Aromatic hydroxylation of ellipticine in rats: lack of an NIH shift

Metabolites of the antitumor agent, elipticine (NSC) 71795), are mainly secreted in rat bile as two conjugates of hydroxylated elipticine. The possible involvement of an arene oxide intermediate prior to hydroxylation and conjugation has been studied using 7,9-dideutero-ellipticine and by determining the conservation of deuterium in the phenolic products. The deuterated drug was synthesized by acid catalyzed exchange and was characterized by nuclear magnetic resonance and high and low resolution mass spectrometry. Mass spectra of two conjugated metabolites from rat bile showed a mass ion at m/e 263 (singly deuterated hydroxylated elipticine). There was no evidence for conservation of deuterium at the position of hydroxylation (m/e 264). These results indicate that the major pathway of metabolism for this cancer chemotherapeutic drug, prior to conjugation and excretion in rat bile, proceeds by aromatic hydroxylation apparently without involving an arene oxide/NIH shift mechanism.