Method for the determination of 4-demethoxydaunorubicin, its quinone and hydroquinone metabolites in human plasma and urine by high-performance liquid chromatography.
4-Demethoxydaunorubicin (4-DMDNR) is a new orally active analogue of daunorubicin (DNR). We have developed a high-performance liquid chromatography (HPLC) method capable of separating and identifying 4-DMDNR, five possible fluorescent quinone metabolites and three possible non-fluorescent hydroquinone metabolites. Methods are described for high-yield synthesis of reference metabolites. The limit of detection of the fluorescence assay was less than 1 ng/ml after extraction of 1 ml plasma or urine with chloroform/propan-2-ol (2:1), with coefficients of variation in k' (HPLC column capacity factors) of less than 3% throughout the day. Efficiency of the extraction method described exceeded 80% in control experiments. Blood and urine samples were analysed from four cancer patients who had received 50 mg/m2 orally as three divided doses every 8 h. A typical urinary profile of the drug and its metabolites was: parent drug, 13%; 4-demethoxydaunorubicinol (4-DMDNOL), 80%; 4-DMDNR 7-hydroxyaglycone, 4% and 4-DMDNOL 7-hydroxyaglycone, 3%. 4-DMDNOL was the major metabolite detected in plasma. A further metabolite identified as the 7-deoxyaglycone of 4-DMDNOL was detected in plasma of two patients at concentrations equal to or greater than the parent drug. In the other two patients no trace of the metabolite was detected.
D018288:Carcinoma, Small Cell / Q000378:metabolism; D002851:Chromatography, High Pressure Liquid / Q000379:methods; D003630:Daunorubicin / Q000031:analogs & derivatives* / Q000097:blood / Q000378:metabolism / Q000652:urine; D006801:Humans; D006873:Hydroquinones / Q000378:metabolism; D015255:Idarubicin; D008175:Lung Neoplasms / Q000378:metabolism; D011809:Quinones / Q000378:metabolism
D006873:Hydroquinones; D011809:Quinones; D015255:Idarubicin; D003630:Daunorubicin