STEREOSPECIFIC PHARMACODYNAMICS AND PHARMACOKINETICS OF CARPROFEN IN THE DOG

The non-steroidal anti-inflammatory drug (NSAID) carprofen (CPF) conta ins 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 in dividual (-)(R) and (+)(S) enantiomers at 2 mg per kg body weight, Eac h of the enantiomers achieved similar plasma bioavailability following administration as the racemate as they did following their separate a dministration, Only the administered enantiomers were detectable when the drug was given in the (-)(R) or (+)(S) form, indicating that chira l inversion did not occur in either direction. Higher plasma concentra tions of the (-)(R) (C-max 18 mu g/ml, AUC(0-24) 118 mu g h/ml) than t he (+)(S) (C-max 14 mu g/ml, AUC(0-24), 67 mu g h/ml) enantiomer were achieved following administration of the racemate, Both enantiomers di stributed into peripheral subcutaneous tissue cage fluids, but C-max a nd AUC values were lower for both transudate (non-stimulated tissue ca ge fluid) and exudate (induced by the intracaveal administration of th e irritant carrageenan) than for plasma. Drug concentrations in transu date and exudate were similar, as indicated by C-max and AUC values, a lthough CPF penetrated more rapidly into exudate than into transudate, Neither rac-CPF nor either enantiomer inhibited thromboxane B-2 (T x B-2) generation by platelets in clotting blood (serum T x B-2), or pro staglandin E(2) (PGE(2)) and 12-hydroxyeicosatetraenoic acid (12-HETE) synthesis in inflammatory exudate. Since other studies have shown tha t rac-CPF at the 4 mg/kg dose rate possesses analgesic and anti-inflam matory effects in the dog, it is concluded that the principal mode of action of the drug must be by mechanisms other than cyclooxygenase or 12-lipoxygenase inhibition.