Maytansine, a potent clinically evaluated plant-derived anti-
tumor drug, and its microbial counterpart, ansamitocin P-3, showed a substantially higher cytoxicity than many other anti-
tumor drugs. Owing to a shortage of material and lack of sufficiently sensitive analytical methods at the time, no metabolism studies were apparently carried out in conjunction with the initial preclinical and clinical studies on
maytansine, but some products of decomposition during the period of storage of the formulated
drug were reported. In the current study, the in vitro metabolism of
maytansine and ansamitocin P-3 was studied after incubation with rat and human liver microsomes in the presence of
NADPH, and with rat and human plasma and whole blood, using liquid chromatography/multi-stage mass spectrometry. Unchanged ansamitocin P-3 and 11 metabolites and unchanged
maytansine and seven metabolites were profiled and the structures of some metabolites were tentatively assigned based on their multi-stage electrospray ion-trap mass fragmentation data and in some cases accurate mass measurement. The major pathway of ansamitocin P-3 metabolism in human liver microsomes appears to be demethylation at C-10. Oxidation and sequential oxidation/demethylation also occurred, although to a lesser extent. However, the major pathway of
maytansine metabolism in human liver microsomes is N-demethylation of the methylamide of the
ester moiety. Several minor pathways including O/N-demethylation, oxidation and hydrolysis of the
ester bond were also observed. There were no differences in
maytansine metabolism between rat and human liver microsomes; however, the rate of metabolism of ansamitocin P-3 was different in rat and human liver microsomes. About 20% of ansamitocin P-3 was converted to its metabolites in rat liver microsomes and about 70% in human liver microsomes under the same conditions. Additionally, 10-O-demethylated ansamitocin P-3 was also detected in the urine after i.v. bolus administration of ansamitocin P-3 to Sprague-Dawley male rats. No metabolites were detected following incubation of
maytansine and ansamitocin P-3 with human and rat whole blood and plasma.