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 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)
Département d'Informatique Médicale, Faculté de Médecine, Dijon, France.
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Dumas
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Dubuet
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D'Athis
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Camus
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Escousse
D000818:Animals; D002851:Chromatography, High Pressure Liquid; D004317:Doxorubicin / Q000031:analogs & derivatives* / Q000493:pharmacokinetics*; D066298:In Vitro Techniques; D008168:Lung / Q000378:metabolism*; D008297:Male; D051381:Rats; D011919:Rats, Inbred Strains
D004317:Doxorubicin; C027260:pirarubicin