Glutathione conjugation of the α-bromoisovaleric acid enantiomers in the rat in vivo and its stereoselectivity. Pharmacokinetics of biliary and urinary excretion of the glutathione conjugate and the mercapturate

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The glutathione (GSH) conjugation of ( R)- and ( S)- α-bromoisovaleric acid (BI) in the rat in vivo, and its stereoselectivity, have been characyerized. After administration of racemic [1- 14C]BI two radioactive metabolites were found in bile: only one of the possible diastereomeric BI-GSH conjugates, ( R)-I-S-G (35 ± 2% of the dose), and an unidentified metabolite “X” (6 ± 1%). In urine, only one of the possible BI-mercapturates, ( R)-I-S-MA (14 ± 1%), minor unidentified polar metabolites (5 ± 1%) and unchanged BI (13 ± 2%) were excreted. When ( R) or ( S)-BI were administered separately, the same metabolites were found. However, a ten-fold difference in excretion half lives of the biliary metabolites was observed following ( S)- and ( R)-BI administration, ( S)-BI being more rapidly excreted. The excretion of the mercapturate in urine shows the same difference in excretion rate: its half life after administration of ( R)-BI was more than 10 times longer than after a dose of ( S)-BI. More of the dose of ( S)-BI was excreted after 5 hr in bile and urine: 58% and 23% respectively for ( S)- and ( R)-BI. Therefore, a pronounced stereoselectivity in GSH conjugation exists for the ( R) and ( S) enantiomers of BI in the rat in vivo, which is a major determinant of their pharmacokinetics. The results suggest that (slow) inversion of the chiral centre of BI occurred in the rat in vivo.