RESUMEN
UCN-01 (7-hydroxystaurosporine; NSC 638850) is a protein kinase antagonist selected for clinical trial based in part on evidence of efficacy in a preclinical renal carcinoma xenograft model. Schedule studies and in vitro studies suggested that a 72-h continuous infusion would be appropriate. In rats and dogs, maximum tolerated doses produced peak plasma concentrations of approximately 0.2-0.3 microM. However, concentrations 10-fold greater are well tolerated in humans, and the compound has a markedly prolonged T1/2. Specific binding to human alpha1-acidic glycoprotein has been demonstrated. These findings reinforce the need to consider actual clinical pharmacology data in "real time" with phase I studies.
Asunto(s)
Alcaloides/farmacología , Antineoplásicos/farmacología , Inhibidores Enzimáticos/farmacología , Proteína Quinasa C/antagonistas & inhibidores , Adulto , Alcaloides/farmacocinética , Alcaloides/toxicidad , Animales , Antineoplásicos/farmacocinética , Antineoplásicos/toxicidad , Proteínas Sanguíneas/metabolismo , Cromatografía Líquida de Alta Presión , Perros , Inhibidores Enzimáticos/farmacocinética , Inhibidores Enzimáticos/toxicidad , Humanos , Infusiones Intravenosas , Ratones , Ratones Desnudos , Unión Proteica , Ratas , Estaurosporina/análogos & derivados , Trasplante Heterólogo/inmunologíaRESUMEN
The pharmacokinetics of UCN-01 after administration as a 72- or 3-h infusion to cancer patients in initial Phase I trials displayed distinctive features that could not have been predicted from preclinical data. The distribution volumes (0.0796-0.158 liters/kg) and the systemic clearance (0.0407-0.252 ml/h/kg) were extremely low, in contrast to large distribution volume and rapid systemic clearance in experimental animals. The elimination half-lives (253-1660 h) were unusually long. In vitro protein binding experiments demonstrated that UCN-01 was strongly bound to human alpha1-acid glycoprotein. The results suggest that unusual pharmacokinetics of UCN-01 in humans could be due, at least in part, to its specifically high binding to alpha1-acid glycoprotein.