COMPARATIVE PHARMACOKINETICS OF TETRAHYDROPYRANYL-DOXORUBICIN AND DOXORUBICIN IN RAT ISOLATED LUNG

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-mu-M. 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 +/- 21%, 20 and 60 min after the beginning of the infusion. respectively. Corresponding values for DXR were 77 +/- 16 and 52 +/- 15%, respectively (P < 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 < 0.05). The pulmonary concentration of THP-DXR reached 0.032 +/- 0.01-mu-mol g-1 60 min after the beginning of a perfusion of 1-mu-M of the drug. This concentration increased to 0.379 +/- 0.11-mu-mol g-1 when the initial dose concentration was 10-mu-M. Corresponding lung concentrations for DXR were 0.013 +/- 0.001 and 0.150 +/- 0.04-mu-mol g-1, respectively (P < 0.05). The perfusate concentration/initial concentration ratio decreased by the same amount whether a 1 or 10-mu-M initial concentration of either drug was used. An initial concentration of 100-mu-M 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. These findings suggest: (1) a higher lung affinity for THP-DXR; (2) a correlation between lung uptake and dose consistent with a passive diffusion transport mechanism for both drugs: (3) a higher acute toxicity induced by THP-DXR: (4) the absence of metabolic activity in the lung with regards to both anthracyclines.