Disposition and effects of flurbiprofen enantiomers in human serum and blister fluid |
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Authors: | R. Oelkers,W. Neupert,K. M. Williams,K. Brune,& G. Geisslinger |
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Affiliation: | Department of Experimental &Clinical Pharmacology and Toxicology, University of Erlangen-Nuernberg, Universitaetsstr. 22, D-91054 Erlangen, Germany and,;Department of Clinical Pharmacology and Toxicology, St. Vincent's Hospital, Sydney, NSW , Australia |
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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. 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 μg 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. |
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Keywords: | non-steroidal antiinflammatory drugs (NSAIDs) variability flurbiprofen enantiomers pharmacokinetics pharmacodynamics prostaglandins suction blister |
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