RT Journal Article
SR Electronic
T1 In Vivo Metabolism of a New Anticancer Agent, 6-<em>N</em>-formylamino-12,13-dihydro-1,11-dihydroxy-13-(β-<span class="sc">d</span>-glucopyranosil)5<em>H</em>-indolo [2,3-<em>a</em>]pyrrolo [3,4-<em>c</em>]carbazole-5,7(6<em>H</em>)-dione (NB-506) in Rats and Dogs: Pharmacokinetics, Isolation, Identification, and Quantification of Metabolites
JF Drug Metabolism and Disposition
JO Drug Metab Dispos
FD American Society for Pharmacology and Experimental Therapeutics
SP 205
OP 212
VO 27
IS 2
A1 N. Takenaga
A1 M. Ishii
A1 S. Nakajima
A1 T. Hasegawa
A1 R. Iwasa
A1 H. Ishizaki
A1 T. Kamei
YR 1999
UL http://dmd.aspetjournals.org/content/27/2/205.abstract
AB 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), 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. TheVdss 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. The American Society for Pharmacology and Experimental Therapeutics