daunorubicinol and daunomycinone

Levels of plasma daunorubicin, daunorubicinol and aglycone metabolites were measured in 47 patients 3 h after daunorubicin was administered daily for three days as part of a cytosine arabinoside/daunorubicin remission induction regimen. High-pressure liquid chromatography with fluorescence detection was used for separation and quantitation of the drug and its metabolites. A wide range of plasma levels were observed regardless of the outcome of therapy. Patients who had high levels of the drug, or daunorubicinol on day 1 of therapy tended to have high levels on days 2 and 3 of the regimen. Three hours after the third daily dose of daunorubicin was administered, patients who would not enter remission had significantly higher levels of aglycone metabolites in plasma than did patients who entered remission. These data indicate that resistance to chemotherapeutic effects of daunorubicin may be connected with metabolism of the drug, especially with enhanced metabolism to aglycones.

Topics: Acute Disease; Biotransformation; Daunorubicin; Humans; Injections, Intravenous; Kinetics; Leukemia; Naphthacenes

One approach currently being used to target drug action selectively to specific cells and tissues is to link active drugs to proteins and peptides that are preferentially recognized by, distributed to or activated by the target cells. Inasmuch as the kidney proximal tubule cells are very active in recapturing and catabolizing peptides and proteins which appear in the glomerular filtrate, we have examined the cellular pharmacology of daunorubicin (DNR) and doxorubicin (DOX) and selected amino acid and dipeptide derivatives in suspensions of rabbit renal proximal proximal tubules. The tubules accumulated the DNR series of drugs and their metabolites to a greater extent than the DOX series. Although all of the amino acid derivatives of these drugs entered the cells for sequestration and metabolism, the dipeptide derivative, alanyl-leucyl-DNR, was not detected within the cells. Using high-performance liquid chromatography to quantify the various metabolites and isopycnic centrifugation of tubule-derived post-nuclear supernates in linear sucrose gradients to resolve various subcellular organelles, the subcellular sites of metabolism of these drugs were examined. A NADPH-dependent reduction of the C-13 carbonyl group of the parent drugs, which was the primary route of metabolism, was localized to the cytoplasm. Formation of aglycones generated by the cleavage of the daunosamine moiety from the anthracycline core followed the microsomal marker, NADPH-cytochrome reductase, in the sucrose gradients. Removal of the terminal amino acid from alanyl-leucyl-DNR was tentatively assigned to a cysteine-requiring enzyme on the plasma membrane.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Amino Acids; Animals; Antibiotics, Antineoplastic; Biotransformation; Daunorubicin; Doxorubicin; Hydrolysis; In Vitro Techniques; Kidney Tubules, Proximal; Naphthacenes; Rabbits