The non-steroidal anti-inflammatory drug (NSAID) carprofen (CPF) contains a single chiral centre. It was administered orally to Beagle dogs as a racemate (rac-CPF) at a dose of 4 mg per kg body weight and as individual (-)(R) and (+)(S) enantiomers at 2 mg per kg body weight. Each of the enantiomers achieved similar plasma bioavailability following administration as the racemate as they did following their separate administration. Only the administered enantiomers were detectable when the drug was given in the (-)(R) or (+)(S) form, indicating that chiral inversion did not occur in either direction. Higher plasma concentrations of the (-)(R) (Cmax 18 micrograms/ml, AUC0-24 118 micrograms h/ml) than the (+)(S) (Cmax 14 micrograms/ml, AUC0-24 67 micrograms h/ml) enantiomer were achieved following administration of the racemate. Both enantiomers distributed into peripheral subcutaneous tissue cage fluids, but Cmax and AUC values were lower for both transudate (non-stimulated tissue cage fluid) and exudate (induced by the intracaveal administration of the irritant carrageenan) than for plasma. Drug concentrations in transudate and exudate were similar, as indicated by Cmax and AUC values, although CPF penetrated more rapidly into exudate than into transudate. Neither rac-CPF nor either enantiomer inhibited thromboxane B2 (T x B2) generation by platelets in clotting blood (serum T x B2), or prostaglandin E2 (PGE2) and 12-hydroxyeicosatetraenoic acid (12-HETE) synthesis in inflammatory exudate.(ABSTRACT TRUNCATED AT 250 WORDS)

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The chirality of drugs, with particular reference to agents used in veterinary medicine, is reviewed. Basic concepts of chirality and aspects of the methodology for the separation of enantiomers are considered. Chiral compounds are in common use in animals and their pharmacological actions and side-effects (pharmacodynamics) and absorption into and fate within the body (pharmacokinetics) are of fundamental importance; pharmacodynamic and pharmacokinetic properties of enantiomeric pairs commonly differ and this has major implications for their effective and safe therapeutic use. As examples of the particular significance of chirality in veterinary medicine, the following drug classes are reviewed; benzimidazole anthelmintics, cloprostenol, verapamil, ketamine, halogenated hydrocarbon anaesthetics and 2-arylpropionic acid anti-inflammatory drugs. The implications of chirality for drug product development and approval by registration authorities are discussed.

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1. H.p.l.c. analyses were performed to investigate the plasma kinetics of albendazole (ABZ), the sulphoxide (SO.ABZ) and sulphone (SO2ABZ) metabolites, as well as the chirality vs time of SO.ABZ, after oral administration to rats, dogs and man of prochiral sulphide antiparasitic drug ABZ. 2. In all three species the initial plasma concentration ratio of the enantiomers, as soon as SO.ABZ could be detected in plasma, was that of a racemate. 3. Subsequently, the ratio (+)/(-) increased linearly with time, reaching values of 13.1 and 9.3 in man and dogs, respectively, while it decreased to 0.6 in rats. 4. The (+) enantiomer represents 80%, 70% and 41% of the area under the curve of the total SO.ABZ in man, dogs and rats, respectively.

Two prochiral sulphide drugs, fenbendazole (FBZ) and albendazole (ABZ) were administered orally to sheep. Blood samples were analysed for parent drug and S-oxidation metabolites and the chirality of the sulphoxide metabolites was determined. The plasma concentrations of the enantiomers of the sulphoxides were never a racemate. On the contrary, the ratios were greater than 1 as soon as the sulphoxide compounds could be detected in plasma. They subsequently increased linearly throughout the time course of the kinetics, reaching the level 86:14 after FBZ and 95:5 after ABZ treatment. The major enantiomer represented 74% and 86% of the total AUC of SO.FBZ and SO.ABZ, respectively.

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This paper is available online at http://dmd.aspetjournals.org ABSTRACT:The expression of flavin-containing monooxygenases (FMOs) in dog liver microsomes was suggested by a high methimazole Soxidase activity. When the reaction was catalyzed by dog liver microsomes, apparent V max and K m values were 6.3 nmol/min/mg and 14 M, respectively. This reaction was highly inhibited (73%) in the presence of imipramine, but it was also weakly affected by trimethylamine, suggesting the involvement of different isoforms.