Studies on the metabolism and chiral inversion of ibuprofen in isolated rat hepatocytes.
The oxidative metabolism and chiral inversion of ibuprofen in freshly isolated rat hepatocytes was studied with the aid of a stereoselective GC/MS assay procedure. Hydroxylation of the isobutyl side chain at the subterminal carbon (to give hydroxyibuprofen) proved to be the major route of metabolism of both R(-)-ibuprofen and S(+)-ibuprofen, while formation of the corresponding diastereoisomeric 2-methylpropionic acid derivatives (carboxyibuprofen) was of minor quantitative importance. Both oxidative pathways were inhibited in the presence of metyrapone, a cytochrome P-450 inhibitor. R(-)-Ibuprofen underwent metabolic chiral inversion to the S(+) enantiomer, whose formation was dependent on incubation time, cell density, and substrate concentration. S(+)-Ibuprofen, on the other hand, was not converted to R(-)-ibuprofen in rat hepatocytes. When cells were incubated with a mixture of unlabeled R(-)-ibuprofen and R(-)-[3,3,3-2H3]ibuprofen, the resultant S(+) enantiomer consisted only of unlabeled and trideutero molecules (formed in the same ratio as the corresponding species of R(-)-ibuprofen), indicating that 2,3-dehydroibuprofen did not serve as the symmetrical intermediate in the chiral inversion reaction. Collectively, these results demonstrate that freshly isolated rat hepatocytes represent a convenient and reproducible in vitro model system for studies on the metabolism and chiral inversion of ibuprofen.
Sanins
S M
SM
Department of Medicinal Chemistry, School of Pharmacy, University of Washington, Seattle 98195.
Adams
W J
WJ
Kaiser
D G
DG
Halstead
G W
GW
Baillie
T A
TA
D000818:Animals; D001711:Biotransformation; D008401:Gas Chromatography-Mass Spectrometry; D007052:Ibuprofen / Q000378:metabolism*; D008099:Liver / Q000166:cytology / Q000378:metabolism*; D008297:Male; D008797:Metyrapone / Q000494:pharmacology; D010084:Oxidation-Reduction; D051381:Rats; D011919:Rats, Inbred Strains
D007052:Ibuprofen; D008797:Metyrapone