RESUMEN
This study investigated the effects of the concomitant administration of theophylline and toborinone on the pharmacokinetics of both compounds in poor and extensive metabolizers via CYP2D6. In period 1, a single dose of 3.5 mg/kg theophylline was administered orally. In period 2, a single dose of 1.0 microg/kg/min toborinone was infused over 6 hours. In period 3, 3.5 mg/kg theophylline was coadministered with 1.0 microg/kg/min toborinone. Serial blood and pooled urine samples were collected before and after toborinone administration for the quantification of toborinone and its metabolites in plasma and urine. Serial blood samples were collected before and after theophylline administration for the quantification of theophylline and its metabolites in plasma. No significant differences were observed in toborinone pharmacokinetics between poor and extensive metabolizers via CYP2D6. Toborinone coadministration with theophylline did not result in a substantive effect on the disposition of theophylline and vice versa.
Asunto(s)
Citocromo P-450 CYP2D6/metabolismo , Quinolonas/administración & dosificación , Quinolonas/farmacocinética , Teofilina/administración & dosificación , Teofilina/farmacocinética , Adulto , Cromatografía Líquida de Alta Presión , Citocromo P-450 CYP2D6/genética , Dextrometorfano/sangre , Dextrometorfano/metabolismo , Dextrometorfano/orina , Dextrorfano/sangre , Dextrorfano/metabolismo , Dextrorfano/orina , Interacciones Farmacológicas , Humanos , Quinolonas/efectos adversos , Quinolonas/metabolismo , Teofilina/efectos adversos , Teofilina/metabolismo , Vasodilatadores/administración & dosificación , Vasodilatadores/efectos adversos , Vasodilatadores/metabolismo , Vasodilatadores/farmacocinéticaRESUMEN
The pharmacokinetics of toborinone was studied in subjects with congestive heart failure (CHF) and concomitant renal and/or hepatic disease. At the time of admission, subjects were grouped based on estimated creatinine clearance and serum bilirubin. Glomerular filtration rate was assessed using iothalamate clearance. Hepatic function was assessed using the caffeine metabolism test and indocyanine green clearance. No significant differences were observed in mean toborinone pharmacokinetic parameters among the four study groups. Positive correlations were observed between toborinone clearance and the measured indices of renal and hepatic function: creatinine clearance, iothalamate renal clearance, paraxanthine/caffeine ratio, and indocyanine green clearance. Toborinone clearance decreased with decreasing creatinine clearance, decreasing glomerular filtration rate, decreasing demethylation metabolic activity, and decreasing hepatic bloodflow, although no significant differences were observed in any mean toborinone pharmacokinetic parameters evaluated among the four study groups.
Asunto(s)
Cardiotónicos/farmacocinética , Insuficiencia Cardíaca/metabolismo , Enfermedades Renales/metabolismo , Hepatopatías/metabolismo , Quinolonas/farmacocinética , Adulto , Anciano , Cardiotónicos/sangre , Cardiotónicos/orina , Cromatografía Líquida de Alta Presión , Femenino , Insuficiencia Cardíaca/complicaciones , Insuficiencia Cardíaca/tratamiento farmacológico , Humanos , Indicadores y Reactivos , Infusiones Intravenosas , Enfermedades Renales/complicaciones , Enfermedades Renales/fisiopatología , Pruebas de Función Renal , Hepatopatías/complicaciones , Hepatopatías/fisiopatología , Pruebas de Función Hepática , Masculino , Persona de Mediana Edad , Quinolonas/sangre , Quinolonas/orina , Reproducibilidad de los Resultados , Factores de TiempoRESUMEN
The understanding of the cell signaling pathways and the molecular events leading to cell death of cancer cells will provide in-depth perspective into the identification and development of potent anticancer agents. A balance between cell proliferation and cell death has been raised as a rational target for the management of malignant tumors. In the present study, the authors demonstrated that chemically synthesized sugar-cholestanols consisting of GlcNAcbeta-, Galbeta- and GlcNAcbeta1,3Galbeta-cholestanols exerted a strong inhibiting activity against cell proliferation of esophageal cancer cells, but cholestanol itself did not show such an activity against the same cancer cells at all. In addition to their predominant role as an antiproliferation agent, evidence based on the molecular analyses suggested that sugar-cholestanols played a regulatory role in multiple signal transduction pathways inducing apoptosis through both the death signal-extrinsic and the mitochondria-intrinsic pathways. Sugar-cholestanols seemed to be more susceptible to esophageal cancer cells than to non-cancerous esophageal cells at the very early event of their exposure and, further, to suppress specifically the expression of vascular endothelial growth factor. Taken together, these novel functions of sugar-cholestanols indicate that they could have promising therapeutic potential against human esophageal cancer.