RESUMEN
Neonicotinoids (neonics), a class of systemic insecticides, have been frequently detected in pollen, vegetables, and fruits. Recently, an increasing concern has been aroused for human exposure to neonics. However, biological monitoring for quantifying body burden of neonics has rarely been reported. In this study, we developed an isotope-dilution ultra-high performance liquid chromatography coupled with tandem mass spectrometry (UPLC-MS/MS) method to simultaneously quantify nine neonics, including acetamiprid (ACE), thiamethoxam (THIAM), imidacloprid (IMIP), clothianidin (CLO), flonicamid (FLO), thiacloprid (THIAC), dinotefuran (DIN), nitenpyram (NIT), and imidaclothiz (IMIT) in urine. The limits of quantification were 0.1⯵g/L for ACE, FLO, DIN, NIT and IMIT, and 0.2⯵g/L for THIAM, IMIP, CLO, and THIAC. The overall recoveries were 80.8-103%, 81.5-91.7% and 83.0-92.3% for QA/QC samples fortifying at 1, 25, and 100⯵g/L levels, respectively. UPLC/MS/MS method was used to analyze urine samples obtained from 10 children in Hangzhou, China. The detection frequencies were 80% for ACE and IMIP, 70% for THIAM and CLO, 20% for DIN and IMIT and 10% for THIAC. FLO and NIT were not detected in those urine samples. The data provided here will be helpful for conducting biological monitoring of neonics exposure in the future.
Asunto(s)
Cromatografía Líquida de Alta Presión/métodos , Monitoreo del Ambiente/métodos , Insecticidas/orina , Neonicotinoides/orina , Espectrometría de Masas en Tándem/métodos , Niño , China , Guanidinas/orina , Humanos , Técnicas de Dilución del Indicador , Isótopos/análisis , Niacinamida/análogos & derivados , Niacinamida/orina , Nitrocompuestos/orina , Oxazinas/orina , Piridinas/química , Tiametoxam , Tiazinas/orina , Tiazoles/análisis , Tiazoles/orinaRESUMEN
A novel colorimetric nanomaterial-assisted optical sensor for pazufloxacin mesilate was proposed for the first time. Pazufloxacin mesilate could induce the aggregation of glucose-reduced gold nanoparticles (AuNPs) through hydrogen-bonding interaction and electrostatic attraction, leading to the changes in color and absorption spectra of AuNPs. The effect of different factors such as pH, the amount of AuNPs, reaction time and reaction temperature was inspected. Under the optimum condition, UV-vis spectra showed that the absorption ratio (A670/A532) was linear with the concentration of pazufloxacin mesilate in the range from 9×10(-8) mol L(-1) to 7×10(-7) mol L(-1) with a linear coefficient of 0.9951. This method can be applied to detecting pazufloxacin mesilate with an ultralow detection limit of 7.92×10(-9) mol L(-1) without any complicated instruments. Through inspecting other analytes and ions, the anti-interference performance of AuNP detection system for pazufloxacin mesilate was excellent. For its high efficiency, rapid response rate as well as wide linear range, it had been successfully used to the analysis of pazufloxacin mesilate in human urine quantificationally.
