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The fate of diastereomeric glutathione conjugates of alpha- bromoisovalerylurea in blood in the rat in vivo and in the perfused liver. Stereoselectivity in biliary and urinary excretion

M Polhuijs, DK Meijer and GJ Mulder

Division of Toxicology, Sylvius Laboratories, University of Leiden, The Netherlands.

The mixture of the two diastereomeric glutathione (GSH) conjugates of alpha-bromoisovalerylurea, (RS)-IU-G, was administered i.v. to anesthetized rats. Bile and urine were collected for 6 hr. Some 70 to 75% was recovered in urine as mercapturates. The half-lives of the urinary excretion were the same for the two mercapturates: 18 min and approximately 130 min, respectively, for the rapid and the slow phase. In bile only 1.5% of the dose of (R) and (S)-IU-G was found; two unidentified metabolites were also found. In rats with ligated kidneys, 4% of the dose of each glutathione conjugate was excreted in bile. Again, the two unidentified metabolites were found. In the isolated recirculating liver perfusion experiments, 1.4% of the administered GSH conjugates was found in bile. The concentration of the GSH conjugates in the perfusion medium remained constant and no other metabolites were formed. When (RS)-alpha-bromoisovalerylurea itself was added to the perfusate, the GSH conjugates in bile increased rapidly. The results show that the GSH conjugate in blood is little excreted in bile due to a slow uptake of the conjugate by the liver. The diastereomeric GSH conjugates show no stereoselectivity in their pharmacokinetics, indicating that the rate limiting step in this process is not stereoselective.

Volume 256, Issue 2, pp. 458-461, 02/01/1991
Copyright © 1991 by American Society for Pharmacology and Experimental Therapeutics




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Copyright © 1991 by the American Society for Pharmacology and Experimental Therapeutics.