Abstract
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.
Footnotes
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Send reprint requests to: Mikio Ishii, Drug Metabolism, Development Research Laboratories, Banyu Pharmaceutical Co., Ltd., 810, Nishijo, Menuma-machi, Osato-gun, Saitama 360-0214, Japan.
- Abbreviations used are::
- NB-506
- 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
- TFA
- trifluoroacetic acid
- HPLC
- high-performance liquid chromatography
- PG
- propylene glycol
- PEG400
- polyethylene glycol 400
- DMSO-d6
- dimethyl-d6 sulfoxide
- AUC
- area under the curve
- RI-HPLC
- HPLC with on-line radioisotope detector
- FAB
- fast atom bombardment
- HMBC
- heteronuclear multiple bond correlation
- CLP
- plasma clearance
- AUMC
- area under the moment curve
- MRT
- mean residence time
- Vdss
- distribution volume
- Received December 31, 1997.
- Accepted September 10, 1998.
- The American Society for Pharmacology and Experimental Therapeutics
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