Glutathione conjugation and pharmacokinetics of 2-bromo-3-phenylpropionic acid in vitro and in the rat in vivo.
Glutathione (GSH) conjugation of the chiral compound 2-bromo-3-phenylpropionic acid (BPP) was studied in vitro and in the rat in vivo. GSH conjugation of BPP, catalyzed by a mixture of glutathione-S-transferases (GST's) from rat liver cytosol in vitro, was stereoselective: at a substrate concentration of 250 microM, (R)-BPP was more rapidly conjugated than (S)-BPP (R/S-ratio = 2.6). The blood elimination kinetics of the separate BPP enantiomers and the biliary excretion kinetics of the corresponding GSH conjugates were studied in the rat in vivo after administration of (R)- or (S)-BPP at a dose level of 50 mumol/kg. Elimination of (R)-BPP from blood was faster than that of (S)-BPP: half lives were 9 +/- 2 min for (R)-BPP and 13 +/- 1 min for (S)-BPP. The biliary excretion rate of the GSH conjugate of (R)-BPP declined monoexponentially, while that of the GSH conjugate of (S)-BPP displayed a biphasic profile. Half lives of excretion were 13 +/- 1 for the GSH conjugate of (R)-BPP, and 11 +/- 2 for the GSH conjugate of (S)-BPP (second phase). The first phase in the biliary excretion of the GSH conjugate of (S)-BPP could not be attributed to capacity limitation of biliary transport carriers as higher excretion rates were attained upon administration of higher doses (100 and 200 mumol/kg) of (S)-BPP). The blood elimination profiles of (R)- and (S)-BPP differed greatly from the biliary excretion profiles of the corresponding GSH conjugates. This suggests that the kinetics of BPP conjugate excretion are determined by other processes than hepatic GSH conjugation.
Snel
C A
CA
Division of Toxicology, University of Leiden, The Netherlands.
Mahadevan
S
S
Polhuijs
M
M
Mulder
G J
GJ
D000818:Animals; D001646:Bile / Q000378:metabolism; D002268:Carboxypeptidases / Q000378:metabolism; D043422:Carboxypeptidases A; D002851:Chromatography, High Pressure Liquid; D003600:Cytosol / Q000201:enzymology; D005978:Glutathione / Q000378:metabolism*; D005982:Glutathione Transferase / Q000378:metabolism*; D007700:Kinetics; D008099:Liver / Q000201:enzymology*; D008297:Male; D010666:Phenylpropionates / Q000138:chemical synthesis / Q000378:metabolism* / Q000493:pharmacokinetics; D051381:Rats; D017208:Rats, Wistar; D013237:Stereoisomerism; D013997:Time Factors; D005723:gamma-Glutamyltransferase / Q000378:metabolism
D010666:Phenylpropionates; C077404:2-bromo-3-phenylpropionic acid; D005723:gamma-Glutamyltransferase; D005982:Glutathione Transferase; D002268:Carboxypeptidases; D043422:Carboxypeptidases A; D005978:Glutathione