidated based on the accurate MS² spectra and comparison of their changes in accurate molecular masses and fragment ions with those of parent drug or metabolite. A total of 18, 18 and 16 metabolites of rats, chickens and pigs were identified, respectively. Among the identified metabolites, 8 known metabolites were confirmed as an early study had stated, and 15 metabolites were found for the first time in vivo. The major metabolic pathways of olaquindox were proposed to be N-O reduction and oxidation of hydroxyl to carboxylic acid followed by N-O reduction. The qualitative species difference on the metabolite profiles of olaquindox among the three species was observed. However, metabolite profiles of olaquindox appeared to be qualitatively similar between female and male for the same species. The proposed metabolic pathways of olaquindox in animals will provide comprehensive data to clarify the metabolism of olaquindox among different species, and will give scientific explanation for toxicities and residues of olaquindox.


Assuntos
Quinoxalinas/farmacocinética , Animais , Antibacterianos/farmacocinética , Galinhas , Fezes/química , Feminino , Substâncias de Crescimento/farmacocinética , Rim/química , Fígado/química , Masculino , Músculo Esquelético/química , Quinoxalinas/análise , Quinoxalinas/sangue , Quinoxalinas/metabolismo , Quinoxalinas/urina , Ratos , Fatores Sexuais , Especificidade da Espécie , Suínos
11.
Chem Res Toxicol ; 23(4): 788-801, 2010 Apr 19.
Artigo em Inglês | MEDLINE | ID: mdl-20192249

RESUMO

A targeted liquid chromatography/tandem mass spectrometry-based metabolomics type approach, employing a triple stage quadrupole mass spectrometer in the product ion scan and selected reaction monitoring modes, was established to profile 2-amino-3,8-dimethylimidazo[4,5-f]quinoxaline (MeIQx), 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP), and their principal metabolites in the urine of omnivores. A mixed-mode reverse phase cation exchange resin enrichment procedure was employed to isolate MeIQx and its oxidized metabolites, 2-amino-8-(hydroxymethyl)-3-methylimidazo[4,5-f]quinoxaline (8-CH(2)OH-IQx) and 2-amino-3-methylimidazo[4,5-f]quinoxaline-8-carboxylic acid (IQx-8-COOH), which are produced by cytochrome P450 1A2 (P450 1A2). The phase II conjugates N(2)-(beta-1-glucosiduronyl)-2-amino-3,8-dimethylimidazo[4,5-f]quinoxaline and N(2)-(3,8-dimethylimidazo[4,5-f]quinoxalin-2-yl)-sulfamic acid were measured indirectly, following acid hydrolysis to form MeIQx. The enrichment procedure permitted the simultaneous analysis of PhIP, N(2)-(beta-1-glucosidurony1)-2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine, N3-(beta-1-glucosidurony1)-2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine, 2-amino-1-methyl-6-(4'-hydroxy)-phenylimidazo[4,5-b]pyridine (4'-HO-PhIP), and the isomeric N(2)- and N3-glucuronide conjugates of the carcinogenic metabolite, 2-hydroxyamino-1-methyl-6-phenylimidazo[4,5-b]pyridine (HONH-PhIP), which is formed by P450 1A2. The limit of quantification (LOQ) for MeIQx, PhIP, and 4'-HO-PhIP was approximately 5 pg/mL; the LOQ values for 8-CH(2)OH-IQx and IQx-8-COOH were, respectively, <15 and <25 pg/mL, and the LOQ values for the glucuronide conjugates of PhIP and HONH-PhIP were 50 pg/mL. The metabolism was extensive; less than 9% of the dose was eliminated in urine as unaltered MeIQx, and <1% was eliminated as unaltered PhIP. Phase II conjugates of the parent amines accounted for up to 12% of the dose of MeIQx and up to 2% of the dose of PhIP. 8-CH(2)OH-IQx and IQx-8-COOH accounted for up to 76% of the dose of MeIQx, and the isomeric glucuronide conjugates of HONH-PhIP accounted for up to 33% of the dose of PhIP that were eliminated in urine within 10 h of meat consumption. P450 1A2 significantly contributes to the metabolism of both HAAs but with marked differences in substrate specificity. P450 1A2 primarily catalyzes the detoxification of MeIQx by oxidation of the 8-methyl group, whereas it catalyzes the bioactivation of PhIP by oxidation of the exocyclic amine group.


