Abstract
KW-2149 is a new derivative of mitomycin C (MMC). The plasma concentrations, distribution, metabolism, and excretion of [3H]-KW-2149 in normal and tumor-bearing mice after i. v. administration of 16.6 mg/kg were investigated. The plasma radioactivity decreased biexponentially after i. v. administration in normal mice. However, the unchanged drug disappeared rapidly, showing a half-life (t 1/2) of 9.7 min, which was shorter than MMC's (18 min). The radioactivity was excreted in mouse urine (33%) and feces (58%) within 144 h. High radioactivity was distributed in the gallbladder, liver, kidney, pancreas, and lung at 1 h after i. v. administration to normal mice. The tumor concentration was lower than the plasma or blood concentration. The lowest radioactivity was observed in the brain. The metabolic rate of KW-2149 was very rapid. The methyl sulfide form (M-16), the symmetrical disulfide dimer (M-18), and the albumin conjugate were detected in plasma, which possessed anticellular activity. The specific anticellular activity of these compounds against uterine carcinoma (HeLa S3) was 1/100, 1, and 1/20 respectively, as compared with that of KW-2149.
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Abbreviations
- MMC:
-
mitomycin C
- LD10 :
-
10% lethal dose
- HPLC:
-
high-performance liquid chromatography
- AUC:
-
area under the concentration-time curve
- t 1/2 :
-
half-life
- Vdss :
-
volume of distribution at steady state
- Cltot :
-
total clearance
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Kobayashi, S., Ushiki, J., Takai, K. et al. Disposition and metabolism of KW-2149, a novel anticancer agent. Cancer Chemother. Pharmacol. 32, 143–150 (1993). https://doi.org/10.1007/BF00685618
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DOI: https://doi.org/10.1007/BF00685618