RESUMEN
Rat isolated perfused lungs (Sprague-Dawley rats, n = 20) were studied to compare the pulmonary uptake of a new anthracycline, tetrahydropyranyl-doxorubicin (THP-DXR) with that of doxorubicin (DXR). Lung perfusions were initiated with a constituted medium containing either drug at concentrations of 1, 10 or 100 microM. Lungs were perfused by recirculation for 60 min. Thirteen perfusate samples were collected over 60 min and subjected to HPLC for assay. The perfusate concentration of THP-DXR decreased to 24 +/- 5% of the initial concentration and to 8 +/- 2%, 20 and 60 min after the beginning of the infusion, respectively. Corresponding values for DXR were 77 +/- 16 and 52 +/- 15%, respectively (P less than 0.05). During the THP-DXR perfusion, the area under the perfusate concentration vs time curve (AUC) was decreased to one-third and the clearance was increased 3-fold (P less than 0.05). The pulmonary concentration of THP-DXR reached 0.032 +/- 0.01 mumol g-1 60 min after the beginning of a perfusion of 1 microM of the drug. This concentration increased to 0.379 +/- 0.11 mumol g-1 when the initial dose concentration was 10 microM. Corresponding lung concentrations for DXR were 0.013 +/- 0.001 and 0.150 +/- 0.04 mumol g-1, respectively (P less than 0.05). The perfusate concentration/initial concentration ratio decreased by the same amount whether a 1 or 10 microM initial concentration of either drug was used. An initial concentration of 100 microM of THP-DXR, unlike DXR, consistently induced oedema in the perfused lung. No metabolite of either drug was revealed during the course of our study.(ABSTRACT TRUNCATED AT 250 WORDS)
Asunto(s)
Doxorrubicina/análogos & derivados , Doxorrubicina/farmacocinética , Pulmón/metabolismo , Animales , Cromatografía Líquida de Alta Presión , Técnicas In Vitro , Masculino , Ratas , Ratas EndogámicasRESUMEN
Fluorescence microscopy and high pressure liquid chromatography were used to study the decrease of doxorubicin (DXR) concentrations in the liver, spleen, heart, lung, kidney and skeletal muscle of two strains of rats at various times after a single intravenous injection of the drug (8 mg kg-1). DXR was located within the cell nucleus and was mostly undegraded, it persisted, especially in heart, lungs and spleen where it was detectable 10 days after injection. The DXR/DNA ratio, was used as an index of nuclear fixation of the drug. A major difference in the DXR/DNA ratio between the two strains were observed in heart and spleen results; the DXR/DNA ratio was significantly higher in heart and spleen compared with lung, liver and kidney in both strains.