Naproxen pharmacokinetics in the elderly.

Abstract

While naproxen pharmacokinetics appear to be altered in the presence of both diminished renal and hepatic function, the degree to which naproxen disposition might be influenced in the elderly by concurrent alteration in these functions is not obvious. Total plasma clearance/bioavailability (CL/F) of naproxen after a single 375 mg oral dose was found to be less in a group of 10 healthy men between 66 and 81 years of age than in 10 healthy men between 22 and 39 years (0.318 +/‐ 0.078, 0.416 +/‐ 0.061 l/h). At steady state (375 mg, 12 hourly), however, CL/F was statistically indistinguishable between the two groups. The fraction of naproxen unbound to plasma protein was doubled in elderly subjects, both at peak and trough drug concentrations. The lowered protein binding tended to obscure a 50% decrement in the intrinsic clearance of naproxen in the elderly as estimated by unbound clearance/bioavailability (213 +/‐ 64, 396 +/‐ 155 l/h). As a result, mean steady‐state plasma concentrations of naproxen were indistinguishable between the elderly and young (64.2 +/‐ 8.5, 58.2 +/‐ 8.1 mg/l) but the elderly generated twice the mean steady‐state unbound plasma drug concentration (0.157 +/‐ 0.039, 0.0859 +/‐ 0.0212 mg/l). Since it is the unbound drug concentration which appears in general to relate more closely to pharmacological and toxic effect, it may be advisable to reduce naproxen doses by half in the elderly, pending plasma drug concentration‐response studies in this age group. If a similar perturbation with age occurs in benoxaprofen protein binding as was observed with naproxen, benoxaprofen intrinsic clearance in the elderly might be only one quarter of that in younger individuals; a factor which may contribute to the toxicity of this drug in the elderly.

Stereoselective disposition of flurbiprofen in uraemic patients.

“…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). In this study the clearance of R-and S-flurbiprofen following a single oral dose increased rather than decreased relative to normal subjects (vide infra) and therefore the futile cycle does not appear to be of significance.…”

“…This so-called 'futile cycle' results in a lowered plasma clearance of parent drug and may explain the changes noted above for ketoprofen, benoxaprofen, and naproxen, for which acylglucuronide formation is a major route of elimination. Although not specifically tested, this phenomenon may be accentuated during chronic drug administration (Upton et al, 1984).…”

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

“…The method for deriving the corresponding unbound concentration of (S)-ketoprofen in serum after spiking blood with racemic drug was based on preliminary studies which confirmed that the unbound fraction of (S)-ketoprofen in plasma (fu(S)) in vitro was equivalent to the unbound fraction in serum. This has also been demonstrated for the protein binding of naproxen [11].…”

“…Few studies have examined the influence of renal function on the disposition of 2-arylpropanoic acid NSAIDs, and still fewer have addressed this issue with regard to unbound drug concentrations [11,23,24]. No studies have described the disposition of ketoprofen enantiomers in terms of unbound drug.…”

“…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].…”