PHARMACOKINETIC STUDIES ON 1-(2-CHLOROETHYL)-3-ISOBUTYL-3-(β-MALTOSYL)-1-NITROSOUREA (TA-077). III. PHARMACOKINETICS OF A NEW NITROSOUREA ANTITUMOR AGENT TA-077 in HUMANS (A PHASE I STUDY)

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A new nitrosourea antitumor agent TA-077,1-(2-chloroethyl)-3-isobutyl-3-(β-maltosyl)-1-nitrosourea, was intravenously administered to 15 cancer patients at doses ranging from 7 to 100 N (1 N=30 mg/m^2) in a phase I clinical trial. Time courses of blood concentrations of TA-077 and its active metabolite TA-G, 3-β-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.
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