Effects of pure enantiomers of flurbiprofen in comparison to racemic flurbiprofen on eicosanoid release from various rat organs ex vivo.
The effects of oral treatment of rats with pure enantiomers of flurbiprofen in comparison to racemic flurbiprofen on ex vivo release of eicosanoids from gastric mucosa, jejunum, lung, brain and clotting whole blood were investigated. With the S(+) enantiomer and the racemate dose-dependent inhibition of release of cyclooxygenase products of arachidonate metabolism in all tissues tested was observed, while release of leukotriene (LT) C4 was inhibited in gastric mucosa, but not in jejunum and lung. On the other hand, the R(-) enantiomer inhibited cyclooxygenase in the various tissues less potently and to a variable degree with no significant effect in the jejunum. The R(-) enantiomer had no effect on LTC4 release from any of the tissues investigated. Furthermore, the effect of a high dose of 25 mg/kg of the S(+) enantiomer on release of cyclooxygenase products from the various tissues was much longer lasting than that of an identical dose of the R(-) enantiomer. Stereoselective pharmacokinetics of the flurbiprofen enantiomers and/or organ specific cyclooxygenase activities could underly these results. The more potent cyclooxygenase inhibition by the S(+) enantiomer correlates with its higher anti-inflammatory activity and gastrointestinal toxicity. On the other hand, both enantiomers have been shown previously to be almost equally effective analgesics. Inhibition of brain cyclooxygenase might contribute to this effect.
Peskar
B M
BM
Department of Experimental Clinical Medicine, Ruhr-University of Bochum, Germany.
Kluge
S
S
Peskar
B A
BA
Soglowek
S M
SM
Brune
K
K
D000818:Animals; D016718:Arachidonic Acid / Q000378:metabolism; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D002851:Chromatography, High Pressure Liquid; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology; D015237:Dinoprost / Q000378:metabolism; D015777:Eicosanoids / Q000097:blood / Q000378:metabolism*; D005480:Flurbiprofen / Q000737:chemistry / Q000494:pharmacology*; D005753:Gastric Mucosa / Q000187:drug effects / Q000378:metabolism; D007583:Jejunum / Q000187:drug effects / Q000378:metabolism; D008168:Lung / Q000187:drug effects / Q000378:metabolism; D051381:Rats; D013189:SRS-A / Q000378:metabolism; D013237:Stereoisomerism; D013929:Thromboxane B2 / Q000097:blood
D016861:Cyclooxygenase Inhibitors; D015777:Eicosanoids; D013189:SRS-A; D016718:Arachidonic Acid; D013929:Thromboxane B2; D005480:Flurbiprofen; D015237:Dinoprost