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1.
Biopharm Drug Dispos ; 38(4): 301-312, 2017 May.
Artículo en Inglés | MEDLINE | ID: mdl-28092695

RESUMEN

Delamanid (OPC-67683, Deltyba™, nitro-dihydro-imidazooxazoles derivative) is approved for the treatment of adult pulmonary multidrug-resistant tuberculosis. The absorption, distribution and excretion of delamanid-derived radioactivity were investigated after a single oral administration of 14 C-delamanid at 3 mg/kg to rats. In both male and female rats, radioactivity in blood and all tissues reached peak levels by 8 or 24 h post-dose, and thereafter decreased slowly. Radioactivity levels were 3- to 5-fold higher in lung tissue at time to maximum concentration compared with plasma. In addition, radioactivity was broadly distributed in various tissues, including the central nervous system, eyeball, placenta and fetus, indicating that 14 C-delamanid permeated the brain, retinal and placental blood barriers. By 168 h post-dose, radioactivity in almost all the tissues was higher than that in the plasma. Radioactivity was also transferred into the milk of lactating rats. Approximately 6% and 92% of radioactivity was excreted in the urine and feces, respectively, indicating that the absorbed radioactivity was primarily excreted via the biliary route. No significant differences in the absorption, distribution and excretion of 14 C-delamanid were observed between male and female rats. The pharmacokinetic results suggested that delamanid was broadly distributed to the lungs and various tissues for a prolonged duration of time at concentrations expected to effectively target tuberculosis bacteria. These data indicate that delamanid, in addition to its previously demonstrated efficacy in pulmonary tuberculosis, might be an effective therapeutic approach to treating extrapulmonary tuberculosis. Copyright © 2017 John Wiley & Sons, Ltd.


Asunto(s)
Antituberculosos/farmacocinética , Antituberculosos/uso terapéutico , Nitroimidazoles/farmacocinética , Nitroimidazoles/uso terapéutico , Oxazoles/farmacocinética , Oxazoles/uso terapéutico , Tuberculosis/tratamiento farmacológico , Animales , Antituberculosos/orina , Bilis/química , Bilis/metabolismo , Heces/química , Femenino , Absorción Intestinal , Hígado/metabolismo , Masculino , Intercambio Materno-Fetal , Leche/química , Nitroimidazoles/orina , Oxazoles/orina , Placenta/metabolismo , Embarazo , Ratas , Ratas Sprague-Dawley , Distribución Tisular
2.
Anal Chim Acta ; 958: 51-58, 2017 Mar 15.
Artículo en Inglés | MEDLINE | ID: mdl-28110684

RESUMEN

A novel one-step hydrothermal synthesis of highly fluorescent platinum nanoclusters protected by polyethylenimine (Pt-NCs@PEI) is described. The products are characterized well by UV-vis absorption, fluorescence spectra, X-ray photoelectron spectroscopy (XPS) and transmission electron microscopy (TEM) imaging. The Pt-NCs@PEI possess high quantum yield at 28%, which is the relatively high one among the reported Pt-NCs; especially, the synthesis is in one-step and the reaction time is much shorter (<1 h) than the related methods. In addition, the Pt-NCs@PEI have large Stocks-shift (∼150 nm), high tolerability to the extreme pH and high ionic strengths, and excellent photo-stability under UV-vis irradiation, lay the foundation for the practical bio-applications. Finally, the obtained Pt-NCs@PEI are used to determine trace amount of metronidazole (MTZ) in buffer solution in showing a linear response over a concentration range of 0.25-300 µM and a low detection limit of 0.1 µM. Furthermore, the related investigation on response mechanism will be helpful to design and synthesize new metal nanoclusters as fluorescent probe to detect the trace amount of harmful medicine residuum as nitroimidazoles in human body.


