RESUMO
The chemotherapeutic agent methotrexate is metabolized by the intestinal flora of normal mice. This metabolism is reduced either by treatment of mice with the antibiotics neomycin and sulfathiazole, or in germ-free mice. In addition to affecting metabolism, these antibiotics alter physiological distribution of methotrexate so that excretion by the intestinal route is significantly enhanced.
Assuntos
Metotrexato/metabolismo , Neomicina/farmacologia , Sulfatiazóis/farmacologia , Animais , Antibacterianos/urina , Fezes/análise , Vida Livre de Germes , Mucosa Intestinal/metabolismo , CamundongosRESUMO
The distribution and excretion of tritiated vincristine were studies in the rat and the dog. Biphasic curves for the disappearance of the drug from blood were found in both species, with an initial half-life of approximately 15 min and a secondary half-life of approximately 75 min. Tissue levels were high in 1 hr in the rat and declined rapidly, except in the brain where very low levels of drug were found at all times. The bile was found to be the major route of excretion. The peak rate of excretion in bile was found to occur earlier in the rat (10 min) than in the dog (60 min). Rats given a higher dose of vincristine (1.0 mg/kg) excreted a larger percentage of the dose in the bile than rats given a lower dose (0.1 mg/kg). In rats given a low dose of vincristine (0.1 mg/kg), more than 85% of the drug was excreted in the feces and the urine over 72 hr. Less than 10% of the total radioactivity in the bile and urine was metabolites whereas, in the plasma, metabolites accounted for 40% of the total radioactivity.
Assuntos
Vincristina/metabolismo , Animais , Bile/metabolismo , Encéfalo/metabolismo , Cães , Fezes/análise , Feminino , Meia-Vida , Masculino , Ratos , Fatores de Tempo , Vincristina/sangue , Vincristina/urinaRESUMO
The uptake of methotrexate (MTX) and the effect of drugs known to either inhibit or enhance MTX transport in L1210 murine leukemia were studied in man using blast cells from patients with acute myelogenous leukemia in vitro. MTX uptake was found to proceed slowly, requiring at least 160 min for cells to reach a "steady state" when extracellular MTX concentrations were 1 muM. Efflux of MTX from preloaded cells required 80 to 120 min and the nonexchangeable or tightly bound fraction was 40% of the total intracellular drug. Utilizing doses that are estimates of achievable peak blood levels following single i.v. injection, cephalothin (21 mug/ml) and hydrocortisone (20 mug/ml) inhibited net MTX accumulation by 20 and 28%, respectively. Vincristine sulfate at 8.3 and 0.083 mug/ml enhanced MTX uptake by 54 and 33%, respectively, by inhibiting MTX efflux, thus increasing the level of intracellular drug in excess of the tightly bound fraction. The potential clinical implications of using MTX in combination with the aforementioned drugs for cancer chemotherapy are discussed.
Assuntos
Leucemia Mieloide Aguda/metabolismo , Metotrexato/metabolismo , Cefalotina/farmacologia , Depressão Química , Humanos , Hidrocortisona/farmacologia , Técnicas In Vitro , Estimulação Química , Fatores de Tempo , Vincristina/farmacologiaRESUMO
The pharmacokinetics, metabolism, and excretion of aromatically labeled tritiated vincristine (VCR) was examined in 4 patients. Clearance of radioactivity from the blood was triphasic with half-life t1/2 values of 0.85, 7.4, and 164 min. The initial phases probably represent distribution and binding to formed blood elements which exceeded 50% of the administered dose by 20 min. Excretion of radioactivity was principally fecal, with 33% recovered in the feces by 24 hr and 69% by 72 hr. Considerably less radioactivity (12%) was excreted in the urine over the 72-hr period. Approximately 40% of fecally excreted and 46% of urinary excreted radiolabel represented metabolites, which suggests that at least 34% of the VCR dose was excreted as metabolies. Plasma metabolites represented from less than 1% to 30% or more of radioactivity in plasma. Ultraviolet spectral analysis of all metabolites revealed preservation of the intact VCR dimer, which suggests that metabolism involves alteration of side groups.
