Vol. 27, Issue 2, 205-212, February 1999

In Vivo Metabolism of a New Anticancer Agent, 6-N-formylamino-12,13-dihydro-1,11-dihydroxy-13-(-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

N. Takenaga, M. Ishii, S. Nakajima, T. Hasegawa, R. Iwasa, H. Ishizaki, and T. Kamei

Drug Metabolism, Development Research Laboratories, Banyu Pharmaceutical Co., Ltd., Saitama, Japan (N.T., R.I., T.K.); Tsukuba Research Institute, Banyu Pharmaceutical Co., Ltd., Ibaragi, Japan (S.N., T.H.); and Pharmaceutical Information Management, Banyu Pharmaceutical Co., Ltd., Tokyo, Japan (H.I.)

6-N-formylamino-12,13-dihydro-1,11-dihydroxy-13-(-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, 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/m² 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 [¹⁴C]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.