Stereoselective metabolism of ibuprofen in humans: administration of R-, S- and racemic ibuprofen.

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.