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[Comparative enantioselectivity of the disposition of two non-steroidal anti-inflammatory agents, ketoprofen and carprofen, in man and animals].
Abstract: After the administration of racemic ketoprofen and carprofen to man, both enantiomers of each compound exhibit similar plasma profiles. This contrasts with the rat where the active S(+) enantiomer is predominant. For carprofen, regardless of the route of administration, the R(-) enantiomer is predominant in the plasma of all investigated animal species. The S(+)/R(-) ratio of the "areas under the curves" during the time course of the kinetics, is: 0.60 in dogs, 0.53 in Yucatan micro-pigs, 0.48 in mini-goats, 0.67 in calves and 0.19 in horses. For ketoprofen, 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 predominant enantiomer in sheep. The interpretation of these inter-species 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 horses, the metabolic chiral inversion from R(-) to S(+), which has been demonstrated in rats, may also take place in the latter two species. In addition, the well documented stereoselective clearance of the glucuronides, possibly in favour of the enantiomer S(+), may explain the lower body clearance of the R(-) enantiomer in sheep. For carprofen, no metabolic chiral inversion was shown in rats and dogs after administration of each enantiomer individually, but for this compound, stereoselective clearance of glucuronides has been demonstrated which may support the idea of a plasma concentration shift of the enantiomeric proportions vs time in favour of the R(-) enantiomer. Regardless of the possible biological mechanisms which are responsible for these inter-species differences, the existence of these differences gives rise to at least two important issues: The choice of animal species which can be used in the research of drugs destined for human therapeutics: the most pertinent animal species will be the one which demonstrates an enantiomeric plasma profile closest to that observed in man. The present data show that the ideal animal species from this respect has still to be identified. For application in veterinary therapeutics, a careful balance must be established between the requirement of favourable bioavailability of the active S(+) enantiomer and the potential of any possible chiral inversion of R(-) to generate hybrid molecules in meat and milk which in turn may lead to residues, the toxicity of which to the human consumer is still unknown.
Publication Date: 1993-03-01 PubMed ID: 8364755 The Equine Research Bank provides access to a large database of publicly available scientific literature. Inclusion in the Research Bank does not imply endorsement of study methods or findings by Mad Barn.
- Comparative Study
- English Abstract
- Journal Article
Summary
This research summary has been generated with artificial intelligence and may contain errors and omissions. Refer to the original study to confirm details provided. Submit correction.
The research article investigates how two non-steroidal anti-inflammatory drugs, Ketoprofen and Carprofen, behave differently in humans and various animal species. The study found differences in how each compound’s enantiomers – mirror-image versions of the molecule, known as S(+) and R(-) – are distributed in the bloodstream.
Study Method and Comparisons Between Species
- The research involved administering racemic (equally mixed) versions of Ketoprofen and Carprofen to humans and various animal species, then monitoring the presence of each drug’s two enantiomers over time.
- For humans, both enantiomers of each drug were found to have similar plasma profiles.
- In stark contrast, in rats, the active S(+) enantiomer was found to be predominant.
- For Carprofen, regardless of how it was administered, the R(-) enantiomer was predominantly found in the blood plasma of all animals investigated.
- Species-specific distinctions were observed, such as the S(+)/R(-) ratio during the activity of the drugs: 0.60 in dogs, 0.53 in Yucatan micro-pigs, 0.48 in mini-goats, 0.67 in calves and 0.19 in horses for carprofen.
- The S(+) version of Ketoprofen was found to be more prevalent in dogs, cats, and horses, while the R(-) form was more common in sheep.
Possible Explanations and Further Study
- The observed differences in drug behavior across species necessitate further investigation. Some of the disparities may be due to metabolic chiral inversion – a process that transforms one enantiomer into the other.
- For Ketoprofen, where S(+) is prevalent in rats, dogs, and horses, it is suggested that this inversion, which has been demonstrated in rats, might also occur in dogs and horses.
- In sheep, the R(-) version of Ketoprofen showed a slower rate of clearance from the body, possibly due to the selective clearance of the glucuronides (part of the metabolic process) favoring the S(+) enantiomer.
- For Carprofen, although no chiral inversion was found in rats and dogs, there was evidence of selective clearance of glucuronides, potentially favoring an accumulation of the R(-) variant over time.
Implications for Human and Veterinary Therapeutics
- The variable behavior of these drugs across species creates two important challenges: first, selecting the most suitable animal species for drug research intended for human therapeutics.
- The ideal animal species would have an enantiomeric plasma profile that closely mimics that in humans, but the study did not definitively identify such a species.
- Second, these findings complicate veterinary therapeutic applications because of the need to balance the requirement for good bioavailability of the active S(+) enantiomer and the potential for the R(-) to chiral invert, leading to hybrid molecules which could leave residues in meat and milk. The toxicity of these residues to humans is still unknown.
Cite This Article
APA
Delatour P, Benoit E, Bourdin M, Gobron M, Moysan F.
(1993).
[Comparative enantioselectivity of the disposition of two non-steroidal anti-inflammatory agents, ketoprofen and carprofen, in man and animals].
Bull Acad Natl Med, 177(3), 515-527.
Publication
Researcher Affiliations
- Département de Toxicologie Métabolique, Ecole Nationale Vétérinaire de Lyon.
MeSH Terms
- Animals
- Anti-Inflammatory Agents, Non-Steroidal / pharmacokinetics
- Carbazoles / pharmacokinetics
- Humans
- Ketoprofen / pharmacokinetics
- Stereoisomerism
Citations
This article has been cited 4 times.- Sidler M, Fouché N, Meth I, von Hahn F, von Rechenberg B, Kronen PW. Preliminary study on carprofen concentration measurements after transcutaneous treatment with Vetdrop® in a microfracture joint defect model in sheep. BMC Vet Res 2014 Dec 9;10:268.
- Montoya L, Ambros L, Kreil V, Bonafine R, Albarellos G, Hallu R, Soraci A. A pharmacokinetic comparison of meloxicam and ketoprofen following oral administration to healthy dogs. Vet Res Commun 2004 Jul;28(5):415-28.
- Igarza L, Soraci A, Auza N, Zeballos H. Some pharmacokinetic parameters of R-(-)- and S-(+)-ketoprofen: the influence of age and differing physiological status in dairy cattle. Vet Res Commun 2004 Jan;28(1):81-7.
- Sabnis S. Factors influencing the bioavailability of peroral formulations of drugs for dogs. Vet Res Commun 1999 Nov;23(7):425-47.
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