Assuntos
Carcinógenos/metabolismo , Imidazóis/metabolismo , Carne/análise , Metaboloma , Quinoxalinas/metabolismo , Carcinógenos/análise , Carcinógenos/toxicidade , Cromatografia Líquida de Alta Pressão , Citocromo P-450 CYP1A2/metabolismo , Humanos , Imidazóis/urina , Quinoxalinas/urina , Extração em Fase Sólida , Espectrometria de Massas por Ionização por Electrospray
12.
Rapid Commun Mass Spectrom ; 24(3): 375-83, 2010 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-20054845

RESUMO

Quinocetone (QCT), 3-methyl-2-cinnamoylquinoxaline-1,4-dioxide, is a quinoxaline-N,N-dioxide used in veterinary medicine as a feed additive. QCT is broadly used in China to promote animal growth, but few studies have been performed to reveal the metabolism of QCT in animals until now. In the present study, the metabolites of QCT in swine urine were investigated using ultra-performance liquid chromatography/electrospray ionization quadrupole time-of-flight mass spectrometry (UPLC/ESI-QTOF-MS). Multiple scans of metabolites in MS and MS/MS modes and accurate mass measurements were performed simultaneously through data-dependent acquisition. Most measured mass errors were less than +/-5 mDa for both protonated molecules and product ions using external mass calibration. The structures of metabolites and their product ions were easily and reliably characterized based on the accurate MS(2) spectra and known structure of QCT. As expected, extensive metabolism was observed in swine urine. Thirty-one metabolites were identified in swine urine, most of which were reported for the first time. The results reveal that the N-O group reduction at position 1 and the hydroxylation reaction occurring at the methyl group, the side chain or on the benzene ring are the main metabolic pathways of quinocetone in swine urine. There was abundant production of 1-desoxyquinocetone and hydroxylation metabolites of 1-desoxyquinocetone. The proposed metabolic pathway of quinocetone in vivo can be expected to play a key role in food safety evaluations.


Assuntos
Cromatografia Líquida de Alta Pressão/métodos , Quinoxalinas/metabolismo , Quinoxalinas/urina , Espectrometria de Massas por Ionização por Electrospray/métodos , Animais , Estrutura Molecular , Quinoxalinas/química , Sensibilidade e Especificidade , Suínos , Espectrometria de Massas em Tandem/métodos
13.
Mol Nutr Food Res ; 53(12): 1496-504, 2009 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-19810020

RESUMO

Heterocyclic amines (HCAs) are potent mutagens/carcinogens to which humans are frequently exposed through the consumption of cooked meat and fish food. The effect of normal intake of HCAs and their role in the aetiology of human cancer is unknown. To some extent, limitations of the existing analytical methods in monitoring the low levels of HCAs in biological samples have hindered obtaining conclusive results. In this study, a method for the analysis of HCAs in human urine has been studied to detect HCAs and metabolites at levels resulting from consumption of food cooked at ordinary conditions. The analytical method consisted of extraction and clean-up by the novel technique liquid-phase microextraction combined with LC-MS/MS. The effect of pH during the extraction and hydrolysis step was examined. High sensitivity was achieved when the extraction was performed in raw urine adjusted to pH 5.5, 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine being detected from 2 pg/g urine, levels comparable with a normal exposure. Good reproducibility and repeatability was obtained for 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine and 2-amino-3,8-dimethylimidazo[4,5-f]quinoxaline, below 9% using isotopic dilution. The performance of the method on 9H-pyrido[3,4-b]indole, 2-amino-1-methyl-6-(4'-hydroxyphenyl)imidazo[4,5-b]pyridine and 2-amino-1-methyl-6-(5-hydroxy)phenylimidazo[4,5-b]pyridine was also studied.


