title: Disposition and effects of flurbiprofen enantiomers in human serum and blister fluid.
abstract: 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.
authors.affiliation: Department of Experimental & Clinical Pharmacology and Toxicology, University of Erlangen-Nuemberg, Germany.
authors.forename: R
authors.initials: R
authors.lastname: Oelkers
authors.forename: W
authors.initials: W
authors.lastname: Neupert
authors.forename: K M
authors.initials: KM
authors.lastname: Williams
authors.forename: K
authors.initials: K
authors.lastname: Brune
authors.forename: G
authors.initials: G
authors.lastname: Geisslinger
mesh_terms: 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
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D013929:Thromboxane B2; D005480:Flurbiprofen; D015232:Dinoprostone