PHARMACOKINETICS AND PHARMACODYNAMICS OF KETOPROFEN ENANTIOMERS IN THE HORSE

Pharmacokinetic and pharmacodynamic parameters were established for en antiomers of the non-steroidal anti-inflammatory drug (NSAID) ketoprof en (KTP), each administered separately at a dose level of 1.1 mg/kg to a group of six New Forest geldings, in a three-period cross-over stud y using a tissue cage model of inflammation. For both S(+)- and R(-)-K TP, penetration into tissue cage fluid (transudate) and inflamed tissu e cage fluid (exudate) was rapid, and clearances from exudate and tran sudate were much slower that from plasma. AUC values were, therefore, higher for exudate and, to a lesser degree, transudate than for plasma . Unidirectional chiral inversion of R(-)- and to S(+)-KTP was demonst rated. Administration of both enantiomers produced marked, time-depend ent inhibition of synthesis of serum thromboxane B-2 and exudate prost aglandin E(2), indicating non-selective inhibition of cyclo-oxygenase (COX) isoenzymes COX-1 and COX-2 respectively. Administration of both enantiomers also produced partial inhibition of beta-glucuronidase rel ease into inflammatory exudate and of bradykinin-induced skin oedema. It is suggested that, although S(+)-KTP is generally regarded as the e utomer. R(-)-KTP was probably at least as active in inhibiting bradyki nin swelling. Pharmacokinetic/pharmacodynamic (PK/PD) modeling of the data could not be undertaken following R(-)-KTP administration because of chiral inversion to S(+)-KTP, but pharmacodynamic parameters, E(ma x), EC(50), N, k(e0) and t(Ve(ke0)), were determined for S(+)-KTP usin g the sigmoidal E(max) equation. PK/DP modelling provided a novel mean s of comparing and quantifying several biological effects of KTP and o f investigating its mechanisms of action.