Disposition and metabolism of KW-2149, a novel anticancer agent.
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 (t1/2) 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.
Kobayashi
S
S
Pharmaceutical Research Laboratories, Kyowa Hakko Kogyo Co., Ltd., Shizuoka, Japan.
Ushiki
J
J
Takai
K
K
Okumura
S
S
Kono
M
M
Kasai
M
M
Gomi
K
K
Morimoto
M
M
Ueno
H
H
Hirata
T
T
D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000378:metabolism / Q000493:pharmacokinetics* / Q000627:therapeutic use; D005260:Female; D006207:Half-Life; D006367:HeLa Cells; D006801:Humans; D007941:Leukemia P388 / Q000188:drug therapy / Q000378:metabolism; D008297:Male; D051379:Mice; D016685:Mitomycin / Q000008:administration & dosage / Q000378:metabolism / Q000493:pharmacokinetics / Q000627:therapeutic use; D008937:Mitomycins; D016339:Spectrometry, Mass, Fast Atom Bombardment; D014018:Tissue Distribution
D000970:Antineoplastic Agents; D008937:Mitomycins; C057625:KW 2149; D016685:Mitomycin