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Antituberculosos/orina , Colorimetría/métodos , Fluoroquinolonas/orina , Oro/química , Mesilatos/orina , Nanopartículas del Metal/química , Oxazinas/orina , Humanos , Límite de Detección , Nanopartículas del Metal/ultraestructuraRESUMEN
PURPOSE: The aims of the present study were to characterize the pharmacokinetics of fostamatinib in two phase I studies in healthy Japanese subjects after single- and multiple-dose administration, and to evaluate the utility of dried blood spot (DBS) sampling. METHODS: In study A, 40 Japanese and 16 white subjects were randomized in a double-blind parallel group study consisting of seven cohorts, which received either placebo or a fostamatinib dose between 50 and 200 mg after single and multiple dosing. Pharmacokinetics of R406 (active metabolite of fostamatinib) in plasma and urine was assessed, and safety was intensively monitored. Study B was an open-label study that assessed fostamatinib 100 and 200 mg in 24 Japanese subjects. In addition to plasma and urine sampling (as for study A), pharmacokinetics was also assessed in blood. RESULTS: Mean maximum plasma concentration (C max) and area under total plasma concentrationtime curve (AUC) increased with increasing dose in Japanese subjects. Steady state was achieved in 57 days for all doses. C max and AUC were both higher in Japanese subjects administered a 150-mg single dose than in white subjects. This difference was maintained for steady state exposure by day 10. Overall, R406 blood concentrations were consistent and â¼2.5-fold higher than in plasma. Minimal (<0.1 %) R406 was excreted in urine. Fostamatinib was well tolerated at all doses. CONCLUSIONS: Fostamatinib pharmacokinetics following single- and multiple-dose administration was approximately dose proportional at all doses ≤150 mg and greater than dose proportional at 200 mg in Japanese subjects. Japanese subjects administered fostamatinib 150 mg had higher exposure than white subjects. R406 could be measured in DBS samples and distributed into red blood cells, and DBS sampling was a useful method for assessing R406 pharmacokinetics.
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Oxazinas/sangre , Oxazinas/farmacocinética , Piridinas/sangre , Piridinas/farmacocinética , Adulto , Aminopiridinas , Pueblo Asiatico , Método Doble Ciego , Eritrocitos/metabolismo , Femenino , Humanos , Péptidos y Proteínas de Señalización Intracelular/antagonistas & inhibidores , Masculino , Morfolinas , Oxazinas/orina , Proteínas Tirosina Quinasas/antagonistas & inhibidores , Piridinas/orina , Pirimidinas , Quinasa Syk , Adulto JovenRESUMEN
Over the last two decades, usage of neonicotinoid (NEO) insecticides has increased due to their high selectivity for insects versus mammals and their effectiveness for extermination of insects resistant to conventional pesticides such as pyrethroids and organophosphates (OPs). However, historical change of the NEO exposure level in humans is poorly understood. The aim of this study is to reveal changes in the levels of NEO and OP exposure in the human body over the last two decades using biomonitoring technique. We quantified urinary concentrations of 7 NEOs (acetamiprid, clothianidin, dinotefuran, imidacloprid, nitenpyram, thiacloprid, and thiamethoxam) and 4 metabolites of OPs (dimethylphosphate, dimethylthiophosphate, diethylphosphate, and diethylthiophosphate) in 95 adult females aged 45-75 in 1994, 2000, 2003, 2009, and 2011 (n = 17-20 different individuals in each year). The results show that the detection rates of urinary NEOs in Japanese women increased significantly between 1994 and 2011, suggesting that intakes of NEOs into the human body rose during that period. In contrast, exposure to OPs having O,O-dimethyl moieties decreased steadily according to a finding that geometric means of urinary dimethylphosphate concentrations kept diminishing considerably. These changes may reflect the amounts of NEOs and OPs used as insecticides in Japan.
