Clinical Pharmacokinetics of Naproxen

Abstract

Naproxen is a stereochemically pure nonsteroidal anti-inflammatory drug of the 2-arylpropionic acid class. The absorption of naproxen is rapid and complete when given orally. Naproxen binds extensively, in a concentration-dependent manner, to plasma albumin. The area under the plasma concentration-time curve (AUC) of naproxen is linearly proportional to the dose for oral doses up to a total dose of 500 mg. At doses greater than 500 mg there is an increase in the unbound fraction of drug, leading to an increased renal clearance of total naproxen while unbound renal clearance remains unchanged. Substantial concentrations of the drug are attained in synovial fluid, which is a proposed site of action for nonsteroidal anti-inflammatory drugs. Relationships between the total and unbound plasma concentration, unbound synovial fluid concentration and therapeutic effect have been established. Naproxen is eliminated following biotransformation to glucuroconjugated and sulphate metabolites which are excreted in urine, with only a small amount of the drug being eliminated unchanged. The excretion of the 6-O-desmethylnaproxen metabolite conjugate may be tied to renal function, as accumulation occurs in end-stage renal disease but does not appear to be influenced by age. Hepatic disease and rheumatoid arthritis can also significantly alter the disposition kinetics of naproxen. Although naproxen is excreted into breast milk the amount of drug transferred comprises only a small fraction of the maternal exposure. Significant drug interactions have been demonstrated for probenecid, lithium and methotrexate.

Nonsteroid drug selectivities for cyclo-oxygenase-1 rather than cyclo-oxygenase-2 are associated with human gastrointestinal toxicity: A full in vitro analysis

“…Second, NSAIDs are used therapeutically at doses that produce more than a 50% reduction in prostanoid formation. Indeed, a survey of the literature established that, for diclofenac (10), etodolac (11), indomethacin (12,13), fenoprofen (12), flurbiprofen (14), ketoprofen (12), ketorolac (13,15), meclofenamate (12), meloxicam (16), naproxen (17), nimesulide (18), piroxicam (19), sulindac (20), and tolmetin (12), the steady-state plasma concentrations of these drugs, as well as the peak concentrations of aspirin (12), would produce average inhibitions in our assay systems of 82 Ϯ 5% (COX-1), 74 Ϯ 5% (WBA-COX-2), and 89 Ϯ 2% (WHMA-COX-2) (n ϭ 15). Comparison of the potencies of the NSAIDs against COX-1 and COX-2 at the IC 80 value, therefore, appears more appropriate.…”

Inhibition of Methotrexate Uptake <i>via</i> Organic Anion Transporters OAT1 and OAT3 by Glucuronides of Nonsteroidal Anti-inflammatory Drugs

“…Although unbound plasma concentrations of NSAIDs-Glu have not been previously reported, total plasma concentrations of glucuronide conjugates of diclofenac (1.8±0.5 µM), 24) ibuprofen (3.6±2.0 µM), 23) naproxen (undetectable) 35) and flurbiprofen (undetectable) 36) have been determined after administration of clinical doses. Therefore, considering plasma concentration and inhibitory potencies, it is unlikely that NSAIDs-Glu other than diclofenac glucuronide inhibit OAT3-mediated MTX uptake at clinical doses.…”

“…21,22) Most NSAIDs-Glu molecules are excreted directly into urine. 23,24) Recently, our laboratory reported that NSAIDs-Glu, as well as parent NSAIDs, are involved in inhibition of urinary excretion of MTX via MRP2 and MRP4. 25) Since the IC 50 of NSAIDs-Glu for MTX transport via MRPs was lower than that of parent NSAIDs, our results suggested that NSAIDs-Glu likely contribute to elevating the plasma concentration of MTX.…”

Massive Naproxen Overdose with Serial Serum Levels

“…Metabolic acidosis and shock have been reported in massive ibuprofen overdose [23,24]. Naproxen is a weak acid with a pKa 4.15 [25]. The most plausible explanation for our patient's early acidosis was the large amount of ingested naproxen as well as its metabolites, considering they are also weak acids.…”

“…Lactic acidosis has been reported before in massive ibuprofen overdose including fatal cases [16,26]. Although naproxen is a weak acid, there is no evidence suggesting that urinary alkalinization can enhance elimination, possibly due to its high protein binding [25].…”