PHARMACOKINETIC STUDIES ON 1-(2-CHLOROETHYL)-3-ISOBUTYL-3-(β-MALTOSYL)-1-NITROSOUREA (TA-077). I. BLOOD AND TISSUE CONCENTRATIONS OF A NEW NITROSOUREA ANTITUMOR AGENT TA-077 AND ITS METABOLITE TA-G AFTER INTRAVENOUS INJECTION OF TA-077 IN VARIOUS EXPERIME
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概要
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1-(2-Chloroethyl)-3-isobutyl-3-(β-maltosyl)-1-nitrosourea (TA-077) is a new masked antitumor agent, which is hydrolyzed by maltase to give rise to a more cell-permeable and, hence, more cytotoxic metabolite, TA-G. TA-077 was intravenously administered to mice, rats, guinea pigs, rabbits and dogs and the time-courses of blood concentrations of TA-077 and TA-G were followed. The time-course patterns of blood TA-077 in these animals were markedly different from one another depending on the level of plasma maltase, while those of blood TA-G were all similar except in the early stage after the injection ; i.e., the blood concentration of TA-G reached a peak shortly after the injection and decreased rapidly with a half-life of 6 to 15 min, and the higher the level of plasma maltase, the earlier the time of peak appearance. Tissue concentrations of TA-077 and TA-G in major organs were also measured at various times after intravenous injection of TA-077 to guinea pigs and VX-2 tumor-bearing rabbits. In both species, tissue concentrations of TA-077 did not exceed the blood concentration and rapidly decreased to insignificant levels by 30 to 45 min. The tissue level of TA-G in the kidney, a maltase-rich organ, was always the highest among the organs examined in both species. The concentration of TA-G in the VX-2 tumor was relatively high. Possible significance of tissue maltase to the cellular uptake and antitumor effect of TA-077 is also discussed.
- 公益社団法人日本薬学会の論文
著者
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Miura Yuji
Biological Research Laboratory Tanabe Seiyaku Co. Ltd.
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NAKAMURA Susumu
Biological Research Laboratory, Tanabe Seiyaku Co. Ltd.
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Nakamura Susumu
Biological Research Laboratory Tanabe Seiyaku Co. Ltd.
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TAKEYAMA Shigeyuki
Research Laboratories, Tanabe Seiyaku Co., Ltd.,
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HAYASHIDA KOHKICHI
Biological Research Laboratory, Tanabe Seiyaku Co., Ltd.
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ARAI YOSHIHISA
Biological Research Laboratory, Tanabe Seiyaku Co., Ltd.
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TAKEYAMA SHIGEYUKI
Biological Research Laboratory, Tanabe Seiyaku Co., Ltd.
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AKAIKE YUKIO
Biological Research Laboratory, Tanabe Seiyaku Co., Ltd.
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ONO YASUTOSHI
Biological Research Laboratory, Tanabe Seiyaku Co., Ltd.
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Akaike Y
Biological Research Laboratory Tanabe Seiyaku Co. Ltd.
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Ono Yasutoshi
Biological Research Laboratory Tanabe Seiyaku Co. Ltd.
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Hayashida Kohkichi
Biological Research Laboratory Tanabe Seiyaku Co. Ltd.
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TAKEYAMA Shigeyuki
Biological Research Laboratory and Organic Chemistry Research Laboratory, Tanabe Seiyaku Co., Ltd.
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