Comparative murine metabolism and disposition of class II anthracycline antibiotics.
The metabolism and tissue distribution of aclacinomycin A (ACL), marcellomycin (MCM), and musettamycin (MST), three new anthracycline antibiotics, were compared after IV administration to mice. In plasma, total MCM- and ACL-derived fluorescence declined according to first-order kinetics, whereas an initial decline followed by a rebound was observed for MST. In plasma, MCM remained the predominant compound. ACL was eliminated more quickly, and was replaced by two metabolites, the reduced glycoside M1, and an aglycone. In the case of MST, two unidentified metabolites were observed in concentrations equivalent to that of the parent drug. The three drugs were distributed widely to organs, but only ACL achieved measurable concentrations in the brain. Initially, high concentrations of all three drugs were present in the lungs, but these decreased quickly to values similar to those present in the liver and kidneys. Intermediate concentrations of the three drugs were measured in heart and skeletal muscle. Splenic concentrations of all three drugs rose progressively, reaching a maximum at 8 h after injection in the case of ACL and MST, and at 24 h after injection in the case of MCM. Concentrations of the metabolites of MCM and MST were low in all organs except liver and kidney, where the aglycones 7-deoxypyrromycinone and bisanhydropyrromycinone were seen. The metabolism of ACL was extensive. Aglycones were dominant in the liver and kidneys, whereas reduced glycosides predominated in the spleen. These observations indicate that the murine pharmacology of these three structurally similar drugs differs markedly.
D015250:Aclarubicin / Q000031:analogs & derivatives*; D000818:Animals; D018943:Anthracyclines; D000903:Antibiotics, Antineoplastic / Q000097:blood / Q000378:metabolism*; D002851:Chromatography, High Pressure Liquid; D003201:Computers; D008297:Male; D051379:Mice; D009279:Naphthacenes / Q000097:blood / Q000378:metabolism; D013050:Spectrometry, Fluorescence; D014018:Tissue Distribution
D018943:Anthracyclines; D000903:Antibiotics, Antineoplastic; D009279:Naphthacenes; C011157:aclacinomycins; C015338:marcellomycin; C015374:musettamycin; D015250:Aclarubicin