title: Stereoselective metabolism of ibuprofen in humans: administration of R-, S- and racemic ibuprofen.
abstract: Using stable isotope methodology, we studied the effect of the enantiomeric composition of dosage form on ibuprofen metabolism. Eight healthy human subjects received racemic ibuprofen (800 mg) plus S-[aromatic-2H4]ibuprofen (10 mg), R-ibuprofen (600 mg) plus S-[aromatic-2H4]ibuprofen (10 mg) and S-ibuprofen (600 mg) orally on separate occasions in random order. Stereoselective gas chromatography-mass spectrometry was used to quantify deuterated and nondeuterated ibuprofen in serum up to 24 h postdose. Urinary excretion of the stereoisomeric forms of carboxyibuprofen, hydroxyibuprofen and ibuprofen glucuronide were determined up to 24 h postdose by stereoselective high performance liquid chromatography. The metabolism of ibuprofen enantiomers was not influenced by the enantiomeric composition of the dose. For racemic ibuprofen, the mean clearances (+/- S.D.) of S-ibuprofen, R-ibuprofen inversion and R-ibuprofen noninversion were 87.4 +/- 25.9, 57.3 +/- 31.0 and 56.3 +/- 29.0 ml/min, respectively. The fractional inversion of ibuprofen was significantly greater (P less than .05) using the stereochemical composition of the urinary metabolites (0.63 +/- 0.05) vs. the method using the clearance of deuterated S-ibuprofen (0.51 +/- 0.08) after the dose of racemate. Unreliable estimates of fractional inversion were obtained when the S-ibuprofen and racemic ibuprofen doses were combined. Metabolite formation clearances suggested that S-ibuprofen is preferred over R-ibuprofen in the formation of hydroxyibuprofen, carboxyibuprofen and ibuprofen glucuronide. Product stereoselectivity in the formation of the four diastereomers of carboxyibuprofen was modest in favor of SS- and RR-carboxyibuprofen for S- and R-ibuprofen, respectively.
authors.affiliation: Department of Medicine, Indiana University School of Medicine, Indianapolis.
authors.forename: A C
authors.initials: AC
authors.lastname: Rudy
authors.forename: P M
authors.initials: PM
authors.lastname: Knight
authors.forename: D C
authors.initials: DC
authors.lastname: Brater
authors.forename: S D
authors.initials: SD
authors.lastname: Hall
mesh_terms: D000328:Adult; D003903:Deuterium; D005260:Female; D006801:Humans; D007052:Ibuprofen / Q000378:metabolism* / Q000493:pharmacokinetics; D008297:Male; D008875:Middle Aged; D013237:Stereoisomerism
chemical_list: D003903:Deuterium; D007052:Ibuprofen