Asunto(s)
Contaminantes Ambientales/orina , Insecticidas/orina , Organofosfatos/orina , Adulto , Anciano , Animales , Monitoreo del Ambiente/métodos , Femenino , Guanidinas/orina , Humanos , Imidazoles/orina , Japón , Persona de Mediana Edad , Neonicotinoides , Nitrocompuestos/orina , Compuestos Organofosforados/orina , Oxazinas/orina , Piridinas/orina , Tiametoxam , Tiazinas/orina , Tiazoles/orinaRESUMEN
OBJECTIVES: Agricultural use of neonicotinoid (NEO) insecticides has been increasing in recent years, but their biological monitoring methods have been scarcely reported. In this study, we developed and validated a rapid and sensitive method for quantifying urinary NEO concentrations using high-performance liquid chromatography-tandem mass spectrometry (LC-MS/MS). METHODS: After phosphate-induced acidification of a urine sample, urinary NEOs were trapped by a solid-phase extraction column and eluted with methanol for acetamiprid, imidacloprid, thiacloprid, thiamethoxam, clothianidin and dinotefuran and with an acetonitrile and methanol solution (1:1, v/v) containing 5% NH3 for nitenpyram. A separation analysis was performed by LC-MS/MS within 10 minutes for the sample. This method was applied to first morning urine obtained from 52 Japanese (40.9 ± 10.5 years old, mean ± standard deviation) without occupational NEO exposure. RESULTS: The linear dynamic ranges and their limit of quantification (LOQ, signal to noise ratio=10) levels were 0.3-20 or 50 µg/l (r=0.998-0.999) and 0.05-0.36 µg/l, respectively. The absolute recovery was 64-95%, and the intra- and inter-day precisions were less than 16.4% (relative standard deviation, %RSD). This method was successfully applied for analysis of NEOs in human urine samples obtained from 52 adults. The frequencies of individuals who showed more than LOD levels was above 90% for imidacloprid, thiamethoxam, clothianidin and dinotefuran, more than 50% for acetamiprid and thiacloprid and 29% for nitenpyram. CONCLUSIONS: These results indicated that our new method could be applied to biological monitoring of NEO exposure even at environmental exposure levels in Japanese adults without occupational spraying histories.
Asunto(s)
Cromatografía Líquida de Alta Presión/métodos , Monitoreo del Ambiente/métodos , Insecticidas/orina , Exposición Profesional/análisis , Espectrometría de Masas en Tándem/métodos , Acetonitrilos , Adulto , Femenino , Guanidinas/orina , Humanos , Imidazoles/orina , Japón , Masculino , Metanol , Persona de Mediana Edad , Neonicotinoides , Nitrocompuestos/orina , Oxazinas/orina , Piridinas/orina , Extracción en Fase Sólida/métodos , Tiametoxam , Tiazinas/orina , Tiazoles/orinaRESUMEN
OBJECTIVE: The aim of this study was to investigate the pharmacokinetics and dose proportionality of a single, intravenous dose of pazufloxacin mesilate, an injectable fluoroquinolone antibiotic, in healthy Korean male volunteers. METHODS: In this open-label, four-dose, parallel study, subjects were randomized to receive a single dose of pazufloxacin mesilate 300, 500, 600, and 1,000 mg (n = 6, 20, 6, and 8, respectively) administered as a 1-h intravenous infusion. Blood and urine samples were collected serially from 0 to 24 h after drug administration and analyzed using a validated HPLC method. Tolerability was assessed by monitoring clinical laboratory parameters and adverse events. RESULTS: After single-dose intravenous administration of pazufloxacin mesilate, the mean C(max) for groups treated with 300, 500, 600, and 1,000 mg doses ranged from 5.11 to 18.06 µg/mL; the mean AUC(0-t) ranged from 13.70 to 58.60 µg × h/mL. Pazufloxacin exhibits Lack of dose proportionality was concluded over the dose range of 300 - 1,000 mg, based on linear regression model and power model . At all four dosages studied, pazufloxacin mesilate was well tolerated. CONCLUSIONS: Our data suggest that all regimens of pazufloxacin administration were well tolerated. Pazufloxacin exhibits lack of dose proportionality over the dose range of 300 - 1,000 mg.
