Summary
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.
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Roberts J.J. and Warwick G.P. (1961): The mode of action of alkylating agents-III. The formation of 3-hydroxytetrahydrothiophene-l:l-dioxide from l:4-dimethanesulphonyloxybutane (myleran), S-β-L-alanyltetrahydrothiophenium mesylate, tetrahydrothiophene and tetrahydrothiophene-1:1-dioxide in the rat, rabbit and mouse. Biochem. Pharmacol.,6, 217–227.
Roberts J.J. and Warwick G.P. (1961): The mode of action of alkylating agents-II. Studies of the metabolism of myleran. The reaction of myleran with some naturally occurring thiols in vitro. Biochem. Pharmacol.,6, 205–216.
Parham W.E. and Wilbur, Jr. J. M. (1959): The reaction of myleran with L-cysteine ethyl ester. J. Am. Chem. Soc.,81, 6071–6072.
Wilbur, Jr. J. M. (1978): Potential bis-alkylating agents for cancer chemotherapy. Approaches to the synthesis of 2-sulfonyl-1,4-bis(methanesulfonoxy)butanes. J. Med. Chem.,21. 1168–1171.
Trams E.G., Nadkarni M.V., DeQuattro V., Maengwyn-Davies G.D. and Smith P.K. (1959): Dimethanesulphonoxybutane (myleran): Preliminary results on distribution and metabolic fate in the rat. Biochem. Pharmacol.,2, 7–16.
Hassan M. and Ehrsson H. (1986): Degradation of busulfan in aqueous solution. J. Pharmaceut. Biomed. Anal.,4, 95–101.
Hassan M. and Ehrsson H. (1983): Gas chromatographic determination of busulfan in plasma with electron-capture detection. J. Chromatogr.,277, 374–380.
Ehrsson H. and Hassan M. (1983): Determination of busulfan in plasma by GC-MS with selected-ion monitoring. J. Pharm. Sci.,72, 1203–1205.
Ward S.A., Mihaly G.W., Tjia J.F. and Back D.J. (1985): The effect of benzimidazoles on the disposition of antipyrine and tolbutamide from the rat isolated perfused liver. J. Pharm. Pharmacol.,37, 62–64.
Danigel H., Schmidt L. and Jungclas H. (1985): Combined thin layer chromatography/mass spectrometry: An application of 252Cf plasma desorption mass spectrometry for drug monitoring. Biomed. Mass Spectrom.,12, 542–544.
Ahokas J.T., Nicholls F.A., Ravenscroft P.J. and Emmerson B.T. (1985): Inhibition of purified rat liver glutathione S-transferase isozymes by diuretic drugs. Biochem. Pharmacol.,34, 2157–2161.
Ketterer B., Coles B. and Meyer D.J. (1983): The role of glutathione in detoxication. Environ. Health Perspect.,49, 59–69.
Sies H., Brigelius R. and Akerboom T.P.M. (1983): Intrahepatic glutathione status. In “Functions of glutathione: Physiological, toxicological and clinical aspects” (A. Larsson et al., eds) pp. 51–64. Raven Press. New York.
Orrenius S. and Moldéus P. (1984): The multiple roles of glutathione in drug metabolism. Trends Pharmacol. Sci.,5, 432–435.
Kaplowitz N., Aw T. Y. and Ookhtens M. (1985): The regulation of hepatic glutathione. Ann. Rev. Pharmacol. Toxicol.,25, 715–744.
Marchand D.H. and Abdel-Monem M.M. (1985): Glutathione S-transferases catalyzed conjugation of 1,4-disubstituted butanes with glutathione in vitro. Biochem. Biophys. Res. Commun.,128, 360–367.
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Supported by Grant No. 87: 280 from the Swedish Cancer Society.
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Hassan, M., Ehrsson, H. Metabolism of14C-busulfan in isolated perfused rat liver. European Journal of Drug Metabolism and Pharmacokinetics 12, 71–76 (1987). https://doi.org/10.1007/BF03189864
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DOI: https://doi.org/10.1007/BF03189864