Detection and identification of human urinary metabolites of biantrazole (CI-941).
The anthrapyrazole derivative biantrazole (7-hydroxy-2-[2-[(2-hydroxyethyl)amino]ethyl]-5-[[2-[(2- hydroxyethyl)amino]ethyl]amino]-anthra[1,9-cd]pyrazol-6(2H)-one dihydrochloride, CI-941) is currently under clinical investigation for the treatment of breast cancer. Up to now, pharmacokinetic data of the drug were acquired using an HPLC assay lacking the capability to detect and separate metabolites of CI-941. Therefore an HPLC separation procedure was developed that is compatible with the ionization methods used most frequently for coupling to mass spectrometry. Application of the HPLC analysis to the urine of a patient treated with biantrazole clearly demonstrated the presence of two more polar metabolites. The molecular masses of the metabolites were determined during an HPLC-MS coupling with ionspray ionization after injection of an extract of only 15 ml of patient urine. Both metabolites have the same UV-VIS spectra as biantrazole and exhibit collision-induced mass spectra typical for aminoalkylamino-substituted anthrapyrazoles. The daughter ion mass spectra acquired during the HPLC separation allowed the identification of the chemical structures of both metabolites. Metabolite 1 was identified as the oxidation product of CI-941 with both side chains oxidized at the hydroxymethylene groups to the corresponding dicarboxylic acid derivative, whereas metabolite 2 was shown to be the analogous monooxidation product. However, the unsymmetrical molecular structure of CI-941 did not allow us to distinguish between two possible isomers of metabolite 2. Quantitation of the drug and its metabolites in patient urine collected during a time period of 100 hr showed that 0.55% of the dose were excreted as metabolite 1, 0.34% of the dose as metabolite 2, and 7.8% of the dose as unchanged drug.
Blanz
J
J
Universität Tübingen, Institut für Organische Chemie, Germany.
Renner
U
U
Schmeer
K
K
Ehninger
G
G
Zeller
K P
KP
D000880:Anthraquinones / Q000302:isolation & purification / Q000652:urine*; D000970:Antineoplastic Agents / Q000302:isolation & purification / Q000652:urine*; D002851:Chromatography, High Pressure Liquid / Q000379:methods; D005260:Female; D006801:Humans; D013058:Mass Spectrometry / Q000379:methods; D008942:Mitoxantrone / Q000302:isolation & purification; D011720:Pyrazoles / Q000302:isolation & purification / Q000652:urine*; D047069:Pyrazolones; D012997:Solvents
D000880:Anthraquinones; D000970:Antineoplastic Agents; D011720:Pyrazoles; D047069:Pyrazolones; D012997:Solvents; C050637:losoxantrone; D008942:Mitoxantrone