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

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 and R(-) 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 of R(-) 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, whereas MRT was much longer. The S(+) enantiomer of KTP penetrated less readily into exudate and transudate. Unidirectional inversion of R(-) to S(+) 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 for S(+) KTP were Emax (%) = 94 and 100; IC50 (microg/mL) = 0.0033 and 0.0030; N = 0.45 and 0.58, respectively, where Emax is the maximal effect, IC50 the plasma drug concentration producing 50% of Emax and N the slope of log concentration/effect relationship. The IC50 ratio, serum TxB2:exudate PGE2 was 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.

Modeling and allometric scaling of s(+)‐ketoprofen pharmacokinetics and pharmacodynamics: a retrospective analysis

“…The bi‐exponential decline in the kinetics of sKTP upon intravenous administration was well characterized by a two‐compartment model, with parameter estimates similar to those reported in the original papers for calf (Landoni & Lees, 1995), horse (Landoni & Lees, 1996), sheep (Landoni et al. , 1999), goat (Arifah et al. , 2003), cat (Lees et al.…”

“…A series of articles addressing the pharmacokinetics and pharmacodynamics (PK/PD) of ketoprofen (KTP) enantiomers in farm animals (calves, horses, sheep, and goats) have been published during the last decade, most of which are available in this journal (Landoni & Lees, 1995, 1996; Landoni et al. , 1999; Arifah et al. , 2003).…”

Enantiospecific ketoprofen concentrations in plasma after oral and intramuscular administration in growing pigs

“…In most species, including horses [12] and pigs [13,14], S-ketoprofen is the predominant enantiomer in the plasma after administration of the racemic drug, whilst R-ketoprofen is predominant in sheep [15]. The plasma concentrations of both enantiomers are similar in goats [16] and calves [17]. …”

The effect of intravenous insulin infusion on renal blood flow in conscious sheep is partially mediated by nitric oxide but not by prostaglandins1

“…The dose of ketoprofen infused [0.2 mg/(kg-min) primed with 6 mg/kg] was greater than the 3 mg/kg used as a single dose in goats by Arifah et al (2003) and in sheep by Junot (2008). In both cases, the authors obtained significant reductions in PG concentrations.…”