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.


METHODS
8 female Dorset crossbred sheep.


METHODS
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 E2 (PGE2) concentrations. Time course of COX-1 inhibition was determined ex vivo by measurement of serum thromboxane B2 (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, IV]), 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 PGE2 synthesis in exudate for 12 hours.


CONCLUSIONS
Inhibition of serum TXB2 concentration and exudate PGE2 synthesis for similar time courses after S(+) KTP administration indicates that it is a nonselective inhibitor of COX in sheep.
Arifah
A K
AK
Department of Veterinary Basic Sciences, Royal Veterinary College, Hatfield, Hertfordshire, United Kingdom.
Landoni
M F
MF
Frean
S P
SP
Lees
P
P
D000818:Animals; D018592:Cross-Over Studies; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; D015232:Dinoprostone / Q000097:blood; D005260:Female; D006207:Half-Life; D007527:Isoenzymes / Q000378:metabolism*; D007660:Ketoprofen / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000494:pharmacology*; D008657:Metabolic Clearance Rate; D011451:Prostaglandin-Endoperoxide Synthases / Q000378:metabolism*; D012756:Sheep / Q000097:blood*; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D013929:Thromboxane B2 / Q000097:blood
D007527:Isoenzymes; D013929:Thromboxane B2; D007660:Ketoprofen; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; D011451:Prostaglandin-Endoperoxide Synthases; D015232:Dinoprostone