Asunto(s)
Relación Dosis-Respuesta a Droga , Fluoroquinolonas/administración & dosificación , Fluoroquinolonas/farmacocinética , Mesilatos/administración & dosificación , Mesilatos/farmacocinética , Oxazinas/administración & dosificación , Oxazinas/farmacocinética , Administración Intravenosa , Adulto , Área Bajo la Curva , Pueblo Asiatico , Cromatografía Líquida de Alta Presión , Fluoroquinolonas/sangre , Fluoroquinolonas/orina , Humanos , Modelos Lineales , Masculino , Oxazinas/sangre , Oxazinas/orina , República de Corea , Adulto JovenRESUMEN
LC coupled to single (LC-MS) and tandem (LC-MS/MS) mass spectrometry is recognized as the most powerful analytical tools for metabolic studies in drug discovery. In this article, we describe five cases illustrating the utility of screening xenobiotic metabolites in routine analysis of forensic samples using LC-MS/MS. Analyses were performed using a previously published LC-MS/MS general unknown screening (GUS) procedure developed using a hybrid linear IT-tandem mass spectrometer. In each of the cases presented, the presence of metabolites of xenobiotics was suspected after analyzing urine samples. In two cases, the parent drug was also detected and the metabolites were merely useful to confirm drug intake, but in three other cases, metabolite detection was of actual forensic interest. The presented results indicate that: (i) the GUS procedure developed is useful to detect a large variety of drug metabolites, which would have been hardly detected using targeted methods in the context of clinical or forensic toxicology; (ii) metabolite structure can generally be inferred from their "enhanced" product ion scan spectra; and (iii) structure confirmation can be achieved through in vitro metabolic experiments or through the analysis of urine samples from individuals taking the parent drug.
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Dibenzotiazepinas/orina , Noscapina/orina , Oxazinas/orina , Prazepam/orina , Trazodona/orina , Cromatografía Líquida de Alta Presión , Dibenzotiazepinas/metabolismo , Descubrimiento de Drogas , Toxicología Forense , Humanos , Noscapina/metabolismo , Oxazinas/metabolismo , Prazepam/metabolismo , Fumarato de Quetiapina , Reproducibilidad de los Resultados , Sensibilidad y Especificidad , Espectrometría de Masas en Tándem , Trazodona/metabolismoAsunto(s)
Ensayos Clínicos Fase I como Asunto , Monitoreo de Drogas/normas , Oxazinas/orina , Rifampin/orina , Alquinos , Fármacos Anti-VIH/uso terapéutico , Fármacos Anti-VIH/orina , Antibióticos Antituberculosos/uso terapéutico , Antibióticos Antituberculosos/orina , Benzoxazinas , Ciclopropanos , Dronabinol/orina , Monitoreo de Drogas/métodos , Reacciones Falso Positivas , Humanos , Oxazinas/uso terapéutico , Rifampin/uso terapéuticoRESUMEN
The present study aims to investigate whether pazufloxacin, a new quinolone antimicrobial agent, is a substrate for P-glycoprotein in vitro, and whether it is excreted from kidney by P-glycoprotein and/or multidrug resistance-associated protein (Mrp2) in vivo. The in vitro experiments showed that the intracellular accumulation of pazufloxacin in adriamycin-resistant human chronic myelogenous leukemia cells (K562/ADR) overexpressing P-glycoprotein was significantly lower than that in human chronic myelogenous leukemia cells (K562/S) not expressing P-glycoprotein. When rats received an intravenous injection of pazufloxacin in combination with or without cyclosporine, cyclosporine significantly delayed the disappearance of pazufloxacin from plasma and decreased the systemic clearance and volume of distribution at steady state of pazufloxacin to 50% and 70% of the corresponding control values, respectively. Renal handling experiments revealed that the renal clearance of pazufloxacin was 75% of that corresponding to the systemic clearance, suggesting that the main route of pazufloxacin elimination is the kidney. Cyclosporine significantly increased the steady-state concentration of pazufloxacin in plasma by decreasing the tubular secretion clearance and glomerular filtration rate. These results suggest the possibility that pazufloxacin is excreted into the urine via P-glycoprotein. No significant differences in the renal and tubular secretion clearances of pazufloxacin were observed between normal rats and Eisai hyperbilirubinemic rats (EHBR), which have a hereditary deficiency in Mrp2, indicating the lack of the involvement of Mrp2 in the renal excretion of pazufloxacin. Sparfloxacin, a P-glycoprotein substrate, also significantly decreased the renal and tubular secretion clearances of pazufloxacin, suggesting that pazufloxacin and sparfloxacin share the same transporters, including P-glycoprotein. The present study at least suggests that pazufloxacin is excreted into the urine via P-glycoprotein and some active drug transporters other than Mrp2.
