In Vivo Metabolism of a New Anticancer Agent, 6-N-formylamino-12,13-dihydro-1,11-dihydroxy-13-(β-d-glucopyranosil)5H-indolo [2,3-a]pyrrolo [3,4-c]carbazole-5,7(6H)-dione (NB-506) in Rats and Dogs: Pharmacokinetics, Isolation, Identification, and Quantification of Metabolites

6- N -formylamino-12,13-dihydro-1,11-dihydroxy-13-(β-d-glucopyranosil)5 H -indolo [2,3- a ]pyrrolo [3,4- c ]carbazole-5,7(6 H )-dione (NB-506), a potent inhibitor of DNA topoisomerase I, is currently under development for the treatment of cancer. We investigated the pharmacokinetics of NB-506 after i.v. administration in rats and dogs. The plasma concentration of NB-506 decreased biexponentially in rats and dogs with terminal half-lives of approximately 2 h. The area under the curve increased nonlinearly with increasing dose in rats. In contrast, there was a linear relationship between the area under the curve and the dose in dogs. In rats, the plasma clearance decreased with increasing dose up to 187.5 mg/m 2 but remained virtually unchanged at the highest dose. The V dss of NB-506 in rats and dogs was much greater than the plasma volume, indicating that NB-506 is highly distributed to tissue from plasma in these animals. There were marked species differences in the plasma concentrations of ED-501 after i.v. administration of NB-506 to rats and dogs. To better understand the mechanisms of nonlinear pharmacokinetics in rats, in vivo metabolites were determined. After i.v. administration of [ 14 C]NB-506 to rats, two unknown metabolites (RBM-1 and RBM-2), deformyl metabolite (ED-501), and unchanged drug (NB-506) were identified. Mass and NMR spectra analysis revealed that RBM-1 is an 11- O -glucuronide of NB-506 (ED-594) and that RBM-2 is an 11- O -glucuronide of ED-501 (ED-595). In this study, the pharmacokinetics of NB-506 was demonstrated to be nonlinear in rats, probably because of saturation of the enzyme systems catalyzing the deformylation and glucuronidation of NB-506 in rats.