Assuntos
Métodos Analíticos de Preparação de Amostras/métodos , Carcinógenos/metabolismo , Harmina/análogos & derivados , Microquímica/métodos , Mutagênicos/metabolismo , Piridinas/urina , Quinoxalinas/urina , Carbolinas , Carcinógenos/análise , Cromatografia Líquida de Alta Pressão , Harmina/urina , Humanos , Concentração de Íons de Hidrogênio , Hidrólise , Imidazóis/análise , Imidazóis/metabolismo , Imidazóis/urina , Limite de Detecção , Mutagênicos/análise , Piridinas/metabolismo , Quinoxalinas/metabolismo , Reprodutibilidade dos Testes , Espectrometria de Massas em Tandem
14.
Clin Pharmacol Ther ; 83(4): 567-76, 2008 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-17971819

RESUMO

Varenicline is predominantly eliminated unchanged in urine, and active tubular secretion partially contributes to its renal elimination. Transporter inhibition assays using human embryonic kidney 293 cells transfected with human renal transporters demonstrated that high concentrations of varenicline inhibited substrate uptake by hOCT2 (IC(50)=890 microM), with very weak or no measurable interactions with the other transporters hOAT1, hOAT3, hOCTN1, and hOCTN2. Varenicline was characterized as a moderate-affinity substrate for hOCT2 (K(m)=370 microM) and its hOCT2-mediated uptake was partially inhibited by cimetidine. Co-administration of cimetidine (1,200 mg/day) reduced the renal clearance of varenicline in 12 smokers, resulting in a 29.0% (90% CI: 21.5%-36.9%) increase in systemic exposure. This increase is not considered clinically relevant, as it should not give rise to safety concerns. Consequently, it can be reasonably expected that other inhibitors of hOCT2 would not cause greater renal interactions with varenicline than that seen with the efficient hOCT2 inhibitor cimetidine.


Assuntos
Benzazepinas/farmacocinética , Benzazepinas/uso terapêutico , Proteínas de Transporte de Cátions Orgânicos/antagonistas & inibidores , Quinoxalinas/farmacocinética , Quinoxalinas/uso terapêutico , Abandono do Hábito de Fumar/métodos , Fumar/metabolismo , Fumar/terapia , Adulto , Benzazepinas/sangue , Benzazepinas/farmacologia , Benzazepinas/urina , Cromatografia Líquida de Alta Pressão , Cimetidina/farmacologia , Embrião de Mamíferos , Inibidores Enzimáticos/farmacologia , Feminino , Humanos , Rim/citologia , Masculino , Pessoa de Meia-Idade , Transportador 1 de Cátions Orgânicos/antagonistas & inibidores , Transportador 2 de Cátion Orgânico , Quinoxalinas/sangue , Quinoxalinas/farmacologia , Quinoxalinas/urina , Receptores Nicotínicos/efeitos dos fármacos , Espectrometria de Massas em Tandem , Vareniclina
15.
Cancer Epidemiol Biomarkers Prev ; 16(8): 1554-60, 2007 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-17684128