Asunto(s)
Nitroimidazoles/orina , Platino (Metal)/química , Polietileneimina/química , Humanos , Límite de Detección , Nanopartículas del Metal , Espectroscopía de Fotoelectrones
3.
Talanta ; 163: 111-120, 2017 Jan 15.
Artículo en Inglés | MEDLINE | ID: mdl-27886759

RESUMEN

A novel capillary electrophoresis-tandem mass spectrometry approach is proposed for the determination of eleven 5-nitroimidazoles in urine samples for therapeutical drug monitoring purposes. A comparison between two separation modes, namely micellar electrokinetic chromatography and capillary zone electrophoresis was carried out, obtaining higher selectivity when 1M formic acid (pH 1.8) was selected as background electrolyte. 5-Nitroimidazoles were hydrodynamically injected in water for 40s at 50mbar and their separation was performed at 28kV and 25°C. To improve migration time repeatability, a pressure of 50mbar was applied to the inlet vial during runs without any loss of peak resolution. Electrospray ionization parameters were established as follow: 6L/min, dry gas flow rate; 51,021.2Pa, nebulization pressure; 160°C, dry gas temperature. Sheath liquid consisted of a mixture of propan-2-ol/water/acetic acid (60.0:38.8:0.2% v/v/v) supplied at 3.3µL/min. MS parameters were optimized for analyte identification through their MS2 and MS3 spectra. The method was applied to the determination of 5-nitroimidazoles in urine samples, applying molecularly imprinted solid phase extraction for sample clean-up. Recoveries higher than 79.2% demonstrated the suitability of the procedure. Limits of detection ranged from 9.6 to 130.2µg/L while precision assays resulted in relative standard deviations for peak areas lower than 16.1%.


Asunto(s)
Electroforesis Capilar/métodos , Nitroimidazoles/aislamiento & purificación , Nitroimidazoles/orina , Extracción en Fase Sólida/métodos , Espectrometría de Masas en Tándem/métodos , Urinálisis/métodos , Humanos , Límite de Detección , Nitroimidazoles/química , Nitroimidazoles/metabolismo
4.
Electrophoresis ; 36(20): 2606-15, 2015 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-26200811

RESUMEN

The separation of eight antibiotics belonging to 5-nitroimidazole family was carried out by means of CEC coupled with MS. Preliminary experiments were carried out with ultraviolet detection in order to select the proper stationary and mobile phase. Among the different stationary phases studied (namely Lichrospher C18, 5 µm particle size; Cogent(TM) Bidentate C18, 4.2 µm; Pinnacle II™ Phenyl, 3 µm; Pinnacle II™ Cyano, 3 µm), Cogent™ Bidentate C18 (4.2 µm) gave the best performance. For CEC-MS coupling, a laboratory assembled liquid-junction-nano-spray interface was used. In order to achieve a good sensitivity, special attention was paid to both optimization of the sheath liquid composition as well as selection of the injection mode. Under optimized CEC-ESI-MS conditions, the separation was accomplished within 22 min by using a column packed with a mixture of Bidentate C18:Lichrospher Silica-60 (5 µm) 3:1 w/w, an inlet pressure of 11 bar, a voltage of 15 kV, and a mobile phase composed by 45:10:45 v/v/v ACN/MeOH/water containing ammonium acetate (5 mM pH 5). A combined hydrodynamic and electrokinetic injection of 8 bar, 15 kV, and 96 s was adopted. The method was validated in terms of repeatability and intermediate precision of retention times and peak areas, linearity, and LODs and LOQs. RSDs values were <2.9% for retention times and <16.1% for peak areas in both intraday and interday experiments. LOQ values were between 0.09 and 0.42 µg/mL for all compounds. Finally, the method was applied to the determination of three most employed 5-nitroimidazole antibiotics (metronidazole, secnidazole, and ternidazole) in spiked urine samples, subjected to a SPE procedure. Recovery values in the 67-103% range were obtained. Furthermore, for the selected antibiotics, CEC-MS(2) spectra were obtained providing the unambiguous confirmation of these drugs in urine samples.


Asunto(s)
Antibacterianos/orina , Electrocromatografía Capilar/métodos , Espectrometría de Masas/métodos , Nitroimidazoles/orina , Humanos , Modelos Lineales , Masculino , Reproducibilidad de los Resultados , Sensibilidad y Especificidad
5.
Electrophoresis ; 36(20): 2538-41, 2015 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-26174089

RESUMEN

Cation-selective exhaustive injection and sweeping followed by a MEKC separation is evaluated for the sensitive analysis of 5-nitroimidazoles in untreated human serum and urine. Deproteinized serum and urine samples were diluted 76 and 143 times, respectively, in a low-conductivity solvent (5.00 mM orthophosphoric acid containing 5.0% v/v methanol). Samples were electrokinetically injected at 9.8 kV for 632 s in a previously conditioned fused-silica capillary (65.0 cm × 50 µm id). Separation was performed at -30 kV and 20°C using 44 mM phosphate buffer (pH 2.5), 123 mM SDS, and 8% v/v tetrahydrofurane as BGE. Signals were monitored at 276 nm and peak area was selected as analytical response. Good linearity (R(2) ≥ 0.988) and LODs lower than 1.5 and 1.8 µg/mL were achieved in serum and urine, respectively.


