DISPOSITION AND EFFECTS OF FLURBIPROFEN ENANTIOMERS IN HUMAN SERUM AND BLISTER FLUID

Aims To investigate the pharmacokinetics of the enantiomers of flurbip rofen and inhibition of prostanoid production in blister fluid and ser um. Methods Eleven healthy volunteers received 75 mg R-, 75 mg S-flurb iprofen or no medication in a randomized 3-way cross-over study. Flurb iprofen concentrations were determined by h.p.l.c. TXB(2) and PGE(2) w ere determined by enzyme immunoassay and chemiluminescence immunoassay respectively. Results S-flurbiprofen produced almost complete (>99% v s baseline) inhibition of thromboxane B-2 (TXB(2)) in serum in all vol unteers and significant inhibition of prostaglandin E(2) (PGE(2)) gene ration in blister fluid, but there was a considerable inter-individual variation in the response ranging from -78 to +190% change from contr ol PGE(2) AUC. After administration of R-flurbiprofen, there was a mea n maximum TXB(2) inhibition of 65.2 +/- 15.0% in serum but no signific ant changes of PGE(2) levels in blister fluid were observed. The pharm acokinetic parameters in serum and blister fluid were not significantl y different between enantiomers. R- to S-inversion did not occur to a clinically relevant extent. For R-flurbiprofen, the complex rate const ant of transfer into blister fluid was greater at the u.v.-exposed sit e (0.110 +/- 0.050) than at the control site (0.079 +/- 0.026, P < 0.0 5) which corresponded to a higher AUC and C-max of R-flurbiprofen in u .v.-exposed blister as compared with control. For inhibition of TXB(2) generation after administration of S-flurbiprofen, a sigmoidal log-li near concentration-response relationship was established in all subjec ts (EC(50): 0.123 +/- 0.092 mu g ml(-1)). In contrast, inhibition of P GE(2) production in blister showed no clear concentration-response rel ationship when correlated with concentrations of S-flurbiprofen in eit her serum or blister fluid. After administration of R-flurbiprofen, no concentration-effect relationship could be established. Conclusions I t is concluded that the blister model may have value for studying the pharmacokinetics and pharmacodynamics of antiinflammatory drugs in hum ans. Interestingly, inter-individual variation in the pharmacokinetics of flurbiprofen enantiomers could not account for the variability in response observed in the blister model.