CLINICAL PHARMACOKINETICS OF NABUMETONE - THE DAWN OF SELECTIVE CYCLO-OXYGENASE-2 INHIBITION

Nabumetone is a nonsteroidal anti-inflammatory drug (NSAID) of the 2,6 -disubstituted naphthyl-alkanone class. Nabumetone is metabolised to a n active metabolite 6-methoxy-2-napthylacetic acid (6-MNA) which is a relatively selective cyclo-oxygenase-2 inhibitor that has anti-inflamm atory and analgesic properties. Nabumetone and its metabolites bind ex tensively to plasma albumin. Nabumetone is eliminated following biotra nsformation to 6-MNA, which does not undergo enterohepatic circulation and the respective glucoroconjugated metabolites are excreted in urin e. Substantial concentrations of 6-MNA are attained in synovial fluid, which is the proposed site of action in chronic inflammatory arthropa thies. A smaller area under the plasma concentration-time curve (AUC) is evident at steady state as compared with a single dose; this is pos sibly due to an increase in the volume of distribution and saturation of protein binding. Relationships between 6-MNA concentrations and the therapeutic and toxicological effects have yet to be elucidated for t his NSAID. Renal failure significantly reduces 6-MNA elimination but s teady-state concentrations of 6-MNA are not increased, possibly becaus e of nonlinear protein binding. Elderly patients with osteoarthritis d emonstrate decreased elimination and increased plasma concentrations o f nabumetone as compared with young healthy volunteers. Rheumatic dise ase activity also influences 6-MNA plasma concentrations, as patients with more active disease and lower serum albumin concentrations demons trate a lower area under the plasma concentration versus time curve. A reduced bioavailability of 6-MNA in patients with severe hepatic impa irment is also evident. Dosage adjustment may be required in the elder ly, patients with active rheumatic disease and those with hepatic impa irment, but not in patients with mild-to-moderate renal failure.