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The inversion from R- to S-enantiomer that occurs for some arylpropionic acids may have both toxicological and therapeutic implications. To characterize some properties of this inversion, arylpropionyl-CoA thioester formation was studied in rat tissue homogenates and subcellular fractions for the enantiomers of fenoprofen, ibuprofen, and flurbiprofen. Thioesters were formed from (R)-fenoprofen (64%) and (R)-ibuprofen (33%) but not from the corresponding S-enantiomers or the enantiomers of flurbiprofen. This correlates with the extensive inversion of fenoprofen and ibuprofen and lack of inversion of flurbiprofen in vivo. Subcellular fractions from rat liver showed thioester formation to occur in mitochondria and microsomes but not cytosol. Once formed, the thioesters were readily racemized by whole rat liver homogenate, mitochondria, and cytosol, but only partially inverted (S:R = 0.3) in microsomes. Thioester formation from fenoprofen and ibuprofen was studied in tissue homogenate obtained from liver, diaphragm, kidney, lung, skeletal muscle, smooth muscle, fat, caecum, and intestines. The liver was at least 50-fold more efficient than the other tissues studied and would be expected to be a major organ of enantiomeric inversion. Our data support the hypothesis that R- to S-enantiomeric inversion of arylpropionic acids proceeds via the stereoselective formation of CoA thioesters followed by enzymatic racemization and hydrolysis of the thioesters to regenerate free acid.

4'-hydroxyflurbiprofen. There was significant enantioselectivity (R > S) in the formation clearances of these metabolites which remained when unbound metabolite formation clearances were considered. 5 In conclusion, the disposition of the enantiomers of flurbiprofen exhibits enantioselectivity at the level of protein binding and metabolite formation.

1 Both single and multiple oral doses of 50 mg racemic flurbiprofen were given to eight patients with mild to moderate renal impairment. The plasma and urine concentrations of the R-and S-enantiomers of flurbiprofen and its major metabolites were measured by a stereoselective h.p.l.c. assay. 2 For R-flurbiprofen the oral clearance (mean ± s.d.: 38.3 ± 12.8 vs 30.8 ± 11.5 ml min-1) and volume of distribution (V.; 17.6 ± 3.9 vs 14.6 ± 2.5 1) were significantly greater (P < 0.05) than for the S-enantiomer. A significantly greater (P < 0.05) percent of the dose was excreted in the urine in the R-configuration (16.4 ± 6.0 vs 10.9 ± 4.2%). 3 Plasma protein binding of the enantiomers of flurbiprofen was determined by ultrafiltration. The unbound clearance and unbound V, were not different between enantiomers consistent with the (not significantly) greater percent unbound of Rflurbiprofen (0.079 ± 0.014%) vs S-flurbiprofen (0.064 ± 0.015%). 4 Relative to normal volunteers, the uraemic subjects exhibited a significantly greater (P < 0.05) oral clearance, V, and percent unbound for both enantiomers; unbound clearance and unbound V, did not differ from healthy controls.5 The disposition of flurbiprofen enantiomers was not changed upon multiple dosing and no evidence of futile cycling was found. Adjustment of flurbiprofen dosing rate in uraemic subjects is not indicated on the basis of pharmacokinetics.

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