RESUMEN
14C-labelled 4-methyl-5(2-pyrazinyl)-1,2-dithiole-3-thione (14C-oltipraz, 35 972 R.P.) was orally administered to rhesus monkeys (20 mg/kg), rats (50 mg/kg) and female mice infected with Schistosoma mansoni (100 and 250 mg/kg). The absorption of oltipraz varied with the animal species and the dose administered. In each species, the pharmacokinetics of oltipraz in the plasma and red blood cells were generally similar. 40 to 57% of the radioactive dose was excreted in urine, depending on the animal species and dose levels. In the mouse, there was negligible elimination of radioactivity as 14CO2. Whole-body autoradiographic studies in mice showed that, during the first 24 h, radioactivity was present mainly in the gastro-intestinal tract, bile, urine, liver and kidneys. In the male and female worms, the nature and amounts of radioactive products present differed.
Asunto(s)
Pirazinas/metabolismo , Schistosoma mansoni/metabolismo , Esquistosomicidas/metabolismo , Animales , Biotransformación , Femenino , Macaca mulatta , Masculino , Ratones , Ratas , Ratas Endogámicas , Esquistosomiasis mansoni/metabolismo , Especificidad de la Especie , Tionas , TiofenosRESUMEN
Evidence for the stabilizing effect of ketoprofen on the lysosomal membrane is presented. Ketoprofen was as potent as indomethacin in stabilizing lysosomes subjected to changes in osmotic pressure. This effect was more marked in rats with adjuvant arthritis than in normal animals.
Asunto(s)
Cetoprofeno/farmacología , Lisosomas/efectos de los fármacos , Fenilpropionatos/farmacología , Animales , Artritis Experimental/enzimología , Técnicas In Vitro , Indometacina/farmacología , Hígado/ultraestructura , Lisosomas/enzimología , Masculino , Ratas , Ratas EndogámicasRESUMEN
4-Methyl-5-(2-pyrazinyl)-1,2-dithiole-3-thione (35 972 R.P., oltipraz) and its metabolites were extracted from human urine and from mouse, rat and monkey urine using Amberlite XAD4 resin. The metabolites were identified by GLC, TLC and HPLC and isolated by preparative TLC or HPLC. The structures of 11 compounds were determined by spectroscopic examination (MS, IR, NMR). Six of the principal metabolites isolated in sufficient quantity from human urine were administered to the mouse, confirming the metabolic pathways of oltipraz.
Asunto(s)
Pirazinas/metabolismo , Acetilación , Animales , Biotransformación , Cromatografía de Gases , Cromatografía Líquida de Alta Presión , Cromatografía en Capa Delgada , Heces/análisis , Femenino , Humanos , Macaca mulatta , Masculino , Ratones , Ratas , Ratas Endogámicas , Especificidad de la Especie , Tionas , Tiofenos , Distribución TisularRESUMEN
Pharmacokinetics and metabolism of a new hypnotic, zopiclone (ZD), were studied under the following conditions: (1) rats and dogs were given oral doses of the molecule, 14C-labeled either on the side chain or on the pyrrolopyrazine nucleus; (2) rats, rabbits and dogs were given increasing oral doses of the cold compound; (3) human subjects in various physiopathological situations--young and elderly healthy volunteers, patients with liver or renal impairments, nursing mothers--were given single or repeated doses, p.o. or i.v. (range 3.5-15 mg). ZD is rapidly and efficiently absorbed: its oral bioavailability was greater than 75% in all species except rats, where a first-pass effect of about 65% was recorded. Plasma protein binding is about 45%. The radioactive material rapidly diffuses from the vascular compartment, with a marked affinity for the brain. Plasma kinetics of ZD are generally well described by a two-compartment open model; in man, terminal half-life is 4-5 h; total body clearance is large (300 ml/mn), renal clearance very low (10 ml/min). The relationship between doses and concentrations, doses and urinary excretion of unchanged compound and major metabolites was linear in all species, except rabbits. The major metabolic routes involve decarboxylation affecting more than 50% of dose (rats and dogs), N-demethylation and N-oxidation--more than 30% as N-desmethyl and N-oxide derivatives in urine (humans). Due to intensive metabolism, only 7-10% of the dose is recovered in urine and feces as unchanged compounds (all species). In nursing mothers, milk and plasma kinetics of ZD are similar with a milk/plasma ratio around 0.80. In human volunteers, plasma half-life of ZD increases with age, while patients with liver or renal impairments show little or no modification of pharmacokinetic parameters.
