Pharmacodynamics, chiral pharmacokinetics and PK–PD modelling of ketoprofen in the goat

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Abstract
There have been few studies of the pharmacodynamics of nonsteroidal antiinflammatory drugs (NSAIDs) using PK–PD modelling, yet this approach offers the advantage of defining the whole concentration–effect relationship, as well as its time course and sensitivity. In this study, ketoprofen (KTP) was administered intravenously to goats as the racemate (3.0 mg/kg total dose) and as the single enantiomers,S(+) KTP andR(−) KTP (1.5 mg/kg of each). The pharmacokinetics and pharmacodynamics of KTP were investigated using a tissue cage model of acute inflammation. The pharmacokinetics of both KTP enantiomers was characterized by rapid clearance, short mean residence time (MRT) and low volume of distribution. The penetration ofR(−) KTP into inflamed (exudate) and noninflamed (transudate) tissue cage fluids was delayed but area under the curve values were only slightly less than those in plasma, whereasMRTwas much longer. TheS(+) enantiomer of KTP penetrated less readily into exudate and transudate. Unidirectional inversion ofR(−) toS(+) KTP occurred. Both rac‐KTP and the separate enantiomers produced marked inhibition of serum thromboxane B2(TxB2) synthesis (ex vivo) and moderate inhibition of exudate prostaglandin E2(PGE2) synthesis (in vivo); pharmacodynamic variables forS(+) KTP wereEmax(%) = 94 and 100; IC50(μg/mL) = 0.0033 and 0.0030;N = 0.45 and 0.58, respectively, whereEmaxis the maximal effect, IC50the plasma drug concentration producing 50% ofEmaxandNthe slope of log concentration/effect relationship. The IC50ratio, serum TxB2:exudate PGE2was 1.10. Neither rac‐KTP nor the individual enantiomers suppressed skin temperature rise at, or leucocyte infiltration into, the site of acute inflammation. These data illustrate for KTP shallow concentration–response relationships, probable nonselectivity of KTP for cyclooxygenase (COX)‐1 and COX‐2 inhibition and lack of measurable effect on components of inflammation.