Pharmacodynamics and pharmacokinetics of ketoprofen enantiomers in sheep

Objective-To establish pharmacokinetic and pharmacodynamic properties of a racemic mixture and individual R(-) and S(+) enantiomeric forms of ketoprofen (KTP) in sheep and determine pharmacodynamic variables of KTP by pharmacokinetic-pharmacodynamic modeling. Animals-8 female Dorset crossbred sheep. Procedure-A tissue cage model of inflammation was used. Carrageenan was administered into tissue cages. Time course of cyclooxygenase (COX)-2 inhibition was determined in vivo by measurement of exudate prostaglandin E-2 (PGE(2)) concentrations. Time course of COX-1 inhibition was determined ex vivo by measurement of serum thromboxane B-2 (TXB2) concentrations. In addition, plasma concentration-time course and penetration of KTP enantiomers into inflammatory exudate and transudate (noninflamed tissue cage fluid) were investigated. Four treatments were compared: placebo, racemic mixture (rac-KTP (3 mg/kg of body weight, [V]), S(+) KTP (1.5 mg/kg, IV), and R(-) KTP (1.5 mg/kg, IV). Results-Both KTP enantiomers had elimination half-life and mean residence time measurements that were short and volume of the central compartment and steady state volume of distribution that were low. Clearance was rapid, particularly for R(-) KTP Elimination of both enantiomers from exudate was > 10 times slower than from plasma. Both rac-KTP and the individual enantiomers significantly inhibited serum TXB2 concentrations for 12 hours. Rac-KTP and S(+) KTP: but not R(-) KTP: also significantly inhibited PGE(2) synthesis in exudate for 12 hours. Conclusions and Clinical Relevance-Inhibition of serum TXB2 concentration and exudate PGE(2) synthesis for similar time courses after S(+) KTP administration indicates that it is a nonselective inhibitor of COX in sheep.