CLINICAL PHARMACOKINETICS OF TIAPROFENIC ACID AND ITS ENANTIOMERS

Tiaprofenic acid is a chiral nonsteroidal anti-inflammatory drug (NSAI D) of the 2-arylpropionic acid (2-APA) class. A common structural feat ure of 2-APA NSAIDs is a sp3-hybridised tetrahedral chiral carbon hete roatom within the propionic acid side chain moiety, with the S-enantio mer possessing most of the beneficial anti-inflammatory activity. Howe ver, all tiaprofenic acid preparations to date are marketed as the rac emate. Tiaprofenic acid has been suggested to exhibit limited pharmaco kinetic stereoselectivity. The synovium is the proposed site of action of NSAIDs when used for musculoskeletal disorders, and substantial co ncentrations of tiaprofenic acid are attained in synovial fluid. Recen t data suggest the possibility of stereoselective distribution of tiap rofenic acid into synovium and cartilage, Hence, data generated using non-stereospecific assays may not always be extrapolated to explain th e disposition of the individual enantiomers. Tiaprofenic acid is rapid ly and almost completely absorbed when given orally. The area under th e plasma concentration-time curve (AUG) of tiaprofenic acid is proport ional to the oral dose administered. A sustained release dosage form i s available, which may be beneficial due to the short terminal phase h alf-life of tiaprofenic acid (3 to 6 hours). The bioavailability is th e same as that with conventional rapid release preparations, although the peak plasma drug concentration is reduced and time to peak is prol onged. Tiaprofenic acid binds extensively to plasma albumin. There is negligible R to S inversion upon oral administration. Tiaprofenic acid is eliminated following extensive biotransformation to glucuronide-co njugated metabolites. Approximately 60% is eliminated as conjugates ex creted in urine. and little drug is eliminated unchanged. The rate of excretion of tiaprofenic acid and its conjugates may be related to ren al function; accumulation of conjugates occurs in end-stage renal dise ase, but not in young individuals or elderly patients. Potentially cli nically important drug interactions with tiaprofenic acid have been de monstrated for some anticoagulants and probenecid. Relationships betwe en tiaprofenic acid concentrations in biological matrices and therapeu tic or toxic effects have not yet been elucidated for this drug.