Identification of the glucuronide and glutathione conjugates of the antitumor drug N2-methyl-9-hydroxyellipticinium acetate (Celiptium). Comparative disposition of this drug with its olivacinium isomer in rat bile.
Two metabolites of the antitumor drug N-2-methyl-9-hydroxyellipticinium acetate (Celiptium) were isolated from bile of 10 mg/kg iv-treated rats. These metabolites were characterized by UV-visible, mass and proton-NMR data and identified as (i) 9-(O)-glucuronide conjugate and (ii) 10-(S)-glutathione adduct. Evidence for the same type of metabolites for the isomer N-2-methyl-9-hydroxyolivacinium acetate was supported by HPLC data. Despite their minor structural differences (change into a methyl position), the biliary excretion profile of these two drugs is rather different quantitatively: total metabolites excreted within a 12-hr period is 33 +/- 4% of the administered dose for ellipticinium and 70 +/- 6% for olivacinium. The major metabolite is the 9-(O)-glucuronide conjugate for those two drugs: 25 +/- 3% of the dose of ellipticinium and 67 +/- 5% for olivacinium derivative. In both cases, the presence of the 10-(S)-glutathione adduct as a minor metabolite [1.5 +/- 0.5 of the dose (ellipticinium) and 1 +/- 0.5 (olivacinium)] supports the hypothesis that a "biooxidative alkylation" process could occur in vivo.
D000470:Alkaloids / Q000378:metabolism*; D000818:Animals; D000970:Antineoplastic Agents / Q000378:metabolism*; D001646:Bile / Q000378:metabolism*; D004611:Ellipticines / Q000378:metabolism*; D005965:Glucuronates / Q000378:metabolism*; D005978:Glutathione / Q000378:metabolism*; D007700:Kinetics; D008297:Male; D051381:Rats; D011919:Rats, Inbred Strains
D000470:Alkaloids; D000970:Antineoplastic Agents; D004611:Ellipticines; D005965:Glucuronates; C027767:elliptinium; D005978:Glutathione