Asunto(s)
Miembro 1 de la Subfamilia B de Casetes de Unión a ATP/fisiología , Fluoroquinolonas/farmacología , Fluoroquinolonas/orina , Riñón/efectos de los fármacos , Oxazinas/farmacología , Oxazinas/orina , Miembro 1 de la Subfamilia B de Casetes de Unión a ATP/orina , Animales , Línea Celular Tumoral , Fluoroquinolonas/química , Riñón/metabolismo , Masculino , Oxazinas/química , Ratas , Ratas Mutantes , Ratas Sprague-DawleyRESUMEN
Methods for simultaneous liquid chromatography-radioactivity monitor (LC-RAM) metabolite profiling and LC-tandem mass spectrometry (MS/MS) characterization of metabolites are described. Profiling and characterization of metabolites from three drug candidates from different therapeutic areas were compared using in-line heterogeneous LC-RAM-MS/MS and homogeneous LC-RAM-MS/MS methods. Although comparison shows that simultaneous metabolite profiling and characterization can be achieved using either heterogeneous or homogeneous-LC-RAM-MS/MS systems, a homogeneous system has the advantage in the following aspects, (1) sensitivity; (2) ease of method transfer; (3) less peak broadening problems due to the drug or metabolites adhering to the RAM cell; (4) accuracy in quantitation of the metabolites; and (5) the ability to load larger volumes of unprocessed biological fluids. Furthermore, the study shows that some of the possible metabolites that do not ionize well with electrospray ionization (ESI) and eluded detection by heterogeneous-LC-RAM detection could be very easily detected and characterized using a homogeneous-LC-RAM-MS/MS system.
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Amidinas/análisis , Anticoagulantes/análisis , Oxazinas/análisis , Piperazinas/análisis , Piridinas/análisis , Monitoreo de Radiación/instrumentación , Amidinas/farmacocinética , Amidinas/orina , Animales , Radioisótopos de Carbono , Cromatografía Liquida/métodos , Antagonistas de los Receptores de Dopamina D2 , Antagonistas de los Receptores de Endotelina , Heces/química , Masculino , Espectrometría de Masas/métodos , Estructura Molecular , Oxazinas/farmacocinética , Oxazinas/orina , Piperazinas/farmacocinética , Piperazinas/orina , Piridinas/farmacocinética , Piridinas/orina , Ratas , Ratas Wistar , Receptor de Endotelina A , Receptores de Dopamina D4RESUMEN
Previously we have proposed and provided evidence for a metabolic scheme leading to 3-carbamoyl-2-phenylpropionaldehyde from the antiepileptic drug felbamate. This aldehyde was found to undergo reversible cyclization to form the more stable cyclic carbamate 4-hydroxy-5-phenyl-tetrahydro-1,3-oxazin-2-one or undergo elimination to form 2-phenylpropenal. The cyclic carbamate bears structural similarity to 4-hydroxycyclophosphamide and there is an intriguing parallelism between the pathway from the cyclic carbamate to 2-phenylpropenal and the known pathway from 4-hydroxycyclophosphamide to acrolein. The similarity of these transformations led us to consider 5-phenyl-1,3-oxazinane-2,4-dione, which could arise from an oxidation of the cyclic carbamate, as a potential metabolite of felbamate. As the formation of this dione species may have both potential pharmacologic and toxicologic implications for felbamate therapy, we wished to study its reactivity. We have developed a synthesis of 5-phenyl-1, 3-oxazinane-2,4-dione and evaluated its reactivity in vitro. This dione was found to undergo base-catalyzed decomposition to three products, one of which is the major human metabolite of felbamate, 3-carbamoyl-2-phenylpropionic acid. Furthermore, we have found evidence for the presence of the dione in human urine after felbamate treatment through the identification of its major in vitro decomposition product, 2-phenylacrylamide 11.
