RESUMO
Thrombin is a potent mitogen for many tumor cells, suggesting that this enzyme may be involved in tumor genesis and metastasis. Inhibition of thrombin expressed on the surface of tumor cells may improve outcomes in some tumor cases. For this reason, a thrombin inhibitor to be applied in antitumor therapy must have favorable pharmacokinetic attributes to exert its action as long as possible in the extravascular compartment of the extracellular space, with a short action intravascularly, avoiding bleeding and/or other undesirable side-effects. None of the thrombin inhibitors in clinical use has these properties. Here, we report for first time a direct thrombin inhibitor, named dipetarudin that could be very useful in antitumor therapy because of its pharmacokinetic behavior characterized by a rapid distribution in the extravascular space with a slow elimination from this compartment.
Assuntos
Antineoplásicos/farmacocinética , Proteínas Recombinantes de Fusão/farmacocinética , Trombina/antagonistas & inibidores , Trombina/uso terapêutico , Algoritmos , Animais , Antineoplásicos/sangue , Antineoplásicos/urina , Área Sob a Curva , Disponibilidade Biológica , Modelos Animais de Doenças , Escherichia coli/genética , Escherichia coli/metabolismo , Espaço Extracelular/efeitos dos fármacos , Meia-Vida , Injeções Intravenosas , Injeções Subcutâneas , Nefrectomia/métodos , Ratos , Ratos Wistar , Proteínas Recombinantes de Fusão/antagonistas & inibidores , Proteínas Recombinantes de Fusão/uso terapêutico , Proteínas Recombinantes/biossíntese , Proteínas Recombinantes/farmacocinética , Proteínas Recombinantes/uso terapêutico , Trombina/farmacocinética , Fatores de TempoAssuntos
Humanos , Heparina de Baixo Peso Molecular/administração & dosagem , Heparina de Baixo Peso Molecular/efeitos adversos , Heparina de Baixo Peso Molecular/farmacocinética , Heparina de Baixo Peso Molecular/farmacologia , Heparina/administração & dosagem , Heparina/farmacocinética , Heparina/farmacologia , Heparina/uso terapêutico , Trombina , Trombina/administração & dosagem , Trombina/antagonistas & inibidores , Trombina/farmacocinética , Trombina/farmacologia , Trombina/uso terapêuticoRESUMO
We have shown that tissue-type plasminogen activator (tPA) and plasma kallikrein share a common pathway for liver clearance and that the hepatic clearance rate of plasma kallikrein increases during the acute-phase (AP) response. We now report the clearance of tPA from the circulation and by the isolated, exsanguinated and in situ perfused rat liver during the AP response (48-h ex-turpentine treatment). For the sake of comparison, the hepatic clearance of a tissue kallikrein and thrombin was also studied. We verified that, in vivo, the clearance of 125I-tPA from the circulation of turpentine-treated rats (2.2 +/- 0.2 ml/min, N = 7) decreases significantly (P = 0.016) when compared to normal rats (3.2 +/- 0.3 ml/min, N = 6). The AP response does not modify the tissue distribution of administered 125I-tPA and the liver accounts for most of the 125I-tPA (>80%) cleared from the circulation. The clearance rate of tPA by the isolated and perfused liver of turpentine-treated rats (15.5 +/- 1.3 microg/min, N = 4) was slower (P = 0.003) than the clearance rate by the liver of normal rats (22. 5 +/- 0.7 microg/min, N = 10). After the inflammatory stimulus and additional Kupffer cell ablation (GdCl3 treatment), tPA was cleared by the perfused liver at 16.2 +/- 2.4 microg/min (N = 5), suggesting that Kupffer cells have a minor influence on the hepatic tPA clearance during the AP response. In contrast, hepatic clearance rates of thrombin and pancreatic kallikrein were not altered during the AP response. These results contribute to explaining why the thrombolytic efficacy of tPA does not correlate with the dose administered.