Assuntos
Vincristina/metabolismo , Adulto , Fezes/análise , Feminino , Meia-Vida , Humanos , Cinética , Linfoma/metabolismo , Masculino , Pessoa de Meia-Idade , Trítio , Vincristina/sangue , Vincristina/urinaAssuntos
Amidas/toxicidade , Carcinógenos , Hidrazinas/toxicidade , Isoniazida/toxicidade , Neoplasias Pulmonares/induzido quimicamente , Neoplasias Experimentais/induzido quimicamente , Animais , Compostos Azo/toxicidade , Cistadenoma/induzido quimicamente , Neoplasias Renais/induzido quimicamente , Leucemia/induzido quimicamente , Masculino , CamundongosAssuntos
Metotrexato/metabolismo , Modelos Biológicos , Especificidade da Espécie , Adaptação Fisiológica , Animais , Sistema Biliar/metabolismo , Medula Óssea/metabolismo , Cães , Humanos , Absorção Intestinal , Rim/metabolismo , Cinética , Fígado/metabolismo , Matemática , Metotrexato/sangue , Metotrexato/toxicidade , Camundongos , Músculos/metabolismo , RatosAssuntos
Antibióticos Antineoplásicos/farmacologia , Antineoplásicos/farmacologia , Leucemia L1210 , Metotrexato , Animais , Asparaginase/farmacologia , Transporte Biológico/efeitos dos fármacos , Bleomicina/farmacologia , Células Cultivadas , Cefalotina/farmacologia , Relação Dose-Resposta a Droga , Sinergismo Farmacológico , Feminino , Glucocorticoides/farmacologia , Hidroxiureia/farmacologia , Canamicina/farmacologia , Leucemia L1210/tratamento farmacológico , Leucemia L1210/metabolismo , Metotrexato/metabolismo , Metotrexato/uso terapêutico , Camundongos , Penicilinas/farmacologia , Vimblastina/farmacologia , Alcaloides de Vinca/farmacologia , Vincristina/farmacologiaAssuntos
Antibióticos Antineoplásicos/farmacologia , Antibióticos Antineoplásicos/uso terapêutico , Animais , Antibióticos Antineoplásicos/administração & dosagem , Pressão Sanguínea/efeitos dos fármacos , Técnicas de Cultura , DNA , Dactinomicina/uso terapêutico , Cães , Eletrocardiografia , Hexobarbital/farmacologia , Leucemia L1210/tratamento farmacológico , Leucemia L1210/metabolismo , Leucemia Experimental/tratamento farmacológico , Leucemia Experimental/metabolismo , Leucemia Linfoide/tratamento farmacológico , Leucemia Linfoide/metabolismo , Masculino , Camundongos , Nucleosídeos , Respiração/efeitos dos fármacos , Análise Espectral , Timidina/metabolismo , Trítio , Raios Ultravioleta , Uridina/metabolismo , ortoaminobenzoatosAssuntos
Antineoplásicos/metabolismo , Biotransformação , Ureia , Animais , Isótopos de Carbono , Cromatografia em Camada Fina , Cães , Fezes/análise , Feminino , Haplorrinos , Leucemia L1210/tratamento farmacológico , Masculino , Camundongos , Compostos Nitrosos/análise , Compostos Nitrosos/sangue , Compostos Nitrosos/líquido cefalorraquidiano , Compostos Nitrosos/metabolismo , Compostos Nitrosos/farmacologia , Compostos Nitrosos/urina , Neoplasias Peritoneais/patologia , Ratos , Neoplasias Cranianas/patologia , Ureia/análise , Ureia/sangue , Ureia/líquido cefalorraquidiano , Ureia/farmacologia , Ureia/urinaAssuntos
Antineoplásicos/metabolismo , Antineoplásicos/uso terapêutico , Neoplasias Encefálicas/tratamento farmacológico , Ependimoma/tratamento farmacológico , Glioma/tratamento farmacológico , Ureia/metabolismo , Ureia/uso terapêutico , Animais , Antineoplásicos/sangue , Neoplasias Encefálicas/metabolismo , Isótopos de Carbono , Cromatografia , Ependimoma/metabolismo , Glioma/metabolismo , Masculino , Camundongos , Compostos Nitrosos/sangue , Compostos Nitrosos/metabolismo , Compostos Nitrosos/uso terapêutico , Ureia/sangueAssuntos
Ácidos Aminoipúricos/farmacologia , Taxa de Filtração Glomerular , Metotrexato/metabolismo , Salicilato de Sódio/farmacologia , Sulfisoxazol/farmacologia , Ácidos Aminoipúricos/metabolismo , Transporte Biológico Ativo/efeitos dos fármacos , Proteínas Sanguíneas/metabolismo , Isótopos de Carbono , Colorimetria , Feminino , Humanos , Inulina/metabolismo , Túbulos Renais/metabolismo , Leucemia/metabolismo , Masculino , Pessoa de Meia-Idade , Neoplasias/metabolismo , Ligação Proteica/efeitos dos fármacos , TrítioAssuntos
Carmustina/farmacocinética , Animais , Cães , Feminino , Humanos , Macaca mulatta , Masculino , Camundongos , Camundongos Endogâmicos , Especificidade da EspécieAssuntos
Antígenos , Doença de Hodgkin/imunologia , Doença de Hodgkin/metabolismo , Triptofano/metabolismo , Adolescente , Adulto , Fatores Etários , Aminoácidos/urina , Anemia/sangue , Anemia/complicações , Candida , Coccidioides , Deficiências Nutricionais/etiologia , Feminino , Histoplasmina , Doença de Hodgkin/sangue , Doença de Hodgkin/complicações , Doença de Hodgkin/diagnóstico , Doença de Hodgkin/urina , Humanos , Cinurenina/urina , Linfopenia/sangue , Linfopenia/complicações , Masculino , Pessoa de Meia-Idade , Fenilbutiratos/urina , Fosfato de Piridoxal/sangue , Fatores Sexuais , Testes Cutâneos , Tuberculina , Xanturenatos/urinaAssuntos
