Disposition and effects of flurbiprofen enantiomers in human serum and blister fluid.
OBJECTIVE
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. TXB2 and PGE2 were determined by enzyme immunoassay and chemiluminescence immunoassay respectively.


RESULTS
S-flurbiprofen produced almost complete (> 99% vs baseline) inhibition of thromboxane B2 (TXB2) in serum in all volunteers and significant inhibition of prostaglandin E2 (PGE2) generation in blister fluid, but there was a considerable inter-individual variation in the response ranging from -78 to +190% change from control PGE2 AUC. After administration of R-flurbiprofen, there was a mean maximum TXB2 inhibition of 65.2 +/- 15.0% in serum but no significant changes of PGE2 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 Cmax of R-flurbiprofen in u.v.-exposed blister as compared with control. For inhibition of TXB2 generation after administration of S-flurbiprofen, a sigmoidal log-linear concentration-response relationship was established in all subjects (EC50: 0.123 +/- 0.092 microgram ml-1). In contrast, inhibition of PGE2 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.
Oelkers
R
R
Department of Experimental & Clinical Pharmacology and Toxicology, University of Erlangen-Nuemberg, Germany.
Neupert
W
W
Williams
K M
KM
Brune
K
K
Geisslinger
G
G
D000328:Adult; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000097:blood / Q000737:chemistry / Q000493:pharmacokinetics*; D019540:Area Under Curve; D001768:Blister / Q000378:metabolism*; D015232:Dinoprostone / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D004305:Dose-Response Relationship, Drug; D005480:Flurbiprofen / Q000097:blood / Q000737:chemistry / Q000493:pharmacokinetics*; D006801:Humans; D008297:Male; D012016:Reference Values; D013237:Stereoisomerism; D013929:Thromboxane B2 / Q000037:antagonists & inhibitors / Q000096:biosynthesis
D000894:Anti-Inflammatory Agents, Non-Steroidal; D013929:Thromboxane B2; D005480:Flurbiprofen; D015232:Dinoprostone