Distribution of daunorubicin and daunorubicinol in human glioma tumors after administration of liposomal daunorubicin.
DaunoXome is a liposome formulation containing daunorubicin (DM). Encapsulation of the drug in liposomes presents the advantage of low-level systemic exposure and better drug penetration into the tumor. We studied the distribution of DM and its 13-dihydro metabolite, daunorubicinol (DMol), in surgical biopsies from different parts of glioblastomas. The study was performed in eight patients with recurrent glioblastoma, all of whom had previously undergone surgery and been treated with radiotherapy and chemotherapy, who received 50 mg of DaunoXome as a 1-h infusion. Surgery was performed at 24 and 48 h after the infusion in seven cases and one case, respectively. Biopsies were divided into three parts: the central area of the tumor, peripheral tumor tissue, and brain-adjacent tumor (BAT) tissue. A complete plasma pharmacokinetics study was conducted in seven cases, with samples being taken for up to 48 h after the end of the infusion. DM and DMol were determined in plasma and tissue by high-performance liquid chromatography with fluorescence detection after solvent extraction. At 24 h, concentrations of DM and DMol in the central part of the tumor ranged between < 0.005 and 0.80 microg/g and between 0.005 and 1.58 microg/g, respectively. Concentrations were similar in the peripheral tumor and in BAT tissue. From the data obtained on the patient who underwent surgery at 48 h it appears that DM and DMol remain in tumor tissue for a long time, the concentrations being 0.4 and 2.8 microg/g, respectively. DaunoXome was rapidly cleared from the body, with the plasma levels of DM and DMol determined at 48 h lying in the range of < 5-50 and < 5-20 ng/ml, respectively. The mean (+/-SD) half-life and plasmatic clearance of DM were 4.8+/-1.0 h and 0.2+/-0.06 l h(-1) m(-2). In conclusion, DaunoXome achieved and maintained potentially cytotoxic levels of both DM and DMol in glioblastoma for a long time in association with low-level systemic exposure. Further studies are therefore warranted. Although only preliminary and obtained in previously treated patients, these data suggest that DaunoXome merits investigation in CNS tumors.
Department of Oncology, Istituto di Ricerche Farmacologiche Mario Negri, Milan, Italy. zucchetti@irfmn.mnegri.it
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M
Zucchetti
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Boiardi
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A
Silvani
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Parisi
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Piccolrovazzi
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D'Incalci
D000328:Adult; D000903:Antibiotics, Antineoplastic / Q000493:pharmacokinetics*; D001932:Brain Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D003630:Daunorubicin / Q000008:administration & dosage* / Q000031:analogs & derivatives* / Q000493:pharmacokinetics*; D004337:Drug Carriers; D005910:Glioma / Q000188:drug therapy* / Q000378:metabolism; D006801:Humans; D008081:Liposomes; D008875:Middle Aged
D000903:Antibiotics, Antineoplastic; D004337:Drug Carriers; D008081:Liposomes; C000847:daunorubicinol; D003630:Daunorubicin