Disease relevance of NSC 256439

• The pharmacokinetics of orally administered idarubicin (22.5 mg/m2/week) and idarubicinol were studied for 12 weeks in 14 patients with breast cancer [1].
• These data also show that idarubicin and idarubicinol toxicity is proliferation-independent [2].
• Granulocytopenia correlated with plasma idarubicinol "estimated" clearance and steady-state volume of distribution, with whole-blood idarubicinol AUC, area under the moment curve (AuMC), and "estimated" clearance and volume of distribution, and with whole-blood combined idarubicin and idarubicinol AUCs [3].
• These studies in human leukemia and human glioblastoma cell lines support the hypothesis that idarubicinol plays an important role in the antitumor activity of idarubicin and that the activities of idarubicin and idarubicinol are related to their ability to damage DNA [4].
• In vitro effect of multidrug resistance modifiers on idarubicinol efflux in blasts of acute myeloid leukemia [5].

High impact information on NSC 256439

• Pharmacokinetics of IDA and its metabolite idarubicinol (IDOL) were evaluated [6].
• The average terminal half-life was 30.5 h for idarubicin and 66.9 h for idarubicinol [7].
• The AUC for idarubicin and its main metabolite idarubicinol revealed a substantial interpatient variation with AUC values ranging from 25.7 to 114 ng x h/ml (average 58.1 ng x h/ml) for idarubicin and from 109.4-445.2 ng x h/ml (average 287.3 ng x h/ml) for idarubicinol [7].
• Cellular pharmacology of idarubicinol in multidrug-resistant LoVo cell lines [8].
• Results for K562 cells (at clinically relevant concentrations) showed that IDA and idarubicinol, its metabolite, formed mainly topo IIalpha cleavable complexes, the level of which decreases at doses > 1 microM for IDA [9].

Biological context of NSC 256439

• IMI-30 (NSC 256439) appears to be rapidly absorbed and rapidly eliminated from plasma by means of a rapid and extensive biotransformation to 13-OH-idarubicin [10].
• Tissue distribution also differed: idarubicin and idarubicinol concentrations were lower in heart, lung, spleen, and kidneys after IDA-SLN administration than after solution administration [11].
• Idarubicin was more potent than the other three anthracycline analogs and idarubicinol was much more effective than the other alcohol metabolites in inducing DNA damage [4].
• Oral bioavailability was determined by comparing oral idarubicin to i.v. drug with respect to the combined idarubicin and idarubicinol plasma AUCs, and it varied from 12%-49% (median, 29%) [3].
• Only association of low concentrations of idarubicin plus idarubicinol induced apoptosis on leukaemic cells [12].

Anatomical context of NSC 256439

• Concentrations of idarubicinol in plasma and blood cells exceeded those of IDA 2 to 4 hours after the start of treatment and remained elevated for a long time [13].
• At the time of allogeneic bone marrow infusion (day 0), patients in cohorts 1 and 2 had plasma concentrations of idarubicin and idarubicinol (its active metabolite) in the range of in vitro cytotoxicity [14].
• We evaluated in vitro the toxicity of idarubicin and its active metabolite idarubicinol on haematopoietic progenitors, using human umbilical cord blood and peripheral blood progenitors to obtain dose-response curves [15].
• Moreover, we have also documented the presence of idarubicinol in the cerebrospinal fluid of pediatric patients who have received idarubicin [4].
• For the metabolites an intracellular concentration of 0.4 nmol/mg protein of idarubicinol and 2.0 nmol/mg protein of daunorubicinol was required to inhibit cells' growth by 50% in drug-sensitive HL60 cells [16].

Associations of NSC 256439 with other chemical compounds

• We examined the in vitro response to different drugs and confirmed the test's ability to detect heterogeneity in response to same drugs (doxorubicin, 4'-epidoxorubicin, vinblastine, cis platinum, and idarubicinol) among the different breast carcinoma cultures as well as heterogeneity among subpopulations within a single carcinoma [17].
• We incubated sensitive and resistant hematopoietic cells from cell lines and patient cells with daunorubicin, idarubicin, and its active derivative idarubicinol, extracted the anthracyclines from whole cells and nuclei, and determined their concentration fluorimetrically [18].
• Effects of idarubicin and idarubicinol on rat coronary resistance and vasoconstrictor responsiveness of isolated aorta and mesentery [19].
• To determine the efficacy of IDA in myeloma cells, the pharmacokinetics and cytotoxicity of IDA and its major metabolite idarubicinol (IDAol) were compared with those of DNR, DOX, and doxorubicinol (DOXol) in the cell line RPMI 8226-S and two MDR sublines (8226-R7 and 8226-Dox40) that overexpress the drug transporter P-glycoprotein (Pgp) [20].

Gene context of NSC 256439

• IDA is converted in the liver into idarubicinol (2HIDA) and, in this form, seems to exert its antitumoral activity in vivo [21].
• A specific, sensitive, and reliable high-performance liquid chromatographic (HPLC) method for the determination of idarubicin (IDA) and its known fluorescent metabolites idarubicinol (IDAol) and 4-demethoxy-daunomycinone (AG1) in biological fluids (human plasma and urine) was developed and tested [22].

Analytical, diagnostic and therapeutic context of NSC 256439

• After i.v. and oral administration in humans, Idarubicin is rapidly metabolized to its 13-dihydroderivative (Idarubicinol) and the plasma levels of this metabolite are consistently higher than those of the unchanged drug [23].
• Idarubicin and its main metabolite idarubicinol were determined in plasma and tissues by reversed-phase high-performance liquid chromatography [11].
• 13-hydroxy metabolites, daunorubicinol (DMol) and 4-demethoxydaunorubicinol (4DDMol), either as such or after glycosidic cleavage, i.e. 4DDMol aglycone, were present in appreciable amounts in the perfusion medium, bile, liver and urine [24].
• Determination of idarubicin and idarubicinol in plasma by capillary electrophoresis [25].
• Comparison of the interaction of doxorubicin, daunorubicin, idarubicin and idarubicinol with large unilamellar vesicles. Circular dichroism study [26].

References