Enantiospecific pharmacokinetics and pharmacodynamics of ketoprofen in sheep.
Pharmacokinetic and pharmacodynamic parameters were established for the enantiomers of the 2-arylpropionic acid (APA) nonsteroidal anti-inflammatory drug (NSAID), ketoprofen (KTP). Each enantiomer was administered separately (1.5 mg/kg) and in a racemic mixture (3 mg/kg) intravenously (i.v.) to a group of eight sheep in a four-way, four-period cross-over study using a tissue cage model of inflammation. Plasma disposition of each KTP enantiomer was similar following separate administration of the pure compounds compared to administration of the racemic mixture. S(+)KTP volume of distribution (Vd(area)) was higher and clearance (ClB) faster than those of R(-)KTP. S(+) and R(-)KTP achieved relatively low concentrations in exudate and transudate. Unidirectional limited chiral inversion of R(-) to S(+)KTP was demonstrated. After R(-)KTP administration S(+)KTP was detected in plasma, but not in either exudate or transudate. Pharmacokinetic/pharmacodynamic (PK/PD) modelling of the data could not be undertaken following R(-)KTP administration because of chiral inversion to S(+)KTP, but the pharmacodynamic parameters, calculated maximum effect (Emax), concentration producing 50% effect (EC50), Hill's coefficient (N), rate constant of elimination of drug effect from the compartment (KeO) and mean equilibration half-life (t1/2KeO) were determined for S(+)KTP after administration of the racemic mixture as well as the pure compound.
Landoni
M F
MF
Cátedra de Farmacologia, Facultad de Ciencias Veterinarias, Universidad Nacional de La Plata, Argentina.
Comas
W
W
Mucci
N
N
Anglarilli
G
G
Bidal
D
D
Lees
P
P
D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics* / Q000494:pharmacology*; D019540:Area Under Curve; D002626:Chemistry, Pharmaceutical; D018592:Cross-Over Studies; D015232:Dinoprostone / Q000032:analysis; D005122:Exudates and Transudates / Q000378:metabolism; D007249:Inflammation / Q000188:drug therapy / Q000378:metabolism / Q000662:veterinary*; D007275:Injections, Intravenous / Q000662:veterinary; D007660:Ketoprofen / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics* / Q000494:pharmacology*; D008297:Male; D012756:Sheep / Q000378:metabolism*; D013929:Thromboxane B2 / Q000097:blood
D000894:Anti-Inflammatory Agents, Non-Steroidal; D013929:Thromboxane B2; D007660:Ketoprofen; D015232:Dinoprostone