Disease relevance of Doxorubicinol

• Our data suggest that this toxicity could involve doxorubicinol, the primary circulating metabolite of doxorubicin [1].
• We investigated whether the tubulin-active taxane paclitaxel increases conversion of doxorubicin to doxorubicinol, thus explaining the high incidence of congestive heart failure when doxorubicin is used with paclitaxel [2].
• The model assumes an initial volume of distribution of 60% of body weight and includes two peripheral adriamycin compartments and a subsystem for adriamycinol, a major metabolite [3].
• This resulted ina significant increase in the CXT (concentration X time) ratio of adriamycinol/Adriamycin in hepatoma patients compared with nonhepatoma patients (2.36 +/- 2.12 vs 0.76 +/- 0.31, (P less than 0.05) [4].
• Disposition kinetics of adriamycin, adriamycinol and their 7-deoxyaglycones in AKR mice bearing a sub-cutaneously growing ridgway osteogenic sarcoma (ROS) [5].

High impact information on Doxorubicinol

• The second step is a nonenzymatic and superoxide anion-independent redox coupling of a large fraction of doxorubicinol (3.2 +/- 0.4 nmol/mg protein per 4 h) with Fe(III)-binding proteins distinct from ferritin, regenerating stoichiometric amounts of DOX, and mobilizing a twofold excess of Fe(II) ions (6.1 +/- 0.7 nmol/mg protein per 4 h) [6].
• Control and Cbr1 +/- mice were administered doxorubicin at 20 mg/kg i.p. Cbr1 +/- mice showed decreased circulating levels of the cardiotoxic metabolite, doxorubicinol, after administration [7].
• Certain products of DOX metabolism, like the secondary alcohol doxorubicinol (DOXol) or reactive oxygen species (ROS), may contribute to cardiotoxicity by inactivating iron regulatory proteins (IRP) that modulate the fate of mRNAs for transferrin receptor and ferritin [8].
• Perfusate and bile were collected during the perfusion, the liver was homogenized after the perfusion, and samples were analyzed by high-pressure liquid chromatography for doxorubicin and the major metabolite doxorubicinol [9].
• In a previous study, we showed that NADPH-supplemented cytosolic fractions from human myocardial samples can enzymatically reduce a carbonyl group in the side chain of DOX, yielding a secondary alcohol metabolite called doxorubicinol (DOXol) [10].

Biological context of Doxorubicinol

• The AUC and T1/2 of doxorubicinol were similar among all patient groups [11].
• Our purpose was to assess the pharmacokinetics of Leu-Dox, Dox, doxorubicinol (Dol) and four other metabolites for pharmacokinetically guided dose-escalation and to verify the prodrug character of Leu-Dox [12].
• ADR underwent little biotransformation; 80% of the 48-hr cumulative fluorescence excretion was attributable to unchanged drug, one-half the remainder was adriamycinol, and the balance was polar conjugates [13].
• We find the doxorubicinol is a potent inhibitor (IC50 less than 5 micrograms/ml) of calcium-stimulated ATPase activity of sarcoplasmic reticulum from canine heart and rabbit skeletal muscle [14].
• Although complete suppression of the PMNL respiratory burst occurred with concentrations of doxorubicinol greater than 0.3 microgram/ml, a marked potentiation of the response was observed at lower concentrations (0.01 or 0.03 microgram/ml) of the same drug [15].

Anatomical context of Doxorubicinol

• Only doxorubicinol was found to be cytotoxic for these lymphocytes, whereas exposure to aglycones at concentrations as high as 5 microM for 1 h had no effect on the proliferative capacity of these cells [16].
• Seventy to 90% of doxorubicin and 60 to 90% of doxorubicinol taken up/retained by the cells were detected in the cell nuclear fraction, whereas only 20 to 40% of the aglycones were localized in the cell nucleus [16].
• Doxorubicinol, between 10 and 50 micrograms/ml, increases resting tension up to 4-fold in isolated papillary muscles cyclically contracting at 30 times/min [14].
• At comparable levels, doxorubicinol is also a potent inhibitor of (Na + K)-ATPase of cardiac sarcolemma and the Mg-dependent ATPase activity referable to the F0F1 proton pump of mitochondria [14].
• No relationships were noted between doxorubicinol exposure and surviving factor of white blood cells or platelets [17].

Associations of Doxorubicinol with other chemical compounds

• Blood samples were collected up to 48 hours after the infusion and analyzed for doxorubicin and its metabolite, doxorubicinol, by high performance liquid chromatography [11].
• Polar drug metabolites, daunorubicinol and adriamycinol, retain inhibitory activity against nucleic acid metabolism but have a decreased membrane binding and permeability [18].
• The pharmacokinetics of sorafenib and doxorubicinol were not affected [19].
• The metabolites of DXR, including Adriamycinol and Adriamycinone, were not detectable in the cell extracts or supernatants at any cell density examined [20].
• Pharmacokinetics of adriamycin, adriamycinol, and antipyrine in patients with moderate tumor involvement of the liver [21].

Gene context of Doxorubicinol

• In contrast to previous studies, we showed that the DOX metabolite, doxorubicinol, had no effect on IRP-RNA-binding activity [22].
• PURPOSE: To develop a population pharmacokinetic model for doxorubicin and doxorubicinol in the presence of zosuquidar.3HCl, a potent P-glycoprotein inhibitor [23].
• Canine RBC showed a higher rate of transformation of adriamycin than the human cells, the only intracellular metabolite being adriamycinol, which is apparently formed by the NADPH-dependent enzyme aldehyde reductase [24].
• The ratio of the doxorubicinol AUC0-36 to the doxorubicin AUC0-36 increased significantly with cyclosporine modulation (8.88 vs. 2.19; P = 0.001) [25].
• Adriamycin was metabolized to adriamycinol by the cytoplasmic aldo-keto reductase and adriamycin and adriamycinol were further metabolized to their deglycosylated aglycones, M3 and M4, respectively, by cytochrome P450 [26].

Analytical, diagnostic and therapeutic context of Doxorubicinol

• PTX, DOX, and their metabolites 6 alpha-hydroxyl-PTX (6 alpha OH-PTX) and doxorubicinol (DOL) were measured by high-pressure liquid chromatography (HPLC) [27].
• Plasma pharmacokinetics of adriamycin and adriamycinol: implications for the design of in vitro experiments and treatment protocols [28].
• Doxorubicinol (DOXol) is a human metabolite of the chemotherapy agent doxorubicin (DOX), and is associated with dose-dependent cardiotoxicity and decreased drug efficacy [29].
• Separation of doxorubicin and doxorubicinol by cyclodextrin-modified micellar electrokinetic capillary chromatography [29].
• Plasma of patients treated with ADR (30 mg/m2) contained adriamycinol as the main detectable metabolite, but at 3 h after treatment its concentration was usually lower than that of the unchanged drug (22 +/- 9 vs 53 +/- 16 pmol/ml) [30].

References