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Anticonvulsivantes/farmacocinética , Oxazinas/síntesis química , Glicoles de Propileno/farmacocinética , Anticonvulsivantes/orina , Biotransformación , Cromatografía Líquida de Alta Presión , Epilepsia/metabolismo , Felbamato , Humanos , Concentración de Iones de Hidrógeno , Cinética , Oxazinas/metabolismo , Oxazinas/orina , Fenilcarbamatos , Glicoles de Propileno/orina , Espectrofotometría UltravioletaRESUMEN
Efavirenz (Sustiva, Fig. 1) is a potent and specific inhibitor of HIV-1 reverse transcriptase approved for the treatment of HIV infection. To examine the potential differences in the metabolism among species, liquid chromatography/mass spectrometry profiles of efavirenz metabolites in urine of rats, guinea pigs, hamsters, cynomolgus monkeys, and humans were obtained and compared. The metabolites of efavirenz were isolated, and structures were determined unequivocally by mass spectral and NMR analyses. Efavirenz was metabolized extensively by all the species as evidenced by the excretion of none or trace quantities of parent compound in urine. Significant species differences in the metabolism of efavirenz were observed. The major metabolite excreted in the urine of all species was the O-glucuronide conjugate (M1) of the 8-hydroxylated metabolite. Efavirenz was also metabolized by direct conjugation with glucuronic acid, forming the N-glucuronide (M2) in all five species. The sulfate conjugate of 8-OH efavirenz (M3) was found in the urine of rats and cynomolgus monkeys but not in humans. In addition to the aromatic ring-hydroxylated products, metabolites with a hydroxylated cyclopropane ring (at C14) were also isolated. GSH-related products of efavirenz were identified in rats and guinea pigs. The cysteinylglycine adduct (M10), formed from the GSH adduct (M9), was found in significant quantities in only rat and guinea pig urine and was not detected in other species. In vitro metabolism studies were conducted to show that the GSH adduct was produced from the cyclopropanol intermediate (M11) in the presence of only rat liver and kidney subcellular fractions and was not formed by similar preparations from humans or cynomolgus monkeys. These studies indicated the existence of a specific glutathione-S-transferase in rats capable of metabolizing the cyclopropanol metabolite (M11) to the GSH adduct, M9. The biotransformation pathways of efavirenz in different species were proposed based on some of the in vitro results.
Asunto(s)
Fármacos Anti-VIH/farmacocinética , Oxazinas/farmacocinética , Inhibidores de la Transcriptasa Inversa/farmacocinética , Alquinos , Animales , Fármacos Anti-VIH/sangre , Fármacos Anti-VIH/orina , Benzoxazinas , Cromatografía Liquida/métodos , Cricetinae , Ciclopropanos , Femenino , Glutatión/metabolismo , Cobayas , Humanos , Riñón/metabolismo , Hígado/metabolismo , Macaca fascicularis , Espectroscopía de Resonancia Magnética/métodos , Masculino , Espectrometría de Masas/métodos , Oxazinas/sangre , Oxazinas/orina , Ratas , Inhibidores de la Transcriptasa Inversa/sangre , Inhibidores de la Transcriptasa Inversa/orina , Especificidad de la Especie , Fracciones Subcelulares/metabolismoRESUMEN
AIDS: Sustiva may cause false positives on urine tests that screen for marijuana use. A false positive, however, is unlikely to appear on a second confirmatory test. If their urine is being tested, patients who take Sustiva should inform testers that the patients are on the drug.^ieng
Asunto(s)
Cannabinoides/orina , Abuso de Marihuana/diagnóstico , Oxazinas/orina , Inhibidores de la Transcriptasa Inversa/orina , Detección de Abuso de Sustancias/métodos , Alquinos , Benzoxazinas , Ciclopropanos , Reacciones Falso Positivas , HumanosRESUMEN
