Chiral inversion of fenoprofen in horses and dogs: in vivo- in vitro study

SORACI, A.; JAUSSAUD, P.; BENOIT, E.; DELATOUR, P

VETERINARY RESEARCH

EDP SCIENCES S A

Lugar: Paris; Año: 1996 vol. 27 p. 13 - 22

0928-4249

Fenoprofen (FPF) is a chiral non-steroid antiinflammatory drug, marketed as a racemic mixture of its R(-) and S(+) enantiomers. Its stereoselective disposition in humans and animals is due to a chiral inversion converting R(-)FPF into S(+)FPF. The first step of this reaction, which produces an acyl-CoA thioester, is catalysed by an acyl-CoA ligase. A stereospecific high performance liquid chro- matography assay was used to study the disposition of FPF enantiomers in four geldings and three male beagle dogs, following intravenous doses of racemic FPF (1 mg/kg 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 stereoinversion of the R(-) enantiomer into its optical antipode (38% in horses, 90% in dogs) was demonstrated. This explained the clear enantioselective behaviour of FPF in both species. Acyl-CoA ligase activity (K m = 473.2 ± g 2.5 pM ; V max = 23 ± 3.3 nmol/min/mg) has also been quantified in vitro on equine hepatic microsomes, using a high performance liquid chromatography method to measure thioester formation. The present study showed that, in horses and dogs, as previously demonstrated in rats and sheep, the R(-)FPF clearance was better correlated with ligase activity than with inversion rate. A highly significant linear relationship was demonstrated between these variables.