Asunto(s)
Hipnóticos y Sedantes/metabolismo , Piperazinas/metabolismo , Administración Oral , Anciano , Envejecimiento , Animales , Autorradiografía , Compuestos de Azabiciclo , Biotransformación , Remoción de Radical Alquila , Perros , Femenino , Edad Gestacional , Humanos , Inyecciones Intravenosas , Fallo Renal Crónico/metabolismo , Cinética , Hígado/metabolismo , Masculino , Leche Humana/metabolismo , Embarazo , Conejos , Ratas , Especificidad de la Especie , Distribución TisularRESUMEN
Pharmacokinetics and metabolism of a new hypnotic, zopiclone (ZD), were studied under the following conditions: (1) rats and dogs were given oral doses of the molecule, 14C-labeled either on the side chain or on the pyrrolopyrazine nucleus; (2) rats, rabbits and dogs were given increasing oral doses of the cold compound; (3) human subjects in various physiopathological situations - young and elderly healthy volunteers, patients with liver or renal impairments, nursing mothers - were given single or repeated doses, p.o. or i.v. (range 3.5-15 mg). ZD is rapidly and efficiently absorbed: its oral bioavailability was greater than 75% in all species except rats, where a first-pass effect of about 65% was recorded. Plasma protein binding is about 45%. The radioactive material rapidly diffuses from the vascular compartment, with a marked affinity for the brain. Plasma kinetics of ZD are generally well described by a two-compartment open model; in man, terminal half-life is 4-5 h; total body clearance is large (300 ml/mn), renal clearance very low (10 ml/min). The relationship between doses and concentrations, doses and urinary excretion of unchanged compound and major metabolites was linear in all species, except rabbits. The major metabolic routes involve decarboxylation affecting more than 50% of dose (rats and dogs), N-demethylation and N-oxidation - more than 30% as N-desmethyl and N-oxide derivatives in urine (humans). Due to intensive metabolism, only 7-10% of the dose is recovered in urine and feces as unchanged compounds (all species). In nursing mothers, milk and plasma kinetics of ZD are similar with a milk/plasma ratio around 0.80. In human volunteers, plasma half-life of ZD increases with age, while patients with liver or renal impairments show little or no modification of pharmacokinetic parameters.
Asunto(s)
Hipnóticos y Sedantes/metabolismo , Piperazinas/metabolismo , Administración Oral , Adulto , Anciano , Envejecimiento , Animales , Autorradiografía , Compuestos de Azabiciclo , Perros , Femenino , Edad Gestacional , Humanos , Hipnóticos y Sedantes/administración & dosificación , Inyecciones Intravenosas , Absorción Intestinal , Fallo Renal Crónico/metabolismo , Cinética , Hígado/metabolismo , Masculino , Leche Humana/metabolismo , Piperazinas/administración & dosificación , Embarazo , Conejos , Ratas , Especificidad de la Especie , Distribución TisularRESUMEN
An electron-capture GLC method to measure nofedone in human serum was developed. A homolog of nofedone was added to the serum as an internal standard before the sample was alkalinized with pH 9.5 phosphate buffer and extracted with ethylene dichloride containing 0.5% isopentyl alcohol. This organic phase was extracted with 0.2N HCl, the acidic aqueous phase was neutralized immediately, and the extraction with ethylene dichloride was repeated. The ethylene dichloride phase was evaporated to dryness, and the residue was reacted with heptafluorobutyric anhydride. The derivatives were chromatographed at 290 degrees on a 1% Dexsil 300 column. Data on apparent recovery, accuracy, and specificity are given. The detection limit was 5 ng/ml of serum. Serum levels over time in one patient after intravenous administration of 1 mg/kg and after oral administration of 50, 100, and 150 mg of nofedone are presented.
Asunto(s)
Antiarrítmicos/sangre , Indoles/sangre , Propanolaminas/sangre , Administración Oral , Antiarrítmicos/administración & dosificación , Fenómenos Químicos , Química Física , Cromatografía de Gases , Humanos , Indoles/administración & dosificación , Inyecciones Intravenosas , Isoindoles , Propanolaminas/administración & dosificaciónRESUMEN
This report concerns the experimental activity and the preliminary clinical results obtained with detorubicin, an anthracycline. Experimentally, in comparison with doxorubicin, detorubicin is less toxic, less immunodepressive, and less mutagenic, its experimental antitumor activity is equal or superior, and differences are found in pharmacokinetics. Its most interesting activities in clinical cancer therapy are found in non-Hodgkin lymphomas, in carcinomas, and in soft-tissue sarcomas.
Asunto(s)
Antibióticos Antineoplásicos/uso terapéutico , Daunorrubicina/análogos & derivados , Animales , Antibióticos Antineoplásicos/farmacología , Antibióticos Antineoplásicos/toxicidad , Supervivencia Celular/efectos de los fármacos , Daunorrubicina/uso terapéutico , Daunorrubicina/toxicidad , Humanos , Inmunosupresores , Leucemia/tratamiento farmacológico , Linfoma/tratamiento farmacológico , Ratones , Mutágenos , Neoplasias/tratamiento farmacológico , Neoplasias Experimentales/tratamiento farmacológicoRESUMEN
Evidence for the stabilizing effect of ketoprofen on the lysosomal membrane is presented. Ketoprofen was as potent as indomethacin in stabilizing lysosomes subjected to changes in osmotic pressure. This effect was more marked in rats with adjuvant arthritis than in normal animals.