AIDS: Efavirenz (Sustiva) is a potent anti-HIV medication that is comparable to Indinavir in lowering viral load and elevating CD4+ counts. One negative side effect of efavirenz is that it may cause false positive results on tests for marijuana use. Confirmatory tests can establish the presence of efavirenz rather than marijuana. Tests used in Canada to detect the presence of marijuana are listed.^ieng
Asunto(s)
Cannabinoides/orina , Infecciones por VIH/tratamiento farmacológico , Oxazinas/orina , Inhibidores de la Transcriptasa Inversa/orina , Alquinos , Benzoxazinas , Cromatografía de Gases , Ciclopropanos , Quimioterapia Combinada , Reacciones Falso Positivas , Humanos , Oxazinas/uso terapéutico , Inhibidores de la Transcriptasa Inversa/uso terapéuticoRESUMEN
Bemoradan is a potent, long-acting orally active inodilator. The pharmacokinetics and bioavailability of bemoradan were studied in twelve normal males following oral administration of single, ascending doses of the bemoradan HCL salt in capsules. Plasma and urine levels of bemoradan were determined by HPLC (detection limits: approximately 0.5 ng/ml for plasma and 5 ng/ml for urine). Bemoradan was rapidly absorbed from the capsule formulation at all doses (Cmax occurred at 2.1-2.4 hours). Bemoradan was slowly eliminated from the body (harmonic mean t1/2 16-23 hours). There was a dose-proportional increase in the AUC (0-48) values of bemoradan in humans following the administration of 0.5, 1, 1.5 and 2 mg of bemoradan. The AUC (0-48) values increased to 2.3, 3.4 and 4.0 times when the dose was increased to 2, 3 and 4 times. Urinary excretion of unchanged bemoradan accounted for approximately 5-12% of the dose. Results from this study and previous studies in rats and dogs indicate that bemoradan is well and rapidly absorbed after oral dosing, has linear pharmacokinetics and long elimination half-lives across species.
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Cardiotónicos/farmacocinética , Oxazinas/farmacocinética , Piridazinas/farmacocinética , Vasodilatadores/farmacocinética , Administración Oral , Adulto , Benzoxazinas , Disponibilidad Biológica , Cardiotónicos/sangre , Cardiotónicos/orina , Cromatografía Líquida de Alta Presión , Semivida , Humanos , Absorción Intestinal , Masculino , Oxazinas/sangre , Oxazinas/orina , Piridazinas/sangre , Piridazinas/orina , Vasodilatadores/sangre , Vasodilatadores/orinaRESUMEN
FK 973, a novel substituted dihydrobenzoxazine structurally similar to mitomycin C, is a derivative of the product isolated from Streptomyces sandaensis. In vitro and in rodents, it is a potent antitumor agent. During Phase I clinical trials, we evaluated the pharmacologic properties of FK 973 in eight adenocarcinoma patients after a 30-min i.v. infusion of doses ranging from 7 to 45mg/m2. An established enzyme immunoassay that measures the stable deacetylated active metabolite FR66980 showed that the plasma drug levels declined biphasically with a terminal half life (t1/2 beta) of 4.7 +/- 1.6hr (mean +/- S.D.) The total clearance rate was 438 +/- 113ml/(min/m2). Both the maximum plasma drug concentrations (Cmax) and the area under the concentration-versus-time curve (AUC) were dose related. In addition to nausea and vomiting, alopecia, and myelosuppression, three patients experienced a delayed vascular-leak syndrome. The 3 patients had received doses among the highest studied, and the toxicity appeared to be dose related and cumulative. The evidence suggests that higher doses generated higher Cmax and AUC values, which may be correlated with toxic effects.
