Disposition and effects of flurbiprofen enantiomers in human serum and blister fluid

Abstract

Aims To investigate the pharmacokinetics of the enantiomers of flurbiprofen and inhibition of prostanoid production in blister fluid and serum. Methods Eleven healthy volunteers received 75 mg R-, 75 mg S-flurbiprofen or no medication in a randomized 3-way cross-over study. Flurbiprofen concentrations were determined by h.p.l.c. TXB 2 and PGE 2 were determined by enzyme immunoassay and chemiluminescence immunoassay respectively. Results S-flurbiprofen produced almost complete (>99% vs baseline) inhibition of thromboxane B 2 (TXB 2 ) in serum in all volunteers and significant inhibition of prostaglandin E 2 (PGE 2 ) generation in blister fluid, but there was a considerable inter-individual variation in the response ranging from −78 to +190% change from control PGE 2 AUC. After administration of R-flurbiprofen, there was a mean maximum TXB 2 inhibition of 65.2±15.0% in serum but no significant changes of PGE 2 levels in blister fluid were observed. The pharmacokinetic parameters in serum and blister fluid were not significantly different between enantiomers. R-to S-inversion did not occur to a clinically relevant extent. For R-flurbiprofen, the complex rate constant of transfer into blister fluid was greater at the u.v.-exposed site (0.110±0.050) than at the control site (0.079±0.026, P<0.05) 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-linear concentration-response relationship was established in all subjects (EC 50 : 0.123±0.092 mg ml −1 ). In contrast, inhibition of PGE 2 production in blister showed no clear concentration-response relationship when correlated with concentrations of S-flurbiprofen in either serum or blister fluid. After administration of R-flurbiprofen, no concentration-effect relationship could be established. Conclusions It is concluded that the blister model may have value for studying the pharmacokinetics and pharmacodynamics of antiinflammatory drugs in humans. Interestingly, inter-individual variation in the pharmacokinetics of flurbiprofen enantiomers could not account for the variability in response observed in the blister model.

Disposition of flurbiprofen in man: influence of stereochemistry and age

“…Cefali et al 1991, Young et al 1991, Knadler et al 1992a, b, Geisslinger et al 1994, Oelkers et al 1997, Suri et al 1997 and comparable between the two volunteer groups. The stereochemical aspects of flurbiprofen disposition are not as complex as other agents in the 2-arylpropionic acid group, e.g.…”

Pharmacodynamics and pharmacokinetics of ketoprofen enantiomers in sheep

“…34 Brune et al 35 reported similar findings; they found that R(-) flurbiprofen was devoid of COX inhibitory activity in vitro. 34 Brune et al 35 reported similar findings; they found that R(-) flurbiprofen was devoid of COX inhibitory activity in vitro.…”

Comparison of inhibitory effects of meloxicam and diclofenac on human thromboxane biosynthesis after single doses and at steady state

“…To assess the effects of meloxicam and diclofenac on platelet cyclooxygenase, the amount of thromboxane A 2 generated during clotting of whole blood was determined by measuring the concentration of its stable breakdown product (TXB 2 ) as described previously 33 , 34 . Serum TXB 2 levels were determined with a commercially available TXB 2 enzyme immunoassay kit (Cayman Chemicals, Ann Arbor, Mich).…”