Antineoplásicos/uso terapêutico , Animais , Antineoplásicos/metabolismo , Azacitidina/uso terapêutico , Bleomicina/uso terapêutico , Ciclofosfamida/uso terapêutico , Citarabina/uso terapêutico , Dacarbazina/farmacologia , Daunorrubicina/uso terapêutico , Doxorrubicina/uso terapêutico , Feminino , Fluoruracila/uso terapêutico , Coração/efeitos dos fármacos , Humanos , Leucovorina/uso terapêutico , Pulmão/efeitos dos fármacos , Masculino , Metotrexato/uso terapêutico , Neoplasias/tratamento farmacológico , Compostos de Nitrosoureia/uso terapêutico , Procarbazina/uso terapêutico , Triazenos/uso terapêutico , Vimblastina/uso terapêutico , Vincristina/uso terapêuticoAssuntos
Ceco/metabolismo , Metotrexato/metabolismo , Pteridinas/metabolismo , Compostos de Anilina/análise , Compostos de Anilina/metabolismo , Compostos de Anilina/urina , Animais , Bactérias/metabolismo , Benzoatos/análise , Benzoatos/metabolismo , Benzoatos/urina , Ceco/microbiologia , Cromatografia em Papel , Cromatografia em Camada Fina , Fezes/análise , Raios Infravermelhos , Metotrexato/análise , Metotrexato/urina , Camundongos , Oxirredução , Pteridinas/análise , Pteridinas/urina , Análise Espectral , Trítio , Raios UltravioletaAssuntos
Leucemia L1210/metabolismo , Leucemia Experimental/metabolismo , Vincristina/metabolismo , Animais , Antimetabólitos/farmacologia , Transporte Biológico , Soluções Tampão , Células Cultivadas , Depressão Química , Cinética , Camundongos , Temperatura , Fatores de Tempo , Trítio , Vimblastina/metabolismoAssuntos
Antagonistas do Ácido Fólico/metabolismo , Administração Oral , Animais , Bile/metabolismo , Cães , Antagonistas do Ácido Fólico/sangue , Humanos , Injeções Intraperitoneais , Injeções Intravenosas , Mucosa Intestinal/metabolismo , Rim/metabolismo , Cinética , Fígado/metabolismo , Metotrexato/administração & dosagem , Metotrexato/sangue , Metotrexato/metabolismo , Metotrexato/urina , Camundongos , Músculos/metabolismo , Coelhos , Ratos , Fatores de Tempo , TrítioRESUMO
This analytical study was undertaken in an effort to develop a model for a quantitative approach to the evaluation of multiple biological marker levels in blood and urine as a means for determining tumor changes during treatment of patients with malignant disease. The potential biologic markers measured in patients with carcinoma of the breast consist of three urinary polyamines (putrescine, spermidine and spermine), three urinary nucleosides (pseudouridine, N2, N2-dimethylguanosine and 1-methylinosine), and plasma carcinoembryonic antigen (CEA). The distribution patterns of the seven markers measured pretreatment and five weeks after initiating therapy were examined by grouping the patients into the three categories of progression, stable, or regression based on their clinical response to treatment. In addition to the individual marker measurements, the pretreatment and posttreatment values of the ratios of the polyamine levels (spermine/putrescine, spermine/spermidine, and spermidine/putrescine) and the nucleoside levels (N2, N2-dimethylguanosine/pseudouridine, 1-methylinosine/pseudouridine, and 1-methylinosine/N2, N2-dimethylguanosine) were also evaluated. In the pretreatment measurements, CEA levels were elevated for 76% of the patients and the three nucleosides were elevated for 36% of the patients and the three nucleosides were elevated for 36% to 37% of the patients. Urinary spermidine and spermine levels were abnormal for 27% and 24%, respectively, while putrescine levels were elevated for 7% of the patients. When all 14 marker measurements and the 12 ratios of these measurements were considered, the multiple regression equation evaluated the treatment results with a multiple correlation coefficient (R = 0.891; P less than 0.100) about 2.4 times higher than with the most sensitive single marker variable, N2, N2-dimethylguanosine/pseudouridine (R = 0.377; P less than 0.05), alone. Stepwise regression analysis revealed that the minimum number of multiple marker measurements and their ratios required to achieve the maximum value of the multiple correlation coefficient (R = 0.653; p = 0.010) was fifteen. These include the pre and posttreatment measurements of CEA, spermine, N2, N2-dimethylguanosine and 1-methylinosine, as well as two ratios of the polyamines and three ratios of the nucleosides in the post-treatment of the polyamines and three ratios of the nucleosides in the post-treatment measurements. These data suggest that the utilization of regression analysis to evaluate the monitoring utility of multiple marker measurements may be of clinical value.