RESUMEN
The influence of age of experimental animals on the antileukemic activity, toxicity and distribution of ambazone, a new potential antineoplastic agent, was studied in 2- and 12-month-old B6D2F1 mice. The predominant effect observed was a significant reduction of the antileukemic action of this compound in old-aged mice. Together with a slight increase in several toxicity parameters this caused a marked reduction of the therapeutic index in 12-month-old mice compared to younger individuals. Furthermore, a general tendency to increased ambazone levels in liver, kidneys and thymus of old-aged mice was observed. Our data therefore provide further evidence that age has to be taken into consideration as one factor that may account for the variety of drug response frequently observed during clinical therapy with anticancer agents.
Asunto(s)
Envejecimiento/efectos de los fármacos , Antineoplásicos/uso terapéutico , Leucemia P388/tratamiento farmacológico , Leucemia Experimental/tratamiento farmacológico , Mitoguazona/análogos & derivados , Envejecimiento/fisiología , Animales , Antineoplásicos/farmacocinética , Antineoplásicos/toxicidad , Radioisótopos de Carbono , Relación Dosis-Respuesta a Droga , Evaluación Preclínica de Medicamentos , Femenino , Dosificación Letal Mediana , Leucemia P388/metabolismo , Ratones , Ratones Endogámicos , Mitoguazona/farmacocinética , Mitoguazona/uso terapéutico , Mitoguazona/toxicidad , Trasplante de Neoplasias , Distribución Tisular/fisiologíaRESUMEN
In rats, the pharmacokinetics of 14C-ambazone after i.v. and oral administration was studied. The results demonstrate that the compound is incompletely absorbed from the gastrointestinal tract, penetrates rapidly and to a high degree into various tissues and is preferentially eliminated via the kidneys. After i.v. administration of 50 mg/kg b.m. disposition half-life in whole blood is about 6-7 h. The extent of absorption from the gastrointestinal tract is about 40%.
Asunto(s)
Antineoplásicos/farmacocinética , Mitoguazona/análogos & derivados , Administración Oral , Animales , Antineoplásicos/administración & dosificación , Antineoplásicos/orina , Bilis/metabolismo , Heces/análisis , Inyecciones Intravenosas , Masculino , Mitoguazona/administración & dosificación , Mitoguazona/farmacocinética , Mitoguazona/orina , Ratas , Ratas EndogámicasRESUMEN
There is some evidence in the literature that the pharmacokinetics of anticancer agents can be influenced by the presence of a tumor. Therefore several authors recommend pharmacokinetic studies of such drugs to be performed also in tumor-bearing animals (2, 5, 7). The aim of the present study was to evaluate the influence of different stages and routes of inoculation of leukemia P 388 in B6D2F1-hybrid mice on the tissue distribution of ambazone, a new potential antineoplastic drug. It could be emphasized that the drug levels in liver, kidneys and thymus were higher in advanced tumor-bearing than in control animals whereas in the spleen and in whole blood the opposite was true. The differences can be explained partially by changes in the erythrocyte binding of ambazone.
Asunto(s)
Antineoplásicos/farmacocinética , Leucemia P388/metabolismo , Leucemia Experimental/metabolismo , Mitoguazona/análogos & derivados , Animales , Radioisótopos de Carbono , Femenino , Riñón/metabolismo , Leucemia P388/patología , Hígado/metabolismo , Masculino , Ratones , Mitoguazona/sangre , Mitoguazona/farmacocinética , Proyectos de Investigación , Bazo/metabolismo , Timo/metabolismoRESUMEN
The pharmacokinetics and pharmacodynamics of repeated oral administration of furosemide were studied in patients with chronic renal failure or nephrotic syndrome using three different dosage regimens (4 x 40, 4 x 80 and 4 x 250 mg/d). Concentrations of the unchanged drug in serum and urine were measured fluorometrically. The elimination kinetics of furosemide was linear over the dose range studied. In contrast, the bioavailability of this diuretic decreased with increasing doses. The diuretic effects of all three dosage regimens were distinct only on the first day of therapy, thereafter decreasing rapidly. It can be concluded that the hormonal regulation of water and electrolyte balance are responsible for this behavior rather than pharmacokinetics. Creatinine and urea nitrogen excretion were not influenced by any furosemide dosage regimen.