RESUMO

Carcinogenic heterocyclic aromatic amines (HAA) are formed in cooked meats, poultry, and fish and arise in tobacco smoke. We measured the concentrations of four prevalent HAAs in spot urine samples collected at baseline from 170 participants of the Shanghai Cohort study, a population-based cohort study of adult men recruited during 1986 to 1989 in Shanghai, China. Sixteen (18.6%) of 86 nonsmokers were positive for urinary 2-amino-9H-pyrido[2,3-b]indole (AalphaC) versus 41 (48.8%) of 84 cigarette smokers; the difference was statistically significant (P < 0.001). The number of cigarettes smoked per day was positively and significantly related to urinary levels of AalphaC in study subjects (P < 0.001); the mean level among nonsmokers was 2.54 ng/g creatinine, whereas the means for light (1-19 cigarettes per day) and heavy (20+ cigarettes per day) smokers were 7.50 and 11.92 ng/g creatinine, respectively. 2-Amino-3,4,8-trimethylimidazo[4,5-f]quinoxaline was undetected in the urine of the 170 subjects. Only 5 (2.9%) and 6 (3.5%) subjects, respectively, showed detectable levels of urinary 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine and 2-amino-3,8-dimethylimidazo[4,5-f]quinoxaline, and smoking status was unrelated to levels of either HAA. Quantitative measurements of HAAs in commonly eaten pork and chicken dishes in Shanghai showed low concentrations of HAAs (<1 ng/g meat). Our data indicate that AalphaC represents a major HAA exposure in adult men of Shanghai, China, and that tobacco smoke is an important point source of their AalphaC exposure.


Assuntos
Carbolinas/urina , Carcinógenos/análise , Fumar/urina , Animais , Carbolinas/análise , Estudos de Casos e Controles , Galinhas , China , Estudos de Coortes , Creatinina/urina , Seguimentos , Humanos , Imidazóis/análise , Imidazóis/urina , Masculino , Carne/análise , Pessoa de Meia-Idade , Vigilância da População , Estudos Prospectivos , Quinoxalinas/análise , Quinoxalinas/urina , Suínos
16.
Drug Metab Dispos ; 34(1): 121-30, 2006 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-16221753

RESUMO

The metabolism and disposition of varenicline (7,8,9,10-tetrahydro-6,10-methano-6H-pyrazino[2,3-h][3]benzazepine), a partial agonist of the nicotinic acetylcholine receptor for the treatment of tobacco addiction, was examined in rats, mice, monkeys, and humans after oral administration of [14C]varenicline. In the circulation of all species, the majority of drug-related material was composed of unchanged varenicline. In all four species, drug-related material was primarily excreted in the urine. A large percentage was excreted as unchanged parent drug (90, 84, 75, and 81% of the dose in mouse, rat, monkey, and human, respectively). Metabolites observed in excreta arose via N-carbamoyl glucuronidation and oxidation. These metabolites were also observed in the circulation, in addition to metabolites that arose via N-formylation and formation of a novel hexose conjugate. Experiments were conducted using in vitro systems to gain an understanding of the enzymes involved in the formation of the N-carbamoylglucuronide metabolite in humans. N-Carbamoyl glucuronidation was catalyzed by UGT2B7 in human liver microsomes when incubations were conducted under a CO2 atmosphere. The straightforward dispositional profile of varenicline should simplify its use in the clinic as an aid in smoking cessation.


Assuntos
Benzazepinas/metabolismo , Benzazepinas/farmacocinética , Quinoxalinas/metabolismo , Quinoxalinas/farmacocinética , Administração Oral , Animais , Área Sob a Curva , Benzazepinas/química , Benzazepinas/urina , Radioisótopos de Carbono , Cromatografia Líquida de Alta Pressão/métodos , Avaliação Pré-Clínica de Medicamentos/métodos , Fezes/química , Feminino , Glucuronídeos/química , Glucuronídeos/metabolismo , Meia-Vida , Haplorrinos , Humanos , Masculino , Espectrometria de Massas/métodos , Camundongos , Monossacarídeos/química , Monossacarídeos/metabolismo , Agonistas Nicotínicos/química , Agonistas Nicotínicos/metabolismo , Agonistas Nicotínicos/farmacocinética , Pentoses/metabolismo , Quinoxalinas/química , Quinoxalinas/urina , Ratos , Ratos Sprague-Dawley , Receptores Nicotínicos/metabolismo , Especificidade da Espécie , Vareniclina
17.
Cancer Chemother Pharmacol ; 56(4): 351-7, 2005 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-15895233

