CLINICAL PHARMACOKINETICS OF NAPROXEN

Naproxen is a stereochemically pure nonsteroidal anti-inflammatory dru g of the 2-arylpropionic acid class. The absorption of naproxen is rap id and complete when given orally. Naproxen binds extensively, in a co ncentration-dependent manner, to plasma albumin. The area under the pl asma concentration-time curve (AUG) of naproxen is linearly proportion al to the dose for oral doses up to a total dose of 500mg. At doses gr eater than 500mg there is an increase in the unbound fraction of drug, leading to an increased renal clearance of total naproxen while unbou nd renal clearance remains unchanged. Substantial concentrations of th e drug are attained in synovial fluid, which is a proposed site of act ion for nonsteroidal anti-inflammatory drugs. Relationships between th e total and unbound plasma concentration, unbound synovial fluid conce ntration and therapeutic effect have been established. Naproxen is eli minated following biotransformation to glucuroconjugated and sulphate metabolites which are excreted in urine, with only a small amount of t he drug being eliminated unchanged. The excretion of the 6-O-desmethyl naproxen metabolite conjugate may be tied to renal function, as accumu lation occurs in end-stage renal disease but does not appear to be inf luenced by age. Hepatic disease and rheumatoid arthritis can also sign ificantly alter the disposition kinetics of naproxen. Although naproxe n is excreted into breast milk, the amount of drug transferred compris es only a small fraction of the maternal exposure. Significant drug in teractions. have been demonstrated for probenecid, lithium and methotr exate.