The stereoselective disposition of the enantiomers of ibuprofen in blood, blister and synovial fluid.

Abstract

1 A sensitive, stereospecific assay using gas chromatography-mass spectrometry (GC/MS) was established to measure the concentrations of the enantiomers of ibuprofen in small volumes (50 gl) 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 behaving as peripheral compartments with respect to plasma.3 The mean rate constants of transfer of R-ibuprofen into (0.14 ± 0.06 h-1) and out of (0.20 ± 0.04 h-1) blister fluid were not significantly different from those for synovial fluid (0.19 ± 0.12 h-1, 0.34 ± 0.11 h-1, respectively). Similarly, the mean rate constants of transfer of S-ibuprofen into (0.22 ± 0.07 h-1) and out of (0.27 + 0.08 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 correlations were poor between the transfer constants for each of the enantiomers 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 than of the R-enantiomer in both blister (116 ± 43 mg 1-' h, 73 ± 32 mg 1-l h, respectively; P < 0.05) and in synovial fluid (110 ± 28 mg 1-' h, 56 ± 8 mg 1-F h, respectively; P < 0.01). The difference between the mean AUC values of the enantiomers in synovial fluid vs blister fluid was not significant. 6 Despite similar concentration-time profiles, and mean pharmacokinetic parameters, blister fluid was not a good model for predicting the kinetics of the enantiomers of ibuprofen in synovial fluid in individual patients. However, the blister as a peripheral compartment, better simulates the time course of concentrations in synovial fluid than does plasma, and consequently drug concentrations therein might better relate to clinical efficacy than do those in plasma.

Ibuprofen: pharmacology, efficacy and safety

“…isomer as well as values of AUC S(?) always exceed those of the R(-) enantiomer (Day et al 1988;Cox et al 1991;Geisslinger et al 1993;Seideman et al 1994) with similar selective accumulation being shown in experimentally induced skin suction blisters (Seideman et al 1994). The patterns of synovial fluid accumulation of the enantiomers follows that of the peak plasma levels with broad peaks of R(-) and S(?)…”

“…The patterns of synovial fluid accumulation of the enantiomers follows that of the peak plasma levels with broad peaks of R(-) and S(?) ibuprofen at about 2-4 h and extending to about 12-15 h (Seideman et al 1994) thus showing persistence of the enantiomers in synovial fluids well past those of the peak plasma concentrations of these enantiomers.…”

A Validated Enantioselective Assay for the Determination of Ibuprofen in Human Plasma Using Ultra Performance Liquid Chromatography with Tandem Mass Spectrometry (UPLC-MS/MS)

“…The indirect techniques include HPLC using UV [26,27], fluorescence [28,29], and mass spectrometric detection [30][31][32][33]. Gas chromatography-mass spectrometry (GC/ MS) methods have been reported as well [2,6,[34][35][36].…”

“…GC/MS methods can be stereoselective, but they use a larger sample size for analysis (i.e., 0.8 mL plasma or 1 mL of serum) [34,6], and their sensitivity is insufficient (i.e., 0.25 µg/mL or LOQ 5 µg/mL) [34,35], or they are not stereoselective [35,36]. Several indirect HPLC/ MS/MS methods were reported for various in vitro [30][31][32] and in vivo [33] analyses of ibuprofen, but these methods are not stereoselective and do not represent significant improvement in comparison to the methodologies reported above.…”

Antiinflammatory effect of tepoxalin Blood and synovial tissue studied in patients with knee arthrosis

“…The concentrations of tepoxalin and its carboxylic acid metabolite in plasma and synovial fluid were determined according to Seidemann et al (1994) and Depre et al (1993).…”