STEREOSPECIFIC PHARMACODYNAMICS AND PHARMACOKINETICS OF CARPROFEN IN THE DOG

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) (C-max 18 mu g/ml, AUC(0-24) 118 mu g h/ml) than the (+)(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 distributed into peripheral subcutaneous tissue cage fluids, but C-max 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 C-max and AUC values, although 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 prostaglandin E(2) (PGE(2)) and 12-hydroxyeicosatetraenoic acid (12-HETE) synthesis in inflammatory exudate. Since other studies have shown that rac-CPF at the 4 mg/kg dose rate possesses analgesic and anti-inflammatory 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.