Metabolism of the anti-tumour drugs N2-methyl-9-hydroxyellipticinium acetate (NSC 264137) and N2-methyl-9-hydroxyolivacinium acetate in the rat: preliminary identification of biliary 9-(O)-glucuronide and 10-(S)-glutathione conjugates.

ABSTRACT

The metabolites of the two anti-tumour drugs, N2-methyl-9-hydroxyellipticinium acetate (9-OH-NME, NSC 264137) and N2-methyl-9-hydroxyolivacinium acetate (9-OH-NMO), in bile of i.v.-treated rats have been studied. Three products have been identified in the bile the unmetabolized drug (17% excreted products for ellipticinium, 3% for olivacinium derivative); a major metabolite, the corresponding 9-(O)-glucuronide (80 and 96%, respectively) and a minor metabolite, a possible 10-(S)-glutathione conjugate (3 and 1%). The elimination yield of these three products excreted over a period of 12 h represents 36% (ellipticinium) and 74% (olivacinium) of the administered dose. The detection of glucuronide and glutathione conjugates of these pyridinium derivatives was possible by direct injection of bile on to h.p.l.c. without prior extraction with organic solvents, in which these polar metabolites are poorly soluble. Metabolites were tentatively identified by the comparison of h.p.l.c. behaviour (retention times and u.v. absorption ratios) with those of reference samples. Reference conjugates have been prepared by chemical synthesis for the 9-(O)-glucuronides and by biosynthesis for the 10(S)-glutathione derivatives. The detection of the GSH conjugates in bile can be considered as the first experimental evidence of the involvement of oxidative activation in vivo of these ellipticine and olivacine derivatives.