IN VITRO METABOLISM OF ACNU, 3-[(4-AMINO-2-METHYL-5-PYRIMIDINYL) METHYL]-1-(2-CHLOROETHYL)-1-NITROSOUREA HYDROCHLORIDE, A WATER-SOLUBLE ANTITUMOR NITROSOUREA

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概要

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• In vitro decomposition of ACNU, 3-[(4-amino-2-methyl-5-pyrimidinyl) methyl]-1-(2-chloroethyl)-1-nitrosourea hydrochloride, in various conditions was studied with the use of the ^<14>C-labeled compound. Metabolite A, 3,4-dihydro-7-methylpyrimido [4,5-d] pyrimidin-2(1 H)-one (an intramolecular cyclized product), was formed spontaneously in the phosphate buffer (pH 7.4) with simultaneous liberation of the alkylating moiety. With rat liver enzyme preparations, formation of three metabolites was observed. Those were metabolite B, 1-[(4-amino-2-methyl-5-pyrimidinyl) methyl]-3-(2-chloroethyl) urea (a denitrosated product), metabolite C, 1-[(4-amino-2-methyl-5-pyrimidinyl) methyl]-5-hydroxy-3-nitroso-2-imidazolidinone (a product via oxidative dechlorination), and metabolite D, 1-[(4-amino-2-methyl-5-pyrimidinyl) methyl]-5-hydroxy-2-imidazolidinone (a denitrosated product of metabolite C). Formation of metabolite B was catalyzed with both cytosolic and microsomal enzymes, not inhibited with SKF-525A, and partly dependent on nicotinamide adenine dinucleotide phosphate (NADPH). These results suggest that at least two enzymatic steps would be involved in the formation of this product. Metabolites C and D were produced by the microsomal preparation, being dependent on O_2 and NADPH, inhibited by CO and SKF-525A, and enhanced by phenobarbital pretreatment. When metabolite C was incubated with cytosolic and microsomal preparations, more efficient formation of metabolite D with the former than the latter was observed. Form these results, it was assumed that oxidative dechlorination of ACNU to metabolite C would be catalyzed with the microsomal mixed function oxidase, and metabolite D would be produced via denitrosation process of metabolite C.

• 公益社団法人日本薬学会の論文

著者

• TANAKA MINORU

  Analytical and Metabolic Research Laboratories Sankyo Co., Ltd.

• Nishigaki Takashi

  Bio-science Research Laboratories Sankyo Company Ltd.

• Nakamura K

  Analytical And Metabolic Research Laboratories Sankyo Company Ltd.

• Nakamura Kan-ichi

  Analytical And Metabolic Research Laboratories Sankyo Co. Ltd.

• Tanaka M

  Analytical And Metabolic Research Laboratories Sankyo Company Ltd.

• Tanaka Minoru

  Analytical And Metabolic Research Laboratories Sankyo Co. Ltd.

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