THE STEREOSELECTIVE DISPOSITION OF THE ENANTIOMERS OF IBUPROFEN IN BLOOD, BLISTER AND SYNOVIAL-FLUID

1 A sensitive, stereospecific assay using gas chromatography-mass spec trometry (GC/MS) was established to measure the concentrations of the enantiomers of ibuprofen in small volumes (50 mu l) of blister fluid. 2 The concentrations of the enantiomers in blister fluid, assessed in eight patients, were similar to those in synovial fluid, both fluids b ehaving as peripheral compartments with respect to plasma. 3 The mean rate constants of transfer of R-ibuprofen into (0.14 +/- 0.06 h(-1)) a nd out of (0.20 +/- 0.04 h(-1)) blister fluid were not significantly d ifferent from those for synovial fluid (0.19 +/- 0.12 h(-1), 0.34 +/- 0.11 h(-1), respectively). Similarly, the mean rate constants of trans fer of S-ibuprofen into (0.22 +/- 0.07 h(-1)) and out of (0.27 +/- 0.0 8 h(-1)) blister fluid were not significantly different from those for synovial fluid (0.29 +/- 0.10, 0.36 +/- 0.11 h(-1)). However, the cor relations were poor between the transfer constants for each of the ena ntiomers between plasma, and both blister and synovial fluid (P > 0.2) . 4 The complex rate constant of transfer of S-ibuprofen into blister fluid (0.22 +/- 0.07 h(-1)) was greater than that of R-ibuprofen (0.14 +/- 0.07 h(-1)), which may be explained by the lesser protein binding of the S-enantiomer. 5 The mean AUC of the S-enantiomer was greater t han of the R-enantiomer in both blister (116 +/- 43 mg 1(-1) h, 73 +/- 32 mg 1(-1) h, respectively; P < 0.05) and in synovial fluid (110 +/- 28 mg 1(-1) h, 56 +/- 8 mg 1(-1) h, respectively; P < 0.01). The diff erence between the mean AUC values of the enantiomers in synovial flui d vs blister fluid was not significant. 6 Despite similar concentratio n-time profiles, and mean pharmacokinetic parameters, blister fluid wa s not a good model for predicting the kinetics of the enantiomers of i buprofen in synovial fluid in individual patients. However, the bliste r as a peripheral compartment, better simulates the time course of con centrations in synovial fluid than does plasma, and consequently drug concentrations therein might better relate to clinical efficacy than d o those in plasma.