Comparative pharmacokinetics and metabolism of doxorubicin and 4-demethoxy-4'-O-methyldoxorubicin in tumor-bearing mice.
It has been reported that 4-demethoxy-4'-O-methyldoxorubicin (4-dm-4'-O-methylDX) is more potent than doxorubicin (DX), equally active in some murine leukemias and solid tumors, and almost devoid of cardiotoxicity. We used HPLC to investigate the metabolism and the disposition of this drug in comparison with DX in mice bearing colon 38 adenocarcinoma SC and treated with IV doses of the two drugs that were equiactive and equitoxic (4-dm-4'-O-methylDX 1 mg/kg; DX 10 mg/kg). 4-Dm-4'-O-methylDX was metabolized to a polar metabolite, presumably 4-demethoxyDX, which was eliminated more slowly than the parent drug from all the organs and accounted for 25%-50% of total fluorescence; traces of two metabolites less polar than the parent drug (2% of total fluorescence) were found only at early times in the liver. In DX-treated mice traces of doxorubicinol (1%-3% of total fluorescence) were found in tumor and organs, and two aglycones were detected only at early times in the liver. In plasma both drugs declined biexponentially and 4-dm-4'-O-methylDX was eliminated slightly faster than DX. The rate of elimination of the new analogue from lung, kidney, spleen, and small intestine was faster than that of DX; in heart and liver 4-dm-4'-O-methylDX was detectable for only up to 24 h, while DX was detectable for up to 7 days. In the tumor the kinetics and the elimination patterns of the two drugs were similar. The distribution of 4-dm-4'-O-methylDX, as a percentage of the administered dose, was 1.3-2 times higher than that of DX in the organs and 3 times higher in the tumor, which suggests an improved selectivity of the new analogue for the tumor compared with DX.
D000818:Animals; D002277:Carcinoma / Q000378:metabolism; D003110:Colonic Neoplasms / Q000378:metabolism; D004317:Doxorubicin / Q000031:analogs & derivatives* / Q000378:metabolism*; D005260:Female; D008099:Liver / Q000378:metabolism; D008657:Metabolic Clearance Rate; D051379:Mice; D014018:Tissue Distribution
D004317:Doxorubicin; C047348:4-demethoxy-4'-O-methyldoxorubicin