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In vitro metabolism of a new anticancer agent, 6-N-formylamino-12, 13-dihydro-1,11-dihydroxy-13-(beta-D-glucopyranosil)5H-indolo+ ++[2,3-a]pyrrolo[3,4-c]carbazole-5,7(6H)-dione (NB-506), in mice, rats, dogs, and humans.

The metabolism of 6-N-formylamino-12,13-dihydro-1, 11-dihydroxy-13-(beta-D-glucopyranosil)5H-indolo [2,3-a]pyrrolo [3, 4-c]carbazole-5,7(6H)-dione (NB-506), a potent inhibitor of DNA topoisomerase I, was characterized in mice, rats, dogs, and humans in vitro. NB-506 was deformylated to ED-501 in mouse and rat plasma with enzyme activity of 140 and 116 pmol/min/mg protein, respectively. The enzyme activity in dog and human plasma was found to be less than 1.7 pmol/min/mg protein. In liver S9 and small intestine S9 samples from mice and rats, activity of the enzyme was very low. Also, there was no activity in the liver or small intestine of dogs and humans. The enzyme involved in the conversion of NB-506 to ED-501 in rat plasma is a rodent-specific serine enzyme with a molecular mass of 138KDa. The Vmax and Km values were 6.3 nmol/min/ml plasma and 54 microM at an optimum pH of 7.4, respectively. Although NB-506 was converted to ED-551 in dog and human plasma in vitro, no conversion was observed in mouse and rat plasma. In human plasma this conversion was not affected by heat treatment (100 degreesC for 1 min), but was inhibited completely by 50 mM EDTA, indicating that the reaction is a chemical reaction catalyzed by metal ions. Although NB-506 was not metabolized by cytochrome P-450 isozymes in liver, this drug was glucuronized in mice, rats, and humans, but not in dogs. These results suggest that a species difference in the metabolism of NB-506 occurred in the liver as well as in plasma. There appeared to be species differences in the metabolism of NB-506 in vitro, correlating well with the species-dependent pharmacokinetics of this drug in vivo.