Asunto(s)
Cromatografía Capilar Electrocinética Micelar/métodos , Nitroimidazoles/sangre , Nitroimidazoles/orina , Cationes , Humanos , Límite de Detección , Modelos Lineales , Nitroimidazoles/química , Nitroimidazoles/aislamiento & purificación , Reproducibilidad de los Resultados
6.
Talanta ; 131: 656-60, 2015 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-25281155

RESUMEN

Monitoring the drug benznidazole in biological fluids is a powerful tool for clinical diagnostic and pharmacological studies in chagasic patients. However, research in this concern needs to be done. The accurate quantitation of this drug in complex matrices represents a highly challenging task complicated by the absence of sensitive analytical methods. It follows that sample processing strategies, preparation/cleanup procedures, and chromatographic/ionization/detection parameters, were evaluated for method optimization. The summation of this work generated a rapid, selective, sensitive methodology based on reversed-phase chromatography-tandem mass spectrometry for the analysis of benznidazole in urine samples. To the best of our knowledge, this is a first report of a LC-MS/MS platform employed for this application. Matrix effect was determined; a 90% of signal suppression was observed. The limits of detection and quantification were 0.75 and 4.85 µg L(-1); respectively. The latter allowed the method's application to the detection of benznidazole in clinical studies and pharmacological monitoring analysis.


Asunto(s)
Enfermedad de Chagas/orina , Cromatografía Liquida/métodos , Nitroimidazoles/orina , Espectrometría de Masas en Tándem/métodos , Tripanocidas/orina , Niño , Humanos , Extracción Líquido-Líquido/métodos , Nitroimidazoles/aislamiento & purificación , Tripanocidas/aislamiento & purificación
7.
Antimicrob Agents Chemother ; 58(7): 4153-61, 2014 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-24820074

RESUMEN

Morinidazole is a novel 5-nitroimidazole antimicrobial drug that undergoes extensive metabolism in humans via N(+)-glucuronidation (N(+)-glucuronide of S-morinidazole [M8-1] and N(+)-glucuronide of R-morinidazole [M8-2]) and sulfation (sulfate conjugate of morinidazole [M7]). Our objectives were to assess the effects of renal impairment on the pharmacokinetics (PK) of morinidazole and to elucidate the potential mechanisms. In this parallel-group study, healthy subjects and patients with severe renal impairment received an intravenous infusion of 500 mg of morinidazole. Plasma and urine samples were collected and analyzed. The areas under the plasma concentration-time curves (AUC) for M7, M8-1, and M8-2 were 15.1, 20.4, and 17.4 times higher, respectively, in patients with severe renal impairment than in healthy subjects, while the AUC for morinidazole was 1.5 times higher. The urinary recovery of the major metabolites was not significantly different between the two groups over 0 to 48 h, but the renal clearances of M7, M8-1, and M8-2 in patients were 85.3%, 92.5%, and 92.2% lower, respectively. In vitro transporter studies revealed that M7 is a substrate for organic anion transporter 1 (OAT1) and OAT3 (Km = 28.6 and 54.0 µM, respectively). Only OAT3 transported M8-1 and M8-2. Morinidazole was not a substrate for the transporter-transfected cells examined. These results revealed that the function or activity of renal uptake transporters might be impaired in patients with severe renal impairment, which accounted for dramatically increased plasma exposure and reduced renal clearance of the conjugated metabolites of morinidazole, the substrates of renal transporters in patients. It will help clinicians to adjust the dose in patients with severe renal impairment and to predict possible transporter-based drug-drug interactions.


