Hepatobiliary metabolism and urinary excretion of 4-demethoxydaunorubicin as compared to daunorubicin in rats.
The hepatic metabolism and biliary excretion of 4-demethoxydaunorubicin (4DDM) was studied in Crl: CD(SD) BR rats by the liver perfusion technique. In the same strains of rats urinary excretion was investigated in vivo. Daunorubicin (DM) was always included for comparison. The drugs and their metabolites were determined in the perfusion medium, in the bile and liver and in the urine by high-performance liquid chromatography with fluorimetric detection. Compared to its analogue DM, 4DDM markedly differed in the metabolic and excretory profile. The cumulative biliary and urinary excretion of 4DDM and the metabolites was quantitatively lower than that of DM (18% vs 36% of the dose) and was consistent with prolonged persistence of 4DDM in plasma in vivo. The extensive carbonyl reduction of 4DDM and DM observed in previous in vivo pharmacokinetic studies was also evident in this study. 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. In the hepatobiliary system, however, the 13-hydroxy derivative of DM amounted to a much lower fraction than the DM aglycone (17% vs 50% of the total dose), 80% of the total 4DDM dose was accounted for by 4DDMol aglycone. In urine uncleaved DMol or 4DDMol represented more than 75% of the total amount excreted for both drugs. Conjugation, a major step in the excretion of aglycones, seems to play a minor role in the biliary and urinary excretion of 4DDM and 4DDMol.