CHIRAL INVERSION OF FENOPROFEN IN HORSES AND DOGS - AN IN-VIVO IN-VITRO STUDY

Fenoprofen (FPF) is a chiral non-steroid antiinflammatory drug, market ed as a racemic mixture of its R(-) and S(+) enantiomers. Its stereose lective disposition in humans and animals is due to a chiral inversion converting R(-)FPF into S(+)FPF. The first step of this reaction, whi ch produces an acyl-CoA thioester, is catalysed by an acyl-CoA ligase. A stereospecific high performance liquid chromatography assay was use d to study the disposition of FPF enantiomers in four geldings and thr ee male beagle dogs, following intravenous doses of racemic FPF(1 mg/k g in horses), R(-)FPF (0.5 mg/kg in horses, 1 mg/kg in dogs), and S(+) FPF (0.5 mg/kg in horses, 1 mg/kg in dogs). A unidirectional stereoinv ersion of the R(-) enantiomer into its optical antipode (38% in horses , 90% in dogs) was demonstrated. This explained the dear enantioselect ive behaviour of FPF in both species. Acyl-CoA ligase activity (K-m = 473.2 +/- 92.5 mu M; V-max = 23 +/- 3.3 nmol/min/mg) has also been qua ntified in vitro on equine hepatic microsomes, using a high performanc e liquid chromatography method to measure thioester formation. The pre sent study showed that, in horses and dogs, as previously demonstrated in rats and sheep, the R(-)FPF clearance was better correlated with l igase activity than with inversion rate. A highly significant linear r elationship was demonstrated between these variables.