RESUMO

As part of an ongoing phase 1 study, we studied the excretion of XK469 and its metabolism in patients and in vitro. Five primary metabolites were identified by HPLC/MS/MS. An oxidized product formed by cytosolic aldehyde oxidase was the predominant species both in urine and human hepatocytes in vitro. Conjugates of XK469 with glycine, taurine, and glucuronic acid, as well as the microsomal product, 4-oxo-XK469, were also found in urine and in vitro, but none were major contributors to the mass balance for XK469 elimination. Based upon the relative concentrations circulating in plasma, systemic exposure to parent drug was 100-fold higher than for the metabolites. Thus, both toxicity and efficacy of XK469 are most likely to be produced by the parent molecule, rather than the metabolites. Urinary recovery of parent drug was low (2% of dose in 24 h), partly because of the long half-life of XK469 (approximately 3 days). In addition, the metabolite profile in urine indicates that only 25% of the XK469-derived material was unchanged drug. Thus, urinary excretion was not a major factor in XK469 elimination. Variations in systemic exposure to XK469 will be strongly influenced by factors that alter the activity of aldehyde oxidase, including pharmacogenetics, enzyme inhibition, and enzyme induction, but no specific modifiers have been reported. The multiday half-life of XK469 hampered our ability to obtain a complete mass balance, and the possibility exists that other routes, such as biliary excretion, may also play a substantial role in XK469 disposition.


Assuntos
Microssomos Hepáticos/metabolismo , Quinoxalinas/metabolismo , Meia-Vida , Humanos , Quinoxalinas/farmacocinética , Quinoxalinas/urina , Estereoisomerismo , Relação Estrutura-Atividade
18.
Chem Res Toxicol ; 18(3): 579-90, 2005 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-15777097

RESUMO

Liquid chromatography electrospray ionization mass spectrometry (MS) with a triple quadrupole MS was used to identify known and novel heterocyclic aromatic amines (HAAs) in human urine. The identities of 2-amino-3,8-dimethylimidazo[4,5-f]quinoxaline (8-MeIQx) and 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) were confirmed by their product ion spectra. The constant neutral loss scan mode was employed to probe for other analytes in urine that display the transition [M+H]+-->[M+H-CH3*]+*, which is common to HAAs containing an N-methylimidazo moiety, and led to the detection of a previously unreported isomer of 8-MeIQx [Holland, R., et al. (2004) Chem. Res. Toxicol. 17, 1121-1136]. We now report the identification of another novel HAA, 2-amino-1-methylimidazo[4,5-b]quinoline (IQ[4,5-b]), an isomer of the powerful animal carcinogen 2-amino-3-methylimidazo[4,5-f]quinoline (IQ). The amounts of IQ[4,5-b] measured in the urine of human volunteers who consumed grilled beef ranged from 15 to 135% of the ingested dose, while the amounts of 8-MeIQx and PhIP excreted in urine were on average <2% of the ingested dose. Base treatment of urine at 70 degrees C increased the concentrations of 8-MeIQx and PhIP by as much as 6-fold, indicating the presence of phase II conjugates; however, the amount of IQ[4,5-b] increased by more than 100-fold. IQ[4,5-b] was also detected in the urine of vegetarians following base hydrolysis. The formation of IQ[4,5-b], but not IQ, 8-MeIQx, or PhIP, also occurred in urine incubated at 37 degrees C. Creatinine and 2-aminobenzaldehyde are likely precursors of IQ[4,5-b]. The detection of IQ[4,5-b] in the urine of both meat eaters and vegetarians suggests that this HAA may be present in nonmeat staples or that IQ[4,5-b] formation may occur endogenously within the urinary bladder or other biological fluids.


