ENANTIOSELECTIVITY IN THE DISPOSITION OF KETOPROFEN AND CARPROFEN IN MAN AND ANIMALS

After the administration of racemic ketoprofen and carprofen to man, b oth enantiomers of each compound exhibit similar plasma profiles. This contrasts with the rat where the active S(+) enantiomer is predominan t. For carprofen, regardless of the route of administration, the R(-) enantiomer is predominant in the plasma of all investigated animal spe cies. The S(+)/R(-) ratio of the << areas under the curves >> during t he time course of the kinetics, is : 0.60 in dogs, 0.53 in Yucatan mic ro-pigs, 0.48 in mini-goats, 0.67 in calves and 0.19 in horses. For ke toprofen, the S(+) enantiomer is predominant in dogs, cats and horses, with ratios of 30.3, 5.3 and 1.5, respectively, while R(-) is the pre dominant enantiomer in sheep. The interpretation of these inter-specie s differences can be supported by experimental evidence, however some informations are lacking and additional investigation is required. In the case of ketoprofen where S(+) is predominant in rats, dogs and hor ses, the metabolic chiral inversion from R(-) to S(+), which has been demonstrated in rats, may also take place in the latter two species. I n addition, the well documented stereoselective clearance of the glucu ronides, possibly in favour of the enantiomer S(+), may explain the lo wer body clearance of the R(-) enantiomer in sheep. For carprofen, no metabolic chiral inversion was shown in rats and dogs after administra tion of each enantiomer individually, but for this compound, stereosel ective clearance of glucuronides has been demonstrated,which may suppo rt the idea of a plasma concentration shift of the enantiomeric propor tions vs time in favour of the R(-) enantiomer. Regardless of the poss ible biological mechanisms which are responsible for these inter-speci es differences, the existence of these differences gives rise to at le ast two important issues : The choice of animal species which can be u sed in the research of drugs destined for human therapeutics : the mos t pertinent animal species will be the one which demonstrates an enant iomeric plasma profile closest to that observed in man. The present da ta show that the ideal animal species from this respect has still to b e identified. For application in veterinary therapeutics, a careful ba lance must be established between the requirement of favourable bioava ilability of the active S(+) enantiomer and the potential of any possi ble chiral inversion of R(-) to generate hybrid molecules in meat and milk which in tum may lead to residues, the toxicity of which to the h uman consumer is still unknown.