Pharmacokinetic studies on 1-(2-chloroethyl)-3-isobutyl-3-(beta-maltosyl)-1-nitrosourea (TA-077). III. Pharmacokinetics of a new nitrosourea antitumor agent TA-077 in humans (a phase I study).
A new nitrosourea antitumor agent TA-077, 1-(2-chloroethyl)-3-isobutyl-3-(beta-maltosyl)-1-nitrosourea, was intravenously administered to 15 cancer patients at doses ranging from 7 to 100 N (1 N = 30 mg/m2) in a phase I clinical trial. Time courses of blood concentrations of TA-077 and its active metabolite TA-G, 3-beta-D-glucopyranosyl analog of TA-077, were followed. The TA-G concentration reached a maximum at 7.0 +/- 2.3 min, and decreased thereafter with a half-life of 12.9 +/- 2.8 min. The time-course patterns and various pharmacokinetic parameters of TA-077 and TA-G were similar to those in the guinea pig, which, like humans, lacks plasma maltase activity. The 2 h-urinary excretion rate of TA-G in the above patients ranged from 0.15 to 7.7% of the dose. The areas under the concentration-time curve and maximal concentration values were both linearly correlated to the dose with correlation coefficients of 0.78 and 0.82, respectively. Repeated administration of TA-077 (29 to 40 N) for 5 or 6 consecutive days did not affect the pharmacokinetic parameters of TA-077 and TA-G in 7 cancer patients except for slight increases in the half-life and area under the curve of blood TA-G.
Biological Research Laboratory, Tanabe Seiyaku Co., Ltd., Saitama, Japan.
K
K
Hayashida
Y
Y
Miura
Y
Y
Arai
S
S
Takeyama
A
A
Wakui
M
M
Yokoyama
R
R
Kanamaru
H
H
Majima
T
T
Taguchi
M
M
Ohmichi
D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents / Q000097:blood / Q000493:pharmacokinetics* / Q000652:urine; D004341:Drug Evaluation; D005260:Female; D006207:Half-Life; D006801:Humans; D007275:Injections, Intravenous; D008297:Male; D008875:Middle Aged; D009369:Neoplasms / Q000378:metabolism*; D009607:Nitrosourea Compounds / Q000097:blood / Q000493:pharmacokinetics* / Q000652:urine
D000970:Antineoplastic Agents; D009607:Nitrosourea Compounds; C035789:TA 077