Assuntos
Creatinina/urina , Dieta Vegetariana , Imidazóis/urina , Carne , Mutagênicos/metabolismo , Quinoxalinas/urina , Humanos , Masculino , Espectrometria de Massas por Ionização por Electrospray
19.
Chem Pharm Bull (Tokyo) ; 52(11): 1322-5, 2004 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-15516754

RESUMO

Zonampanel monohydrate (YM872) has a potent and selective antagonistic effect on the glutamate receptor subtype, alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) receptor. Metabolic fingerprinting in rat urine after a single intravenous administration of (14)C-labeled YM872 ((14)C-YM872) revealed the presence of two metabolites, R1 and R2. The two metabolites were semi-purified by preparative HPLC from rat urine after a single intravenous administration of non-labeled YM872, and their structures were elucidated by various instrumental analyses involving LC-NMR. The results showed that R1 and R2 have a hydroxyamino group and an amino group at the C-7 position of the quinoxalinedione skeleton, respectively. Therefore, the proposed metabolic pathway of YM872 in rats involves the reduction of the nitro group to a hydroxyamino group and then subsequent reduction to an amino group.


Assuntos
Imidazóis/urina , Espectroscopia de Ressonância Magnética/métodos , Quinoxalinas/urina , Animais , Cromatografia Líquida/métodos , Imidazóis/química , Imidazóis/metabolismo , Masculino , Quinoxalinas/química , Quinoxalinas/metabolismo , Ratos , Ratos Sprague-Dawley
20.
Chem Res Toxicol ; 17(8): 1121-36, 2004 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-15310244

RESUMO

A rapid and facile tandem solvent solid phase extraction method was established to isolate the heterocyclic aromatic amines (HAAs) 2-amino-3,8-dimethylimidazo[4,5-f]quinoxaline (8-MeIQx), 2-amino-3,4,8-trimethylimidazo[4,5-f]quinoxaline, 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine, and 2-amino-9H-pyrido[2,3-b]indole from urine. The HAAs were separated by reversed phase liquid chromatography and quantified by electrospray ionization tandem mass spectrometry (ESI/MS/MS) using selected reaction monitoring. The limits of detection and quantitation of these HAAs approached 1-3 and 2-8 pg/mL, respectively, using only 0.3 mL of urine for analysis. Full product ion spectra were acquired to corroborate analyte identities. The pretreatment of urine from human volunteers that had consumed a grilled beef meal with acid or base at 70 degrees C increased the concentration of HAAs by as much as 6-fold, indicating the presence of phase II conjugates of the parent compounds. HAAs containing an N-methylimidazole moiety undergo facile cleavage of the N-methyl group under collision-induced dissociation conditions, and MS/MS analysis in the constant neutral loss scan mode monitoring the transition [M + H](+) --> [M + H - CH(3)(*)](+) revealed the presence of two other HAAs. 2-Amino-3-methylimidazo[4,5-f]quinoxaline (IQx) was identified by coelution of the analyte with synthetic IQx and by acquisition of the product ion spectrum. The second HAA was present in a relatively high abundance in urine. The molecule had the same nominal mass as 8-MeIQx (MH(+) at m/z 214), and the product ion spectrum was similar to that of 8-MeIQx. This novel HAA was also found in the grilled meat consumed by the volunteers at a concentration of 8 parts per billion. The accurate mass measurement and product ion spectrum of this molecule by ESI quadrupole time-of-flight mass spectrometry revealed that it was an isomer of 8-MeIQx. This tandem solvent solid phase extraction LC/ESI/MS/MS procedure may be used to rapidly assess the daily exposure to a variety of HAAs in urine.


Assuntos
Aminas/urina , Cromatografia Líquida/métodos , Hidrocarbonetos Policíclicos Aromáticos/urina , Espectrometria de Massas por Ionização por Electrospray/métodos , Animais , Carbolinas/urina , Bovinos , Alimentos/toxicidade , Compostos Heterocíclicos/efeitos adversos , Compostos Heterocíclicos/urina , Humanos , Masculino , Hidrocarbonetos Policíclicos Aromáticos/efeitos adversos , Quinoxalinas/urina
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