Human pharmacokinetics of the daunorubicin-DNA complex. An alternative view of the lysosomotropic theory.

Plasma kinetics and urinary execretion of daunorubicin (DNR) and its active metabolite, daunorubicinol (DNR-ol) were studied in 15 leukemic patients after a 4-h infusion of 75 mg DNR/m2 either as the free drug or as a complex with DNA. The data obtained after infusion of the DNR-DNA complex were compared with the data obtained after infusion of the free drug. The DNR plasma levels were found to be higher during the 2 h following the infusion of the complex; the levels of DNR-ol were only higher for a few minutes after infusion. Kinetic analysis showed that complexing with DNA does not fundamentally modify the three-compartment model described for DNR. Only quantitative modifications were observed: a marked lengthening of the alpha-phase and a shortening of the gamma-phase. Urinary excretion of DNR and DNR-ol was increased after infusion of the complexed drug, in relation to the persistence of higher plasma levels. The data recorded in this work do not confirm the lysosomotropic mechanism postulated for the DNR-DNA complex, but show a delayed distribution of DNR, which is progressively released by dissociation of the circulating DNR-DNA complex, as previously demonstrated in rabbits infused under same conditions.