title: Studies on the metabolism and chiral inversion of ibuprofen in isolated rat hepatocytes.
abstract: 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.
authors.affiliation: Department of Medicinal Chemistry, School of Pharmacy, University of Washington, Seattle 98195.
authors.forename: S M
authors.initials: SM
authors.lastname: Sanins
authors.forename: W J
authors.initials: WJ
authors.lastname: Adams
authors.forename: D G
authors.initials: DG
authors.lastname: Kaiser
authors.forename: G W
authors.initials: GW
authors.lastname: Halstead
authors.forename: T A
authors.initials: TA
authors.lastname: Baillie
mesh_terms: 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
chemical_list: D007052:Ibuprofen; D008797:Metyrapone