Plasma and human leukemic cell pharmacokinetics of oral and intravenous 4-demethoxydaunomycin

On 3 consecutive days, 4-demethoxydaunomycin (D-DNM) was administered orally (30 mg/m2) as bolus injection and 4- or 24-hour infusion to seven patients with acute leukemia. Cellular (nucleated blood and bone marrow cells) and plasma drug concentrations were studied. After bolus injection, peak plasma D-DNM concentrations were about 50 mg/ml. D-DNM plasma t1/2s were 0.4 +/- 0.3 hours (T1/2 alpha) and 16.4 +/- 4.7 hours (T1/2 beta). D-DNM concentrations in nucleated blood and bone marrow cells were on the same order of magnitude and amounted to more than 400 times the plasma concentration, whereas 4-demethoxydaunomycinol (D-DNMol) concentrations were about 200 times higher. Cellular D-DNM concentrations were maximal at the end of intravenous dosing and at 2 to 4 hours after D-DNM ingestion. D-DNMol concentrations increased more slowly and accumulated on subsequent treatment days in cells and plasma; D-DNM and D-DNMol cellular t1/2 times were 42 and 72 hours, respectively. Antileukemic activity was observed.