Assuntos
Reação de Fase Aguda/enzimologia , Fígado/metabolismo , Trombina/farmacocinética , Calicreínas Teciduais/farmacocinética , Ativador de Plasminogênio Tecidual/metabolismo , Animais , Células de Kupffer/metabolismo , Masculino , Taxa de Depuração Metabólica , Perfusão , Ratos , Ratos Wistar , Ativador de Plasminogênio Tecidual/sangueRESUMO
We have shown that tissue-type plasminogen activator (tPA) and plasma kallikrein share a common pathway for liver clearance and that the hepatic clearance rate of plasma kallikrein increases during the acute-phase (AP) response. We now report the clearance of tPA from the circulation and by the isolated, exsanguinated and in situ perfused rat liver during the AP response (48-h ex-turpentine treatment). For the sake of comparison, the hepatic clearance of a tissue kallikrein and thrombin was also studied. We verified that, in vivo, the clearance of 125I-tPA from the circulation of turpentine-treated rats (2.2 + or - 0.2 ml/min, N = 7) decreases significantly (P = 0.016) when compared to normal rats (3.2 + or - 0.3 ml/min, N = 6). The AP response does not modify the tissue distribution of administered 125I-tPA and the liver accounts for most of the 125I-tPA (>80 percent) cleared from the circulation. The clearance rate of tPA by the isolated and perfused liver of turpentine-treated rats (15.5 + or - 1.3 µg/min, N = 4) was slower (P = 0.003) than the clearance rate by the liver of normal rats (22.5 + or - 0.7 µg/min, N = 10). After the inflammatory stimulus and additional Kupffer cell ablation (GdCl3 treatment), tPA was cleared by the perfused liver at 16.2 + or - 2.4 µg/min (N = 5), suggesting that Kupffer cells have a minor influence on the hepatic tPA clearance during the AP response. In contrast, hepatic clearance rates of thrombin and pancreatic kallikrein were not altered during the AP response. These results contribute to explaining why the thrombolytic efficacy of tPA does not correlate with the dose administered
Assuntos
Animais , Masculino , Ratos , Reação de Fase Aguda/enzimologia , Fígado/enzimologia , Trombina/farmacocinética , Calicreínas Teciduais/sangue , Calicreínas Teciduais/farmacocinética , Ativador de Plasminogênio Tecidual/metabolismo , Células de Kupffer/metabolismo , Taxa de Depuração Metabólica , Perfusão , Ratos Wistar , Ativador de Plasminogênio Tecidual/sangueRESUMO
La trombina favorece la producción de postaciclina en células endoteliales, produce cambios en el tono vascular, estimula la liberación del factor relajante del endotelio, y potencia la respuesta del músculo liso vascular a varios agonistas. En este estudio se compararon los efectos vasculares de la trombina en arterias femoral y pulmonar caninas con los obtenidos en la arteria umbilical humana. Esto en presencia de inhibidores de cicloxigenasa y lipooxigenasa, beta antagonista, antagonista muscarínico, antiserotonina, antihistamínicos, alfa antagonista y un bloqueador de canales de calcio -además de heparina-, con y sin endotelio. Las concentraciones crecientes de trombina produjeron relajación y en arterias umbilicales se produjo contracción. La relajación fue dependiente del endotelio, mientras que la contracción no fue dependiente del endotelio. La relajación y contracción no fueron afectadas por inhibición del metabolismo del ácido araquidónico, ni por la presencia de los antagonistas utilizados. La heparina produjo en las arterias umbilicales una desviación de la curva dosis respuesta a trombina hacia la derecha y el bloqueador de canales de calcio produjo inhibición de esta contracción. En las arteria caninas la relación producida por trombina fue dependiente del endotelio, lo que haría pensar en un mediador endotelial. En arterias umbilicales la trombina produjo contracción en arterias con y sin endotelio por lo que se pensaría que esta respuesta no es producida por un factor endotelial. Parece estar mediada por un mecanismo que requiere de la unión de la trombina y la activación de entrada del calcio a las células.