Asunto(s)
Antibacterianos/farmacocinética , Nitroimidazoles/farmacocinética , Proteína 1 de Transporte de Anión Orgánico/metabolismo , Transportadores de Anión Orgánico Sodio-Independiente/metabolismo , Insuficiencia Renal/metabolismo , Adulto , Antibacterianos/sangre , Antibacterianos/orina , Área Bajo la Curva , Línea Celular , Cimetidina/farmacología , Femenino , Células HEK293 , Humanos , Infusiones Intravenosas , Riñón/metabolismo , Masculino , Persona de Mediana Edad , Nitroimidazoles/sangre , Nitroimidazoles/orina , Proteína 1 de Transporte de Anión Orgánico/genética , Transportadores de Anión Orgánico Sodio-Independiente/genética , Probenecid/farmacología , Unión Proteica , Transfección , Adulto Joven
8.
J Clin Lab Anal ; 27(5): 384-90, 2013 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-24038224

RESUMEN

OBJECTIVE: Chagas disease constitutes a major public health problem in Latin America. Correctly designed pharmacokinetic, safety, and bioequivalence studies are desirable in order to fill the knowledge gaps that presently exist on available drugs. It is necessary to develop accurate, simple, reproducible, and sensitive high-performance liquid chromatography (HPLC)/UV methods for the quantization of benznidazole (BNZ) in human plasma and urine for clinical applications, specially in pediatric patients. METHODS: Quantization of BNZ in human plasma involved freeze-drying and re-suspension in organic solvent followed by reverse phase HPLC with UV detection. Analysis of BNZ in urine involved liquid/liquid extraction followed by reverse phase HPLC with UV detection. RESULTS: Limits of quantization (LOQ) were 0.32 µg/ml for plasma and 5.2 µg/ml for urine. No metabolite interferences were showed in both methods. CONCLUSION: The LOQ of methods seems appropriate in pediatric clinical contexts. Both procedures were applied with good results, to the quantization of BNZ in plasma and urine of patients treated for Chagas disease.


Asunto(s)
Cromatografía Líquida de Alta Presión/métodos , Nitroimidazoles/sangre , Nitroimidazoles/orina , Enfermedad de Chagas/tratamiento farmacológico , Niño , Liofilización , Humanos , Nitroimidazoles/uso terapéutico , Manejo de Especímenes/métodos , Tripanocidas/sangre , Tripanocidas/uso terapéutico , Tripanocidas/orina
9.
Drug Metab Dispos ; 40(3): 556-67, 2012 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-22184458

RESUMEN

Morinidazole [R,S-1-(2-methyl-5-nitro-1H-imidazol-1-yl)-3-morpholinopropan-2-ol] is a new 5-nitroimidazole class antimicrobial agent. The present study aimed to determine the metabolism and pharmacokinetics of morinidazole in humans and to identify the enzymes responsible for the formation of the major metabolites. Plasma and urine samples were collected before and after an intravenous drip infusion of 500 mg of racemic morinidazole. Ultraperformance liquid chromatography/quadrupole time-of-flight mass spectrometry revealed 10 metabolites. Morinidazole glucuronidation, followed by renal excretion, was the major elimination pathway, accounting for 35% of the dose. The metabolic pathway displayed regioselectivities and stereoselectivities. Unexpectedly, the nitrogen atom of the morpholine ring, rather than the aliphatic hydroxyl group at the side chain, was glucuronidated to form S-morinidazole glucuronide (M8-1) and R-enantiomer glucuronide (M8-2). The plasma exposure of M8-2 was 6-fold higher than that of M8-1, accounting for 22.9 and 3.96% of the parent drug exposure, respectively. Investigation of morinidazole glucuronidation using human liver microsomes (HLMs) and 12 recombinant UDP glucuronosyltransferases (UGTs) indicated that this biotransformation was mainly catalyzed by UGT1A9. A kinetic study showed that N(+)-glucuronidation of racemic morinidazole in both HLMs and in UGT1A9 obeyed a typical Michaelis-Menten plot. The K(m) values for M8-1 and M8-2 formation by HLMs were similar (11.3 and 15.1 mM), but the V(max) values were significantly different (111 and 1660 pmol · min(-1) · mg protein(-1)). Overall, after an intravenous administration, morinidazole and its metabolites were eliminated in humans primarily via renal excretion. The major metabolites were two diastereoisomeric N(+)-glucuronides, and UGT1A9 played an important role in N(+)-glucuronidation.


