CLINICAL PHARMACOKINETICS OF IBUPROFEN - THE FIRST 30 YEARS

Ibuprofen is a chiral nonsteroidal anti-inflammatory drug (NSAID) of t he 2 arylpropionic acid (2-APA) class. A common structural feature of 2-APA NSAIDs is a sp(3)-hybridised tetrahedral chiral carbon atom with in the propionic acid side chain moiety with the S-(+)-enantiomer poss essing most of the beneficial antiinflammatory activity. Ibuprofen dem onstrates marked stereoselectivity in its pharmacokinetics. Substantia l unidirectional inversion of the R-(-) to the S-(+) enantiomer occurs and thus, data generated using nonstereospecific assays may not be ex trapolated to explain the disposition of the individual enantiomers. T he absorption of ibuprofen is rapid and complete when given orally. Th e area under the plasma concentration-time curve (AUG) of ibuprofen is dose-dependent. Ibuprofen binds extensively, in a concentration-depen dent manner, to plasma albumin. At doses greater than 600 mg there is an increase in the unbound fraction of the drug, leading to an increas ed clearance of ibuprofen and a reduced AUC of the total drug. Substan tial concentrations of ibuprofen are attained in synovial fluid, which is a proposed site of action for nonsteroidal anti-inflammatory Ibupr ofen is eliminated following biotransformation to glucuronide conjugat e metabolites that are excreted in urine, with little of the drug bein g eliminated unchanged. The excretion of conjugates may be tied to ren al function and the accumulation of conjugates occurs in end-stage ren al disease. Hepatic disease and cystic fibrosis can alter the disposit ion kinetics of ibuprofen. Ibuprofen is not excreted in substantial co ncentrations into breast milk. Significant drug interactions have been demonstrated for aspirin (acetylsalicylic acid), cholestyramine and m ethotrexate, A relationship between ibuprofen plasma concentrations an d analgesic and antipyretic effects has been elucidated.