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Antineoplásicos/farmacocinética , Oxazinas/farmacocinética , Acetilación , Adulto , Anciano , Antineoplásicos/sangre , Antineoplásicos/orina , Relación Dosis-Respuesta a Droga , Semivida , Humanos , Técnicas para Inmunoenzimas , Masculino , Persona de Mediana Edad , Neoplasias/sangre , Neoplasias/metabolismo , Neoplasias/ultraestructura , Oxazinas/sangre , Oxazinas/orinaRESUMEN
After intravenous bolus injection of single doses of 25, 50, 75 and 100 mg of ofloxacin (HOE 280) to 34 healthy male volunteers, concentrations of unchanged drug were estimated at various times in serum and urine over 32 and 48 h. Ofloxacin concentrations were determined using high-pressure liquid chromatography (HPLC). A linear relationship between dose and Cmax (r = 0.91), AUC0-32 (r = 0.95), AUC infinity (r = 0.96) and urinary recovery (r = 0.98) was demonstrated for the doses tested (25-100 mg). The biological half-life (t1/2,beta was determined by fitting a two-compartment open model to the data: t1/2,beta was about 4.5-5.1 h (HPLC, mean values) and was not dose-dependent. Clinically relevant high concentrations of unchanged ofloxacin were detected in urine after the lowest dose (25 mg) for about 24 h, and after the highest dose (100 g) for at least 36 h. General tolerance was good. A slight transient drop in blood pressure was seen after 25 mg in one case; in another, local venous irritation and later restlessness were observed after 75 mg. No specific countermeasures, except for a saline injection into the vein, were needed. All volunteers completed the study as planned.
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Oxazinas/farmacocinética , Adulto , Presión Sanguínea/efectos de los fármacos , Cromatografía Líquida de Alta Presión , Relación Dosis-Respuesta a Droga , Semivida , Humanos , Inyecciones Intravenosas , Masculino , Ofloxacino , Oxazinas/administración & dosificación , Oxazinas/farmacología , Oxazinas/orinaRESUMEN
The authors evaluated the tissue levels of ofloxacin in 63 patients with urogenital diseases, in comparison to the minimum inhibitory concentrations 80% (MIC80) of some strains. The drug was administered in a single dose (300 mg) about 3 hours before surgery. After washing carefully, the tissue-levels were measured by using the HPLC method. In the normal renal parenchyma of 8 patients, the mean value was 22.10 micrograms/g of tissue; 19.23 micrograms/g in 13 patients with deranged excretory pathways; 10.62 micrograms/g in 25 patients with benign prostatic hypertrophy; 10.90 micrograms/g in 14 deferent duct patients. These results indicate that the drug is promptly distributed in various tissues of the urinary-genital apparatus at high concentrations.
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Antibacterianos/metabolismo , Oxazinas/metabolismo , Sistema Urogenital/metabolismo , Adulto , Antibacterianos/orina , Bacterias/efectos de los fármacos , Femenino , Humanos , Enfermedades Renales/metabolismo , Cinética , Masculino , Pruebas de Sensibilidad Microbiana , Persona de Mediana Edad , Ofloxacino , Oxazinas/orina , Próstata/metabolismoRESUMEN
Ofloxacin is a fluoroquinolone that is mainly eliminated through the kidneys. We studied ofloxacin pharmacokinetics following administration of a single oral 200 mg dose to each of 16 elderly patients (77 +/- 2.4 years). Serum and urine concentrations were assayed using high performance liquid chromatography. Peak serum ofloxacin concentrations were 3.60 (+/- 0.36) micrograms/ml; residual concentrations were 1.33 (+/- 0.15) and 0.62 (+/- 0.10) micrograms/ml at 12 and 24 hours respectively. Urine concentrations approximating 100 micrograms/ml were found up to the 12th hour. As compared to healthy adults, in elderly subjects ofloxacin distribution volume (85.3 +/- 6.3 l) was decreased by 34%, apparent clearance (4.97 +/- 0.53 l/h) was divided by 2.6 and elimination half life (13.3 +/- 1.2 h) was almost doubled. A linear correlation was found between individual apparent ofloxacin clearances and creatinine clearances. In view of these significant changes in ofloxacin pharmacokinetics found in elderly subjects, we advocate reducing the usual dosage by half.