Asunto(s)
Glucurónidos/metabolismo , Glucuronosiltransferasa/metabolismo , Morfolinas/metabolismo , Nitroimidazoles/metabolismo , Adulto , Biotransformación , Catálisis , Cromatografía Líquida de Alta Presión/métodos , Femenino , Humanos , Cinética , Masculino , Espectrometría de Masas/métodos , Microsomas Hepáticos/enzimología , Microsomas Hepáticos/metabolismo , Nitroimidazoles/sangre , Nitroimidazoles/farmacocinética , Nitroimidazoles/orina , Estereoisomerismo , UDP Glucuronosiltransferasa 1A9 , Adulto Joven
10.
J AOAC Int ; 89(4): 1116-9, 2006.
Artículo en Inglés | MEDLINE | ID: mdl-16915853

RESUMEN

A reliable and sensitive method was developed for determination of nitroimidazoles in porcine urine. Sample preparation involves an extraction with ethyl acetate, followed by a solid-phase extraction cleanup step. The final extract is injected into the liquid chromatography/tandem mass spectrometry system in the positive-ion electrospray ionization mode. A C8 column with water and acetonitrile as the mobile phase is used for chromatographic separation under gradient conditions. Overall average recoveries ranged from 83 to 107%. The limits of detection ranged from 0.03 to 0.05 ng/mL, and the limits of quantitation, from 0.1 to 0.2 ng/mL.


Asunto(s)
Técnicas de Química Analítica/métodos , Cromatografía Liquida/métodos , Espectrometría de Masas/métodos , Nitroimidazoles/análisis , Nitroimidazoles/orina , Orina , Animales , Calibración , Iones , Reproducibilidad de los Resultados , Sensibilidad y Especificidad , Solventes/química , Porcinos , Temperatura
11.
J Pharm Biomed Anal ; 16(6): 1067-73, 1998 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-9547711

RESUMEN

Pharmacokinetic and dosimetric parameters of the hypoxic tissue imaging agent iodoazomycin arabinoside (123I-IAZA) have been investigated in human volunteers. In conjunction with this study it was necessary to develop an assay for low levels of the radiolabelled compound in blood and urine. A combination of high-performance liquid chromatography (HPLC) and gamma counting produced a highly selective, sensitive and rapid assay for the analysis of 123/125I-IAZA in human and animal blood and urine samples. Conventional HPLC assays for the tracer quantities of this radioactive agent in blood have not been reported previously. The addition of non-radiolabelled IAZA to the blood and urine samples containing radiolabelled IAZA allowed the pharmaceutical to serve as its own internal standard. This reverse isotope dilution approach permitted identification of the appropriate HPLC peak by UV detection, followed by highly sensitive quantification of the radiolabelled species by gamma counting. Blood samples were prepared for HPLC by a solid-phase extraction without the loss of IAZA from serum, with an extraction efficiency of 99.7 +/- 7.1% from human serum. Urine samples could be analyzed directly by HPLC, without the solid-phase extraction step. The detection limit in biological fluids depends on the specific activity of radiolabelled 123/125I-IAZA. In this study it was possible to detect serum concentrations of 123I-IAZA as low as 7.46 pg (21 fmol) per ml. The radiometric detection limit for 123I-IAZA in this assay was 10.8 Bq ml-1 of serum.


Asunto(s)
Hipoxia de la Célula/fisiología , Nitroimidazoles/análisis , Biomarcadores/análisis , Biomarcadores/sangre , Biomarcadores/orina , Calibración , Cromatografía Líquida de Alta Presión , Humanos , Indicadores y Reactivos , Radioisótopos de Yodo , Nitroimidazoles/sangre , Nitroimidazoles/orina , Estándares de Referencia , Espectrofotometría Ultravioleta
12.
Anticancer Drug Des ; 11(3): 231-42, 1996 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-8663910

RESUMEN

N-(2-Hydroxy-3,3,3-trifluoropropyl)-2-(2-nitro-1-imidazolyl) acetamide (SR-4554) is a fluorinated 2-nitroimidazole which has been rationally designed as a non-invasive probe for tumor hypoxia. The key selection criteria for this molecule were low central nervous system penetration and toxicity, high metabolic stability other than nitroreduction, good tumor uptake and high sensitivity for detection by magnetic resonance spectroscopy. As part of the pre-clinical development strategy, pharmacokinetic, bioavailability and biodistribution studies were performed in mice. Pharmacokinetic studies in mice demonstrated that SR-4554 was rapidly absorbed into plasma following i.p. administration and eliminated with a half-life of 42 min, similar to other 2-nitroimidazoles. By comparing the areas under the concentration-time curve (AUC), the tumor exposure towards SR-4554 was on average 84% of the value obtained for the plasma exposure. SR-4554 penetrated tumor tissue extremely well but, in contrast to misonidazole and certain other fluorinated analogues, its distribution into brain tissue was poor (AUCbrain/AUCplasma = 0.07), suggesting potentially lower toxicity in spite of its higher lipophilicity (P = 0.43 versus 0.63, respectively). The bioavailability of SR-4554 from i.p. and p.o. routes was 100 and 96% respectively. In non-tumor-bearing mice, SR-4554 was excreted mainly as unchanged drug. The percentage of the injected i.p. dose of SR-4554 excreted unchanged in the urine over 24 h was 68 +/- 8%. Neither SR-4554 nor its metabolites were detected in mouse feces. We propose that these favorable pharmacokinetic properties of SR-4554 are due to the hydrophilic character and hydrogen-bonding capability of the amide and hydroxyl functions in the compound.


