Glutathione conjugation of the alpha-bromoisovaleric acid enantiomers in the rat in vivo and its stereoselectivity. Pharmacokinetics of biliary and urinary excretion of the glutathione conjugate and the mercapturate.
The glutathione (GSH) conjugation of (R)-and (S)-alpha-bromoisovaleric acid (BI) in the rat in vivo, and its stereoselectivity, have been characterized. 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.
Polhuijs
M
M
Division of Toxicology, University of Leiden, The Netherlands.
te Koppele
J M
JM
Fockens
E
E
Mulder
G J
GJ
D000111:Acetylcysteine / Q000378:metabolism*; D000818:Animals; D001646:Bile / Q000378:metabolism*; D002851:Chromatography, High Pressure Liquid; D005243:Feces / Q000032:analysis; D005978:Glutathione / Q000378:metabolism*; D006207:Half-Life; D008297:Male; D010421:Pentanoic Acids / Q000493:pharmacokinetics* / Q000652:urine; D051381:Rats; D011919:Rats, Inbred Strains; D013237:Stereoisomerism; D014631:Valerates / Q000493:pharmacokinetics*
D010421:Pentanoic Acids; D014631:Valerates; C057043:2-bromoisovaleric acid; D005978:Glutathione; D000111:Acetylcysteine