Pharmacokinetics of naproxen in subjects with normal and impaired renal function

Abstract

The pharmacokinetics of naproxen after a single oral dose of 250 mg has been studied in 8 subjects with normal renal function and 16 patients with varying degrees of chronic renal insufficiency. Unchanged naproxen and its main unconjugated metabolite, 6-0-desmethylnaproxen, were determined fluorometrically in serum. In healthy subjects the elimination half-life of naproxen was 17.7 +/- 3.0 h (mean +/- SD) and it was not significantly prolonged in patients with renal failure (18.1 +/- 5.3) h. No accumulation of naproxen in serum occurred in uraemic patients. On the contrary, serum drug levels were slightly but significantly lower in patients with severe renal failure. The total body clearance and apparent volume of distribution of naproxen were significantly increased in this group of patients. Decreased binding of naproxen to serum proteins was observed in patients with renal failure. The apparent half-life of desmethylnaproxen was of the same order of magnitude as that of naproxen (18.6 +/- 4.4 h), and was also independent of renal function. A good correlation was found between the area under the curve (AUC), the peak concentration of the metabolite and the serum creatinine concentration. These observations suggest increased metabolism and an increased apparent volume of distribution of naproxen in severe renal failure, probably caused by decreased serum protein binding of the drug. However, it is proposed that in naproxen therapy no adjustment of the dosage regimen is necessary in patients with impaired renal function.

Stereoselective disposition of flurbiprofen in uraemic patients.

“…In such a cycle the renal excretion of the acylglucuronides, which are major metabolites of the latter compounds, is decreased leading to increased plasma concentrations of conjugated drug which is then hydrolyzed to regenerate the parent compound. The futile cycle may therefore explain the decreased clearance of benoxaprofen (Aronoff et al, 1982), ketoprofen (Stafanger et al, 1981), and naproxen (Anttila et al, 1980), in patients with renal impairment. For the latter drugs, acyl-glucuronide formation constitutes a major pathway of elimination (Aronoff et al, 1982;Delbarre et al, 1976;Upton et al, 1984).…”

“…Traditionally, elimination of such drugs was considered to be insensitive to changes in renal function (Fabre & Balant, 1976) but more recently a number of exceptions to this expectation have been documented. For example, clearance of ketoprofen (Stafanger et al, 1981), benoxaprofen (Aronoff et al, 1982), and naproxen (Anttila et al, 1980), all of which are arylpropionic acids eliminated primarily by metabolism, is reduced in patients with renal impairment.…”

Naproxen pharmacokinetics in the elderly.

“…The significant reduction in plasma albumin concentrations in the elderly (4.3 + 0.2 vs 4.8 + 0.2 g/IlO ml) appears, however, to be too slight to account alone for the two-fold difference observed in the fraction of naproxen unbound to plasma proteins at steady state. While other proteins may be partly responsible or the nature of albumin might be altered with age, diminished renal or hepatic function or both in elderly individuals probably allows accumulation of higher levels of endogenous compounds competing for or otherwise inhibiting naproxen binding (Anttila et al, 1980) which even in younger individuals shows evidence of saturation.…”

“…altered with impaired renal (Anttila et al, 1980) It is commonly used for treatment of both or hepatic function (Williams et al, 1984) and rheumatoid and osteo-arthritis and is thus fre-with changes in plasma protein (Williams et al, quently taken by the elderly. Several descrip-1984).…”

The influence of renal function on the enantioselective pharmacokinetics and pharmacodynamics of ketoprofen in patients with rheumatoid arthritis.

“…A low percentage of the dose of such drugs is cleared renally in unchanged form yet, paradoxically, a number of them have diminished clearance in patients with renal dysfunction, or in elderly patients in whom renal function is reduced [8][9][10][11][12][13][14]. Moreover, coadministration of probenecid has caused a decrease in the plasma clearance of these NSAIDs [15][16][17][18][19].…”