Asunto(s)
Hipoxia de la Célula , Neoplasias Mamarias Experimentales/metabolismo , Sondas Moleculares , Nitroimidazoles/farmacocinética , Animales , Disponibilidad Biológica , Encéfalo/metabolismo , Femenino , Hígado/metabolismo , Ratones , Ratones Endogámicos BALB C , Trasplante de Neoplasias , Nitroimidazoles/orina , Distribución Tisular
13.
Cancer Chemother Pharmacol ; 28(2): 118-22, 1991.
Artículo en Inglés | MEDLINE | ID: mdl-2060082

RESUMEN

During a clinical toxicity study it was possible to obtain urine samples from six patients receiving either the R-(-)- or S-(+)-stereoenantiomeric forms of the developmental 2-nitroimidazole radiosensitizer Ro 03-8799 (pimonidazole). Paired plasma samples were also obtained from four patients. The pharmacokinetic data were compared with those for the racemic mixture in the same individuals. The results revealed no major differences in the plasma pharmacokinetics, urinary clearance or N-oxidation of the individual enantiomers as compared with the racemic mixture. A similar lack of stereoselectivity with respect to the acute dose-limiting CNS toxicity syndrome suggests that this may not involve a specific CNS receptor interaction.


Asunto(s)
Adenocarcinoma/metabolismo , Carcinoma de Células Escamosas/metabolismo , Neoplasias Pulmonares/metabolismo , Nitroimidazoles/farmacocinética , Fármacos Sensibilizantes a Radiaciones/farmacocinética , Anciano , Femenino , Humanos , Masculino , Persona de Mediana Edad , Nitroimidazoles/sangre , Nitroimidazoles/metabolismo , Nitroimidazoles/orina , Fármacos Sensibilizantes a Radiaciones/metabolismo , Estereoisomerismo
14.
Int J Radiat Oncol Biol Phys ; 16(4): 1083-4, 1989 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-2522918

RESUMEN

Following an IV infusion of 2.0 g/m2 of Etanidazole, the mean tumor concentration 40 min after injection was 126 micrograms/g in bladder cancer and 65 micrograms/g in cervical cancer. The tumor/plasma concentration ratio was 1.88 in bladder and 0.85 in cervical cancer. This high tumor concentration in bladder cancer could be accounted for by diffusion from a highly concentrated urine. This renders bladder cancer a suitable clinical model for testing this sensitizer.


Asunto(s)
Carcinoma de Células Escamosas/metabolismo , Nitroimidazoles/farmacocinética , Fármacos Sensibilizantes a Radiaciones/farmacocinética , Neoplasias de la Vejiga Urinaria/metabolismo , Neoplasias del Cuello Uterino/metabolismo , Carcinoma de Células Escamosas/orina , Difusión , Etanidazol , Femenino , Humanos , Nitroimidazoles/orina , Fármacos Sensibilizantes a Radiaciones/orina , Neoplasias de la Vejiga Urinaria/orina , Neoplasias del Cuello Uterino/orina
15.
Braz J Med Biol Res ; 21(5): 1069-77, 1988.
Artículo en Inglés | MEDLINE | ID: mdl-3248236

RESUMEN

1. The mutagenicity of serum and urine from guinea pigs treated with a single oral dose (500 mg/kg) of benznidazole and nifurtimox was assayed using the Salmonella/plate incorporation test with strain TA 100 and a nitroreductase-deficient derivative, TA 100NR. 2. The urine and blood of animals treated with nifurtimox were not mutagenic for either tester strain. 3. The urine and blood of animals receiving benznidazole were mutagenic to the TA 100 but not to the TA 100NR strain. Similar results were obtained with nitrofurantoin-treated animals. Maximum mutagenicity values were obtained in serum and urine of treated animals 90 min and 24 h after administration, respectively. 4. Mutagenicity induced by benznidazole in the serum and urine of treated animals was not altered when assayed in anaerobic environments. 5. These results indicate that benznidazole and nifurtimox are not metabolized by the mammalian host into stable mutagenic derivatives detectable by the Ames test. Based on these data, we suggest that the potential cancer risk to patients treated with these drugs is small but should be further evaluated.


