Metabolism of14C-busulfan in isolated perfused rat liver

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Abstract
1,4-14C Busulfan gave one main metabolite in the isolated perfused rat liver during 4 hr cyclic perfusion. The cumulative bile excretion contained about 38% of the total radioactivity. About 1% of unchangedl4C-busulfan was excreted in the bile. The metabolite was identified as ψ-glutamyl-β-(S-tetrahydrothiophenium) alanyl-glycine (sulfonium ion of glutathione) by252Cf-plasma desorption time-of-flight mass spectrometry. The formation of the metabolite was drastically decreased when the glutathione-S-transferase was inhibited, which indicates that the major reaction of busulfan with glutathione is enzymatic in nature. The sulfonium ion was more stable in the perfusate ( t1/2=22.4 hr, 37°C) than in the bile ( tl/2=3.2 hr, 37°C) at pH 7.4.