Asunto(s)
Nifurtimox/metabolismo , Nitrofuranos/metabolismo , Nitrofurantoína/metabolismo , Nitroimidazoles/metabolismo , Animales , Femenino , Cobayas , Masculino , Pruebas de Mutagenicidad , Mutación , Nifurtimox/sangre , Nifurtimox/orina , Nitrofurantoína/sangre , Nitrofurantoína/orina , Nitroimidazoles/sangre , Nitroimidazoles/orina
16.
J Med Chem ; 29(4): 555-61, 1986 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-3959031

RESUMEN

Many processes are involved in the renal excretion of drugs, but very little is known about their quantitative structure-activity relationship. The relationship between urinary excretion and lipophilic character of a series of nitroimidazoles and nitrothiazoles was studied. The unmetabolized forms of the drugs were detected in the urine by means of UV and HPLC procedures. The urinary excretion of unmetabolized forms is parabolically related with the log P, as an expression of lipophilic character of molecules.


Asunto(s)
Nitroimidazoles/orina , Tiazoles/orina , Animales , Cromatografía Líquida de Alta Presión , Femenino , Riñón/metabolismo , Ratas , Ratas Endogámicas , Solubilidad , Espectrofotometría Ultravioleta , Relación Estructura-Actividad , Factores de Tiempo
17.
J Pharm Sci ; 73(12): 1731-4, 1984 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-6527245

RESUMEN

1H-NMR and MS were employed to identify 13 rat urinary metabolites of 14C-labeled cis-3a,4,5,6,7,7a- hexahydro-3-(1-methyl-5-nitro-1H-imidazol-2-yl)-1,2-benzisoxazole (MK-0436). The major free (unconjugated) metabolite was cis-3a,4,5,6,7, 7a-hexahydro-3-carboxamido-1,2-benzisoxazole; it was also the second most abundant metabolite released during hydrolysis of the conjugated fraction. All other identified metabolites were hydroxylated analogues substituted at C(4)-C(7a) of the cyclohexane ring. the 4-equatorial,5-axial,7a-triol was the second most abundant metabolite excreted in an unconjugated form. Four monohydroxy (5-axial, 6-axial, 6-equatorial, 7-equatorial) metabolites of the drug were identified; they were found in the conjugated fraction only and were released by hydrolysis. The 5-axial hydroxy compound is the major conjugated metabolite and is overall the most abundant of all the metabolites. Six dihydroxy metabolites were identified: one was found exclusively in the free state, three as conjugates only (including the 7-axial,7a-diol, which is the major dihydroxy species), and two both free and conjugated. A second triol was found both free and conjugated.


Asunto(s)
Antiprotozoarios/orina , Nitroimidazoles/orina , Animales , Antiprotozoarios/metabolismo , Biotransformación , Hidrólisis , Espectrometría de Masas , Nitroimidazoles/metabolismo , Ratas , Ratas Endogámicas
18.
Int J Radiat Oncol Biol Phys ; 10(8): 1361-3, 1984 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-6469757

RESUMEN

Chemical studies have indicated that, following reduction of misonidazole to the hydroxylamine derivative, reaction with guanosine leads to the formation of a 2-carbon addition product of guanosine. In this study, the formation of the guanosine product is used to detect the presence of a reactive metabolite of misonidazole in the urine of patients treated with misonidazole. Urine samples were incubated with [14C]guanosine and the guanosine product was separated by HPLC analysis. The quantities of product vary as much as 10-fold from patient to patient and it is suggested that the assay might be useful as a predictor of patients susceptible to the development of peripheral neuropathy or other effects of misonidazole.


Asunto(s)
Misonidazol/orina , Nitroimidazoles/orina , Terapia Combinada , Femenino , Humanos , Misonidazol/uso terapéutico , Fármacos Sensibilizantes a Radiaciones/uso terapéutico , Neoplasias del Cuello Uterino/tratamiento farmacológico , Neoplasias del Cuello Uterino/radioterapia , Neoplasias del Cuello Uterino/terapia
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